Review

Cite This: Chem. Rev. XXXX, XXX, XXX−XXX pubs.acs.org/CR

Structural Simplification of Natural Products

Shengzheng Wang,†,‡,# Guoqiang Dong,†,# and Chunquan Sheng*,†
†
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai,
200433, P.R. China
‡
Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi’an,
710032, P.R. China

ABSTRACT: Natural products (NPs) are important sources of clinical drugs due to
their structural diversity and biological prevalidation. However, the structural
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complexity of NPs leads to synthetic difficulties, unfavorable pharmacokinetic profiles,

and poor drug-likeness. Structural simplification by truncating unnecessary
substructures is a powerful strategy for overcoming these limitations and improving
the efficiency and success rate of NP-based drug development. Herein, we will provide
a comprehensive review of the structural simplification of NPs with a focus on design
strategies, case studies, and new technologies. In particular, a number of successful
examples leading to marketed drugs or drug candidates will be discussed in detail to illustrate how structural simplification is
applied in lead optimization of NPs.

CONTENTS 3.3.1.5. Structural Simplification of Sanguinar-

1. Introduction
2. Strategies for the Structural Simplification of NPs
3. Structural Simplification of NPs: Case Studies
3.1. Structural Simplification Leading to Clinical
Drugs
3.1.1. Structural Simplification of Morphine: A
Classic Story in Medicinal Chemistry
3.1.2. Structural Simplification of Schisandrin
C: Discovery of Bicyclol
3.1.3. Structural Simplification of Myriocin:
Discovery of Fingolimod
3.1.4. Structural Simplification of Trichostatin
A: Discovery of Vorinostat
3.1.5. Structural Simplification of Halichon-
drin B: Discovery of Eribulin
3.2. Structural Simplification Leading to Clinical
Candidates
3.2.1. Structural Simplification of Staurospor-
ine: Discovery of Ruboxistaurin and
Enzastaurin
3.2.2. Structural Simplification of Asperlicin:
Discovery of Devazepide
3.3. Structural Simplification Leading to Preclin-
ical Candidates or Lead Compounds
3.3.1. Structural Simplification by Reducing
the Ring Number
3.3.1.1. Structural Simplification of Trabecte-
din
3.3.1.2. Structural Simplification of Erythri-
nane
3.3.1.3. Structural Simplification of Sampan-
gine
3.3.1.4. Structural Simplification of Gambogic
Acid
ine S
B 3.3.1.6. Structural Simplification of Dynemicin S
D 3.3.1.7. Structural Simplification of Merrilac-
E tone A T
3.3.1.8. Structural Simplification of Pyripyro-
E pene A T
3.3.1.9. Structural Simplification of Pladieno-
G lide B U
3.3.1.10. Structural Simplification of Melico-
I bisquinolinone B U
3.3.1.11. Structural Simplification of Campo-
I tothecin V
3.3.1.12. Structural Simplification of Yohim-
J bine V
3.3.1.13. Structural Simplification of Withano-
J lide A W
3.3.2. Structural Simplification by Removing
K Chiral Centers W
3.3.2.1. Structural Simplification of Podophyl-
lotoxin W
K 3.3.2.2. Structural Simplification of Taxuspine
X AA
L 3.3.2.3. Structural Simplification of Cortistatin
A AA
M 3.3.2.4. Structural Simplification of Bryostatin
1 AA
N 3.3.2.5. Structural Simplification of Cyclop-
amine 1 AA
N 3.3.2.6. Structural Simplification of Carolacton AA
3.3.2.7. Structural Simplification of Promysalin AB
P
P
Received: August 9, 2018
Q

© XXXX American Chemical Society A DOI: 10.1021/acs.chemrev.8b00504

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3.3.3. Structural Simplification by Truncating
Unnecessary Substructures AB
3.3.3.1. Structural Simplification of Chaetocin AB
3.3.3.2. Structural Simplification of Largazole AB
3.3.3.3. Structural Simplification of Lobata-
mide C AB
3.3.3.4. Structural Simplification of Sanglifeh-
rin A AB
3.3.3.5. Structural Simplification of Anguino-
mycin AC
3.3.3.6. Structural Simplification of Capraza-
mycin B AC
3.3.3.7. Structural Simplification of Militari-
none D AC
3.3.3.8. Structural Simplification of Bistramide
A AD
3.3.3.9. Structural Simplification of Withaferin
A AD
3.3.3.10. Structural Simplification of Rakicidin
A AD
3.3.3.11. Structural Simplification of Spongis-
tatins AD
3.3.3.12. Structural Simplification of Migrasta-
tin AE
3.3.4. Recent Examples of Structural Simplifi-
cation AE
4. Conclusions and Perspectives AE
Author Information AE
Corresponding Author AE
ORCID AE
Author Contributions AE
Notes AE
Biographies AE
Acknowledgments AF
Abbreviations AF
References AF
1. INTRODUCTION
Natural products (NPs) have historically been the primary
source of medicines for the treatment of a wide range of
human disease.1,2 In modern drug discovery and development,
NPs continue to play a vital role and inspire innovative
research in chemistry, biology, and medicine.3−6 Detailed
analysis of the new drugs approved by the U.S. Food and Drug
Administration (FDA) between 1981 and 2014 revealed that
more than half of the clinical drugs were derived from NPs or
their synthetic derivatives.7 Moreover, NPs are also rich
sources of chemical probes for chemical biology studies
investigating biological mechanisms.8−11
NPs are biologically prevalidated because they are produced
by evolutionary selection.12 During their biosynthesis, NPs
have already interacted with various enzymes and proteins,
which are similar to the environment of the drug targets.13
Thus, NPs inherently fall into biologically relevant chemical
space as their molecular scaffolds (or pharmacophores) have
evolved as preferred ligand-target binding motifs, which are
often considered privileged structures in drug discovery.14
Structurally, NPs possess unique features in terms of diversity
and complexity.15 Compared with synthetic compounds, NPs
generally have more stereogenic centers, fewer rotatable bonds,
more oxygen atoms, fewer nitrogen, sulfur, and halogen atoms,
more fused, bridged, or spiro rings, and so on.16−18 This
B DOI: 10.1021/acs.chemrev.8b00504
biological prevalidation and structural diversity have made NPs
valuable lead compounds for drug discovery, particularly in the
field of cancerous and infectious diseases.19
Currently, three strategies have been widely used for NP-
based drug discovery and development (Figure 1). The first
strategy is the developing and marketing the NP itself.20 On
the basis of the small-molecule drugs approved by the FDA
from 1981 to 2014, the percentage of unaltered NPs is 6% of
the drugs.7 However, most NP-derived drugs are NP
derivatives, which account for 26% of FDA approved small-
molecule drugs.7 The shortcomings of unmodified NPs mainly
include limited compound availability, poor solubility, and
metabolic instability.21 More importantly, the structural
complexity of NPs results in synthetic difficulties and
unfavorable absorption, distribution, metabolism, excretion,
and toxicity (ADMET) properties.18 Due to their complex
chemical structures, NPs rarely meet the demands for drug-
likeness (e.g., Lipinski’s rule-of-five, RO5), and thus their drug
development is always hampered by low absorption from the
gut into the blood and poor oral bioavailability.22 In addition,
clarifying the mode of action and molecular target of NPs also
remains a major bottleneck.
Therefore, structural modification of NPs is generally
required before they can be developed into clinical drugs
(the second strategy in Figure 1).21−23 For structural
optimization of NPs, a general procedure includes the design,
synthesis, and evaluation of analogues of NPs, and clarifying
the structure−activity relationship (SAR).21 Selective mod-
ifications can be designed to improve the pharmacokinetic
(PK)/pharmacodynamic (PD) properties, such as potency,
selectivity, water solubility, metabolic stability, and oral
bioavailability. Moreover, reducing side effects is also an
important goal in structural optimization. This strategy has
been successfully applied in the development of a number of
clinical therapeutics to treat various human diseases.
NPs generally have a structurally complex framework and a
high molecular weight (MW), leading to synthetic difficulty
and an unfavorable ADMET profile. In some cases, standard
structural modification and SAR approaches fail to generate
drug-like NP derivatives because the PK limitations are always
caused by the “heavy” or “fat” structures of NPs. Moreover, a
number of bioactive NPs (e.g., marine NPs) are still
synthetically intractable due to the highly complex structures.
In these circumstances, simplifying the complex structures of
NPs without interfering with the desired biological activity
provides an alternative approach for both NP lead optimization
and the development of new generation of NP-based drugs
(the third strategy in Figure 1). Different from standard NP
SAR, structural simplification could lead to new, simpler, and
synthetically more accessible compounds that show improved
drug-likeness. However, the structural simplification of NPs is
a highly challenging task because maintaining potency and
selectivity may be daunting and the molecular targets (or
binding modes) of the NPs are typically unknown at the early
stage of lead optimization. Different from standard NP
modifications focusing on derivatization, simplification design
is generally based on the SAR obtained from step-by-step
truncation of NP structures.4,24 After the pharmacophores
essential to the desired activity are identified, substructures
that are unnecessary for the biological activity can be removed
or modified. This strategy has been successfully used in the
lead optimization of NPs and yielded a number of marketed
drugs and drug candidates.
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Figure 1. Strategies for NP-based drug discovery and development.

Figure 2. General process for structural simplification of NPs.

Due to its importance in NP-based drug discovery, we simplification of NPs. The focus will be on design strategies,
herein present a comprehensive review of the structural representative examples, and new technologies. A number of
C DOI: 10.1021/acs.chemrev.8b00504
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Figure 3. Process of the structural simplification of morphine.
case studies of particularly successful examples leading to
marketed drugs or drug candidates will be discussed in detail to
illustrate how structural simplification is applied in lead
optimization of NPs.
2. STRATEGIES FOR THE STRUCTURAL
SIMPLIFICATION OF NPS
“Molecular obesity” is considered an important factor in the
high attrition rates of drug candidates in pharmaceutical
industries.25−27 According to Polanski’s analysis, less complex
drugs were more likely to achieve better market success.28 To
reduce molecular obesity, structural simplification by the
appropriate removal of nonessential groups represents a
practical and powerful strategy in the process of lead
optimization.25−27 Structural simplification is defined as the
reduction of molecular complexity of a target compound.
Thus, the first step of structural simplification design is to
analyze the molecular complexity of NPs (Figure 2). Although
there is not a global definition for molecular complexity, it is
generally associated with MW, the number and connectivity
(linked, fused or bridged) of rings, the number and
configuration of chiral centers, and so on.29 Molecular
complexity is a crucial concept in drug discovery because it
is associated with target selectivity, ADMET, and safety
profiles.30,31 Recently, progress has been made in the
quantification of the molecular complexity and complexity−
property relationships.31
The strategy for designing simplified analogues of NPs
depends on whether the binding targets are known. In most
cases, the molecular target or binding mode of the NP is
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unknown during the early stage of structural simplification.
The simplification strategies mainly include step by step
dissection of the complex structure, the elimination of
redundant chiral centers, the reduction of the number of
rings, and scaffold hopping.32−34 During the simplification
process, structural units should be systematically removed to
determine the relative importance of the different components.
On the basis of the SAR and pharmacophores, the essential
substructures are retained in the simplified analogues.
Recently, important progress has been made in identifying
the targets of NPs.35,36 If the target of the NP is known, the
binding mode should be clarified by structural biology,
chemical biology, or molecular modeling studies. Then, the
key structural motifs responsible for the ligand−target
interactions can be obtained, which will guide the rational
design of simplified derivatives via the removal of unnecessary
fragments.
Several issues should be considered during the structural
simplification process. First, the biological activity is not the
only criteria in simplification. The main purpose of structural
simplification is to overcome the drawbacks of the lead
compound and improve the drug-likeness. In some cases, the
activity of the simplified compounds may be lower than that of
the lead, but it is more important to achieve a balance between
the pharmacological potency and the ADMET properties. In
addition to the activity, drug-likeness filters, such as RO5 and
ligand efficiency (LE), should be considered. However, it is
also should be noted that several classes of drugs, such as
antibiotics and antitumor agents, tend to violate RO5
guidelines.37−40 Second, as the size of a molecule decreases,
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Figure 4. Structural simplification of schisandrin C.

Figure 5. Structural simplification of ISP-1.

Figure 6. Structural simplification of trichostatin A (A) and the binding modes of trichostatin A (B, PDB code: 1C3R) and vorinostat (C, PDB
code: 1C3S) with HDAC.

the simplified derivatives may act by a new mode of action.41
NPs gain some of their high binding affinity and exquisite
selectivity from their structural complexity and overly simple
analogues may bind well to other targets. Therefore, the
structural simplification must be moderate. Overly simplified
molecules tend to show reduced biological activity and target
selectivity. Third, notably, not all lead compounds can be
simplified (e.g., digitalis).42 NPs are often metabolites that
evolved for their unique structural features, and form specific
interactions with the targets. As a result, structural
simplification of NPs does not always work.
E DOI: 10.1021/acs.chemrev.8b00504
3. STRUCTURAL SIMPLIFICATION OF NPs: CASE
STUDIES
3.1. Structural Simplification Leading to Clinical Drugs
The effectiveness of structural simplification in NP-based drug
development has been validated by several clinical drugs.
Structural simplification of morphine has successfully gen-
erated a series of semisynthetic and synthetic analgesics that
are widely used in the clinic. Bicyclol, fingolimod, vorinostat,
and eribulin also represent successful examples of structural
simplification of NPs. From the five case studies discussed in
the following sections, the initial impetus for structural
simplification is to reduce the synthetic difficulty. The most
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Figure 7. Structural simplification of complex NP halichondrin B and the binding mode of eribulin with tubulin (PDB code: 5JH7).

Figure 8. Structural simplification of staurosporine.

Table 1. Inhibitory Activity of Simplified Analogues of Staurosporine towards PKC Isoforms

PKC subtypes (IC50, μM)
α βI βII γ δ ε ζ η
enzastaurin 0.8 0.03 0.03 2 1 0.3 8 0.4
ruboxistaurin 0.36 0.0047 0.0059 0.3 0.25 0.6 >100 0.052
staurosporine 0.045 0.023 0.019 0.11 0.028 0.018 >1.5 0.005

frequently used simplification strategies include reducing the activity, the simplified derivatives generally showed comparable
ring number and removing chiral centers. For the biological activity or even slightly lower activity at the molecular and
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Figure 9. Structural simplification of asperlicin.

Table 2. In Vitro Antitumor Activity of Trabectedin and and eribulin), MW is only one of the factors in reducing the
Phthalascidin (IC50, nM) structural complexity. The MW of several morphine derivatives
(e.g., compounds 3−6, 9, and 11) and bicyclol is even slightly
higher than their parent molecules because a reoptimization
process is often required to achieve favorable potency,
selectivity and other drug-like properties. Even though, better
synthetic accessibility can be observed in all the five cases.
3.1.1. Structural Simplification of Morphine: A Classic
Story in Medicinal Chemistry. The development of
simplified morphine derivatives as analgesics is a classic
example of the structural simplification of a NP (Figure 3).43
The chemical structure of morphine (1)44 features a complex
five-ring system. It is mainly a μ-opioid receptor agonist (Ki =
compounds A549 HCT116 A375 PC3 1.8 nM).45 The elimination of the bridging furan ring (E ring)
trabectedin 0.95 0.38 0.17 0.55
of morphine afforded morphinans (Figure 3, compounds 2 and
phthalascidin 1.0 0.50 0.15 0.70
3), which have a similar stereo configuration to that of
morphine. For example, levorphanol (2)46 was obtained after
several chemical transformations of morphine, including the
cellular level compared with the original NP. The reduced elimination of the E ring, reductive hydrogenation of the C
structural complexity is helpful to improve the synthetic ring, and removal of the hydroxyl group. Levorphanol showed
accessibility, and PK/PD profiles and contributes to the clinical an excellent analgesic effect (4-fold more potent than
development. Although MW is always significantly decreased morphine). Mechanism study revealed that levorphanol was
during the simplification process (e.g., fingolimod, vorinostat, 6−8 times as potent as morphine at the μ-opioid receptor (Ki

Table 3. Structural Simplification and Binding Affinity of Simplified Erythrinane Analogues towards nAChRs

binding affinity toward nAChRs (Ki, μM)

compounds R R’ α4β2 α4β4 α3β4 α7/5-HT3A
38 CH3 CH3 ∼100 ∼100 ∼100 ∼30
39 CH3 CH3 5.5 ∼100 ∼300 >500
40 CH3 CH3 0.87 ∼300 ∼300 >500

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Table 4. Structural Simplification of Antifungal NP Sampangine and In Vitro Antifungal Activity (MIC80, μg/mL)a

compounds C. alb. C. par. C. neo. C. gla. A. f um. T. rub. M. gyp.

42 4 8 0.25 4 1 2 2
43 0.5 0.5 0.25 0.25 2 1 0.125
44 0.5 1 0.5 2 4 1 1
sampangine 0.5 4 2 ≤0.125 16 16 >64
a
Abbreviations: A. fum., Aspergillus f umigatus; C. neo., Cryptococcus neoformans; C. alb., Candida albicans; C. par., Candida parapsilosis; C. gla.,
Candida glabrata; T. rub., Trichophyton rubrum; M. gyp., Microsporum gypseum.

Table 5. Structural Simplification and Antitumor Activity of GA and Its Simplified Analogues (IC50, μM)a

compounds MCF-7 BGC-823 SMMC-7721 HepG2 MDA-MB-231

46 9.16 3.59 8.06 2.37 0.32
47 68.3 81.1 147 95
gambogic acid 2.19 2.35 3.20 2.40 1.5
a
Abbreviations: MCF-7, mammary carcinoma; BGC-823, gastric carcinoma; SMMC-7721, hepatocellular carcinoma; HepG2, liver carcinoma;
MDA-MB-231, breast cancer.

Table 6. In Vitro Antibacterial Activities of Simplified agonist (K i = 2.5 nM) and μ receptor competitive
Analogues of Sanguinarinea antagonist,49,50 and is widely used for the treatment of
moderate to severe pain, such as postoperative pain, trauma,
cancer pain, and renal or biliary colic.
The elimination of both the C and E rings of morphine led
to benzomorphans (4−6, Figure 3), whose conformations
were similar to that of morphine. The introduction of
hydrophobic substituents on the nitrogen atom could adjust
the analgesic and addictive effects. The analgesic effect of
phenazocine (4)51 was 10-fold more potent than that of
S.
S.
aureus S. S. B. B.
morphine. Although pentazocine (5)52 was 3-fold less active
compounds aureus PR epidermidis pyogenes subtilis pumilus than morphine, it displayed lower addictive side effects and
49 0.06 0.25 0.125 1 0.06 0.06 was approved as the first nonaddictive opioid analgesic. Similar
50 0.06 0.25 0.125 1 0.125 0.125 to butorphanol, pentazocine is a κ-opioid receptor agonist and
51 0.06 1 0.25 2 0.125 0.125 μ receptor antagonist.50
sanguinarine 8 4 8 4 4 4 Although pethidine (7),53 also known as meperidine, was
a
Abbreviations: S. aureus, Staphylococcus aureus ATCC25923 not discovered by the direct structural simplification of
(penicillin-susceptible strain); S. aureus PR, Staphylococcus aureus morphine, it could be seen as a simplified analogue of
PR (penicillin-resistant strain); S. epidermidis, Staphylococcus morphine by the elimination of the B, C, and E rings.
epidermidis; S. pyogenes, Staphylococcus pyogenes; B. subtilis, Bacillus Compared with morphine, pethidine displayed a better
subtilis; B. pumilus, Bacillus pumilus. analgesic effect and oral potency. Further structural mod-
ifications led to the development of a series of synthetic
= 0.21 nM), and was also an agonist of the δ-opioid receptor analgesics such as α-prodine (8)54 and fentanyl (9).55 Like
(Ki = 4.2 nM) and κ-opioid receptor (Ki = 2.3 nM).46 The morphine, fentanyl exerts its analgesic effects by acting as an
addition of a hydroxyl group on the BC ring and replacement agonist of μ-opioid receptor. Synthetic aminoketone analgesic
of the N-methyl group with a cyclobutylmethyl group afforded methadone (11)56 was derived from the optimization of the
butorphanol (3),47,48 which was 10-fold more potent than derivatives of fluorene-9-carboxylate analgesic 10.57 Meth-
morphine, and more importantly, the addiction side effect was adone can be regarded as the ring-opened analogue of
greatly reduced. Butorphanol acts as a κ-opioid receptor piperidine analgesics without the B, C, D, and E rings of
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Figure 10. Structural simplification of dynemicin and the mechanism of dynemicin DNA damage.
Figure 11. Structural simplification of neurotrophic sesquiterpenes.
Figure 12. Structural simplification of pyripyropene A.
morphine. Although methadone is a simple and highly flexible
molecule, its stereo configuration is similar to that of pethidine
(Figure 3). Similar to morphine, methadone is a potent μ
receptor agonist.50 Moreover, methadone also acts as a N-
methyl-D-aspartate (NMDA) antagonist and serotonin reup-
take inhibitor, which could enhance its analgesic properties.50
Currently, methadone is widely used for the treatment of
morphine addiction because of its relatively low risk of
addiction.
The structural simplification of morphine highlights the
importance of retaining the proper conformation and the key
pharmacophore. Although simplified morphine derivatives
have diverse chemical structures, they share similar con-
formations and common pharmacophores including an
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aromatic ring, a basic tertiary amine, and a piperidine or
piperidine-mimic group.
3.1.2. Structural Simplification of Schisandrin C:
Discovery of Bicyclol. Schisandrin C (12, MW = 384), a
NP isolated from the fruit of the traditional Chinese medicine
Fructus Schizandrae, displays antihepatitis B virus (HBV)
activity and significantly decreases transaminase levels.58
Initially, the chemical structure of schisandrin C was
incorrectly assigned (13, Figure 4). Furthermore, a total
synthesis of the wrong structure was performed. Interestingly,
the intermediate bifendate (14) was found to possess potent
activity in the decrease of aminotransferase levels.59 Compared
with schisandrin C, bifendate lacks the seven-membered ring,
and thus its synthetic accessibility is greatly improved.
Importantly, bifendate retained the potent pharmacological
activity of its parent compound. Bifendate has been widely
used in the clinical treatment of patients with elevated
aminotransferase levels, which is caused by viral hepatitis or
drug-induced liver injury. However, its water solubility is poor
due to its high melting point (180 °C),60 which is possibly a
result of its symmetric structure and high lattice energy. To
reduce the molecular symmetry, one carboxylic ester group was
reduced to a hydroxymethyl group, which afforded bicyclol
(15, MW = 390).61 As a result, the melting point of bicyclol
was decreased to 138 °C.62 Compared with bifendate, bicyclol
had improved solubility, greater in vivo absorption, better
bioavailability, and biological activity.63 Pharmacologically,
bicyclol displayed obvious antifibrotic and hepatoprotective
effects against liver injury induced by CCl4 or other
hepatotoxins in mice and rats.64 It also exhibited antihepatitis
virus activity in duck viral hepatitis.64 Bicyclol has been
approved for treating patients with elevated aminotransferase
levels caused by chronic viral hepatitis in China since 2004.58,65
3.1.3. Structural Simplification of Myriocin: Discovery
of Fingolimod. Myriocin (16, MW = 401), also known as
antibiotic ISP-1, is a metabolite of the fungus Isaria sinclairii,
and it has immunosuppressive activity.66 Although myriocin
showed better in vitro and in vivo immunosuppressive activity
than ciclosporin A, it was 100-fold more toxic and poorly
soluble. Myriocin is a structural analogue of endogenous
sphingosine-1-phosphate (S1P) and acts as an agonist of S1P
receptors. It has a complex chemical structure that includes
three chiral centers, one trans-double bond, and five polar
groups (three hydroxyl groups, one carboxyl, and one amino
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Figure 13. Structural simplification of pladienolide B.
Figure 14. Structural simplification of melicobisquinolinone B based
on MCRs.
group). A SAR study indicated that the C-14 ketone group, C-
6 double bond, and C-4 hydroxyl group of myriocin were not
essential for the activity, and the stereo configuration of the C-
3 hydroxyl group had little effect on the activity.66,67 On the
basis of the SAR, Fujita et al. designed and synthesized
simplified analogues (18) with a symmetric 2-alkyl-2-amino-
propane-1,3-diol side chain to mimic the structure of the
terminal group of sphingosine (17, Figure 5).68 Derivatives
containing a side chain with 13−15 carbon atoms displayed
higher activities than that of ciclosporin A. However, the
molecular conformation became more complicated, which was
caused by the flexibility of the alkyl side chain. To solve this
problem, Fujita et al. replaced part of the side chain with a
phenyl group to restrict the molecular conformations.66
Therefore, derivatives 19 were designed and synthesized. On
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the basis of a systematic SAR study, derivatives with m and n
values (in the side chain) of 2 and 8, respectively, displayed the
most potent activity. Among these derivatives, fingolimod (20,
MW = 307) was successfully developed in 2010 for treating
patients with multiple sclerosis.69
3.1.4. Structural Simplification of Trichostatin A:
Discovery of Vorinostat. Trichostatin A (TSA, 21, MW =
302), isolated from the actinomycete Streptomyces hygroscopi-
cus, is a potent noncompetitive histone deacetylase (HDAC)
inhibitor (Ki = 3.4 nM).70 It reversibly inhibited HDAC at
nanomolar concentrations by chelating the zinc in the active
site of HDAC with its hydroxamic acid group. SAR analysis
revealed that two conjugated trans double bonds and the chiral
center are not essential for the activity. Breslow et al.
performed a structural simplification study of TSA by
eliminating the conjugated double bonds and chiral center
and retaining the hydroxamic acid group as the key
pharmacophore (Figure 6A).71 The simplified analogue,
vorinostat (22, MW = 264), can be easily synthesized, and it
retained excellent HDAC inhibitory activity (HDAC1, IC50 =
0.04 μM).72 Crystal structures revealed that TSA and
vorinostat adopted a similar binding mode in the active site
of HDAC (Figure 6B,C).73 Vorinostat was approved in 2006
for the treatment of advanced primary cutaneous T-cell
lymphoma.74
3.1.5. Structural Simplification of Halichondrin B:
Discovery of Eribulin. Halichondrin B (23, Figure 7) is a
large polyether macrolide (MW = 1110) that was isolated from
the marine sponge Halichondria okadai Kadota.75 The marine
macrolide showed excellent activity against B16 melanoma
cells (IC50 = 0.093 ng/mL) and potent in vivo activity in
inhibiting tumor growth in mice.76 Mechanism studies revealed
that it acted as a tubulin-destabilizing agent and inhibited
tubulin polymerization and microtubule assembly.77 Despite its
promising biological activity, the limited supply of the NP from
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Figure 15. Structural simplification of campotothecin based on MCRs.
Table 7. In Vitro Antitumor Activity of Campotothecin and Simplified Analogue 81 (IC50, μM)a
compounds Hela Jurkat MCF-7
81 0.17 0.05 0.45
campotothecin 1.3 0.09 6.0
a
Abbreviations: Hela, cervical cancer; Jurkat, human T-cell leukemia; LoVo, colon cancer; U373, human glioblastoma; SKMEL, melanoma; PC3,
prostate cancer.
its marine source and its extremely complex structure are
serious obstacles for its total synthesis and drug development.
In 1992, Kishi et al. reported the first total synthesis of
halichondrin B, but the synthetic route needed nearly 120
steps.78 Despite the length, the total synthesis provided enough
material to support preclinical development. Interestingly, in
an investigation of the bioactivities of the synthetic
intermediates and analogues, the C1−C38 macrolide was
found to show antitumor activity similar to that of the parent
compound.79 Further investigations revealed that the unstable
lactone moiety could be replaced by a non-hydrolyzable ester
bioisostere, and the keto analogues displayed the best activity.
As a result, a simplified analogue, named eribulin (24), was
developed.80,81 Compared with halichondrin B, the structure of
eribulin is greatly simplified (MW = 729). Additionally, the
synthetic route was significantly shortened. In the crystal
structure of tubulin in complex with eribulin, eribulin forms
directly or water-mediated hydrogen bonds with residues
Tyr224, Val177, and Asp179 within the binding pocket (Figure
7).82 Eribulin displayed superior efficacy over other anti-
mitotics such as paclitaxel,81 and its mesylate derivative was
approved by the FDA in 2010 for the treatment of patients
with refractory metastatic breast cancer.83
3.2. Structural Simplification Leading to Clinical
Candidates
In contrast to successful clinical drugs, candidate drugs derived
from structural simplification of NPs are relatively limited.
Herein only two examples of clinical candidates are introduced,
in which reducing the number of rings and chiral centers is also
used as the simplification strategy. The first example
(simplification of staurosporine) illustrates structural simplifi-
cation guided by different biological activity, while the second
example (simplification of asperlicin) discusses pharmacophore
inspired structural simplification.
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A549 LoVo U373 SKMEL PC3
0.61 0.29 0.10 0.23 0.19
0.20 0.008 0.033 0.047 0.48
3.2.1. Structural Simplification of Staurosporine:
Discovery of Ruboxistaurin and Enzastaurin. Staurospor-
ine (25, Figure 8), an alkaloid originally isolated from cultures
of Streptomyces sp. AM-2282, shows a wide range of biological
activities including antitumor and neurotrophic potency.84,85
Staurosporine was validated as an inhibitor of protein kinase C
(PKC), which is a family of serine/threonine-specific kinases
that is composed of at least 12 isozymes or subtypes.86
Therapeutically, a selective PKC antagonist could treat a
variety of diseases including diabetes and cancer.87,88 However,
staurosporine had limited selectivity for both ATP-dependent
kinases and individual PKC isozymes. The complex structure
of staurosporine includes eight rings and four chiral centers,
making its total synthesis challenging. Lilly’s research group
reported the structural simplification of staurosporine and
identified a novel class of macrocyclic bisindolylmaleimides
(represented by ruboxistaurin, 26).89 The simplification
process included opening the central benzene and tetrahy-
dropyrane rings and oxidizing the pyrrolidone into maleimide.
After the ring opening, ruboxistaurin contains only one chiral
center and displayed good selectivity for PKC β. For example,
compared with staurosporine, 26 exhibited better activity
against PKC βI and βII with IC50 values of 0.0047 μM and
0.0059 μM, respectively. Moreover, its selectivity for inhibiting
PKC α is significantly increased (Table 1). Ruboxistaurin
mesylate was evaluated in the clinic for the treatment of
diabetic retinopathy, but the phase III clinical trial of
ruboxistaurin was terminated because of limited efficacy. In
2016, a phase I and II study for ruboxistaurin was conducted
for treating adult patients with heart failure.90 Furthermore,
Faul et al. identified a series of acyclic (N-azacycloalkyl)
bisindolylmaleimides (represented by enzastaurin, 27).91
Enzastaurin displayed nanomolar activity against PKC βI and
βII with an IC50 value of 0.03 μM. Meanwhile, it had good
selectivity for PKC α. Enzastaurin was advanced into clinical
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Figure 16. Structural simplification of yohimbine by the SCONP scaffold tree.
trials; however, its phase III clinical trials failed due to the poor
efficacy for treating glioblastoma, breast and lung cancer.92
Now, clinical trials of enzastaurin are focused on treating
tumor patients with specific biomarkers.93
In addition to its PKC inhibitory activity, staurosporine was
also confirmed to be an effective Janus kinase 3 (JAK3)
inhibitor with an IC50 value of 6 nM.84,94,95 The simplification
of staurosporine led to a series of new simplified analogues
with highly potent JAK3 inhibitory activity.95 Initially, Yang et
al. replaced the amino-sugar group with an alkyl ring in which
an attached hydroxymethyl group mimicked the methylamino
fragment of the amino-sugar. SAR studies revealed that a
suitable substituent at the C3 and/or C9 position could
increase the JAK3 inhibitory activity. Therefore, further
optimization focused on regioselective functionalization of
the indolocarbazole unit. As a result, simplified analogues 28
(IC50 = 3 nM) and 29 (IC50 = 3 nM) were synthesized and
demonstrated excellent inhibitory activity against JAK3.95
3.2.2. Structural Simplification of Asperlicin: Discov-
ery of Devazepide. Asperlicin (30), a mycotoxin isolated
from Aspergillus alliaceus,96 is a selective antagonist (IC50 = 1.4
μM) of pancreatic cholecystokinin receptors (CCK) with
potential therapeutic effects in CCK-related disorders of the
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gastrointestinal system.96,97 However, several limitations, such
as its complicated structure, difficulties in total synthesis,
limited SAR information, and poor oral bioavailability, have
hampered the direct clinical application of asperlicin.98,99
Through a systematic structural analysis of asperlicin, Evans et
al. found that the 1,4-benzodiazepine (BZD, 31) and L-
tryptophan (L-Trp, 32) groups were the essential structural
motifs (Figure 9).100 Moreover, the 5-phenyl-1,4-benzodiaze-
pine scaffold is a privileged structure for the inhibition of G-
protein coupled receptors (GPCRs),101−103 which might be
the pharmacophore that binds with CCK. Therefore, the 5-
phenyl-1,4-benzodiazepine scaffold was used as the lead
structure for further modification. The right-hand side of
asperlicin was an analogue of L-Trp, which is the key residue
for the interaction of cholecystokinin with CCK. Therefore, a
series of simplified derivatives (33) were designed by
combining the BZD and L-Trp groups. After a systematic
SAR study, devazepide (MK-329, 34) was discovered,104,105
and it displayed potent antagonistic activity against CCK with
an IC50 value of 0.8 nM. Moreover, 34 showed good selectivity
for the benzodiazepine receptor.100 Although a pilot clinical
trial of devazepide in patients with advanced pancreatic cancer
failed to demonstrate any impact on tumor progression,106 this
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Figure 17. BIOS libraries inspired by withanolide A and bioactive simplified analogues.

Figure 18. Structural simplification of podophyllotoxin (A) and the binding modes of podophyllotoxin (B, PDB: 1SA1), analogues 97 (C) and 98
(D) with tubulin. Molecular docking was used to reproduce the binding modes of analogues 97 and 98.

compound is widely used as a tool compound for the analysis of the case studies described in the following sections,
investigation of CCK receptors. reducing the number of rings and chiral centers is also the
3.3. Structural Simplification Leading to Preclinical most commonly used simplification strategy, after which
Candidates or Lead Compounds synthetic difficulty can be significantly reduced. Notably,
Currently, most examples in structural simplification of NPs most of the simplified compounds were only evaluated at the
are still at the stage of identifying new lead compounds. After molecular and/or cellular level, and only two examples (i.e.,
M DOI: 10.1021/acs.chemrev.8b00504
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Chemical Reviews
Figure 19. Structural simplification of taxuspine X.
Figure 20. Structural simplification of cortistatin A.
simplified erythrinane and largazole derivatives) reported the
in vivo potency. The lack of in vivo PK/PD evaluations limits
further development of these simplified NP derivatives.
Moreover, the in vivo evaluations are also helpful to identify
the problems to be overcome and guide further structural
optimizations. Target identification is a bottleneck in NP-based
drug discovery.10,107 In the following structural simplification
examples, although targets of a large portion of NPs have been
validated, the lack of binding mode information limited the
efficiency to design simplified analogues. Thus, structural
biology studies are highly required to clarify the key structural
motifs for binding NPs with their targets and guide the rational
simplification design. Also, the change of molecular targets has
been observed in some cases (e.g., simplified bryostatin and
campotothecin derivatives). Therefore, validation of the
mechanisms is necessary to confirm whether the simplified
compounds act on the same target as the parent NP. Recently,
highly efficient and practical synthetic methods, such as
multicomponent reactions (MCRs),108−110 FOS,111 DTS,112
and BIOS,113 have been applied to synthesize simplified NP
analogues. Although successful examples are still limited, these
new methods will contribute to improve the efficiency of
structural simplification of NPs.
3.3.1. Structural Simplification by Reducing the Ring
Number. 3.3.1.1. Structural Simplification of Trabecte-
din. Trabectedin (35, Table 2), also known as ecteinascidin-
743, is a bis-tetrahydroisoquinoline-fused alkaloid isolated
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from the extracts of the marine organism Ecteinascidia
turbinate.114 Trabectedin is a highly potent antitumor agent
and has been approved as the first marine-derived antitumor
drug for the treatment of soft tissue sarcoma and ovarian
cancer. Mechanism study revealed trabectedin could bind to
the minor groove of DNA, thus bending the DNA helix toward
the major groove.115 Moreover, it interfered with cellular
transcription-coupled nucleotide excision repair to induce cell
death and cytotoxicity.115 With an aim to discover new
trabectedin analogues with simpler chemical structures, better
synthetic accessibility, and higher stability, Corey et al.
performed a structural simplification of trabectedin in which
the third isoquinoline ring was substituted with a phthalimide
moiety (Table 2).116 Compared with trabectedin, structurally
more simpler phthalascidin (36) displayed comparable or
higher antitumor activity against A549 (lung cancer), HCT116
(colon cancer), and A375 (malignant melanoma) and PC
(prostate cancer) cell lines. Moreover, the antiproliferative
activity of phthalascidin (IC50 range: 0.1−1 nM) is better than
those of several well-known natural antitumor agents (e.g.,
Taxol, camptothecin, adriamycin, and etoposide) by 1−3
orders of magnitude. Moreover, compound 36 could be easily
synthesized from known synthetic intermediates (in six
chemical steps) and displayed better stability than trabectedin
which contains the unstable spiro 10-member lactonic ring. A
mechanism study revealed that phthalascidin shared a similar
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Figure 21. Structural simplification of bryostatin 1.

Figure 22. Structural simplification of cyclopamine 1.

Figure 23. Diverted total synthesis and simplification of carolacton-inspired analogues.

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Figure 24. Diverted total synthesis of promysalin-inspired analogues.
Figure 25. Structural simplification of chaetocin.
mode of action to trabectedin and acted by inducing DNA−
protein cross-linking.116
3.3.1.2. Structural Simplification of Erythrinane.
Erythrinane (37, Table 3), a member of the Erythrina alkaloid
family, is characterized by a unique tetracyclic spiroamine
framework, and it was found to be a potent antagonist of
nicotinic acetylcholine receptors (nAChRs).117 However, the
limited availability of erythrinane and its analogues from
natural sources hampers their broad application. In the pursuit
of simpler and more synthetically accessible analogues, Crestey
et al. performed a structural simplification of erythrinane in
which the tetracyclic scaffold was simplified step by step to
identify the groups essential to the nAChRs inhibitory activity
(Table 3).118 First, the A-ring methoxyl group and the two
double bonds in the A and B rings were sequentially deleted,
resulting in tetracyclic derivatives 38, which showed retained
affinity for a variety of nAChR subtypes. When the A ring was
removed, tricyclic derivative 39 showed improved affinity for
α4β2 (Ki = 5.5 μM). Notably, the selectivity of 39 for other
subtypes was also significantly increased. Further deletion of
the B ring gave bicyclic tetrahydroisoquinoline analogue 40,
which displayed a submicromolar binding affinity toward α4β2
(Ki = 0.87 μM) with more than 300-fold selectivity over the
other subtypes. In a mouse forced swim test, compound 38
showed an in vivo antidepressant-like effect at a dose of 30
mg/kg.
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3.3.1.3. Structural Simplification of Sampangine.
Invasive fungal infections (IFIs) are associated with high
mortality in immune-compromised hosts. Despite the high
mortality of IFIs, effective and safe antifungal agents are very
rare. More importantly, increasing resistance is being
developed to almost all the clinically available antifungal
agents. Sampangine (41, Table 4), an azaoxoaporphine
alkaloid extracted from the stem bark of Canangaodorat,
displayed broad-spectrum in vitro antifungal activity.119
Further lead optimization and drug development were
hampered because the aromatic tetracyclic derivatives had
poor water solubility (kinetic solubility 12.6 μg/mL) and were
inactive in vivo.120 To address these bottlenecks, our group
performed a series of scaffold hopping and structural
simplification studies, and identified a thiophene analogue,
ZG-20 (42), with improved activity and water solubility
(kinetic solubility 48 μg/mL, Table 4).121 After rings A and B
were removed, simplified tricyclic analogue ZG-20-07 (43) and
bicyclic analogue ZG-20−41 (44) displayed improved
antifungal activities (Table 4) and water solubility. Moreover,
they showed good in vivo antifungal potencies with low
toxicities in a C. elegans−C. albicans infection model.122,123
Compounds 43 and 44, which were developed via a structural
simplification, had several advantages over fluconazole, such as
superior fungicidal activity, higher potency against fluconazole-
resistant strains, and better inhibition of biofilm formation and
yeast-to-hypha morphological transitions.122,123
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Figure 26. Structural simplification of largazole (A) and the binding mode of largazole thiol (B, PDB code: 3RQD) with HDAC8.

Figure 27. Structural simplification of lobatamide C.

3.3.1.4. Structural Simplification of Gambogic Acid. with low toxicity to normal cells.124 It prevented cancer
Gambogic acid (GA, 45), the major component of gamboges metastasis and angiogenesis, and was evaluated in phase II
resin, displayed potent in vitro and in vivo antitumor activity clinical trials in China.125,126 However, further clinical trial of
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Figure 28. Structural simplification of sanglifehrin A (A) and the binding modes of sanglifehrin A (B, PDB code: 1YND), analogues 142 (C, PDB
code: 1NMK), 143 (D, PDB code: 5T9U), 146 (E, PDB code: 5T9Z), 147 (F, PDB code: 5TA2), and 148 (G, PDB code: 5TA4) with cyclophilin
A.

GA was terminated because of limited antitumor efficacy. The
structure of GA can be divided into two fragments: a planar
region that contains rings A, B, and C and the caged core D
ring (4-oxa-tricyclo[4.3.1.03,7]dec-2-one) system. A prelimi-
nary SAR study revealed that the 4-oxa-tricyclo[4.3.1.03,7]dec-
2-one ring system was essential for the antitumor activ-
ity.125,127 To get more SAR information and improve the
antitumor potency, You’s group performed a systematic step
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by step simplification of GA to obtain a series of analogues
with a simplified planar region (Table 5).125 Compound 46, a
simplified analogue obtained by removal of the A ring,
displayed in vitro antitumor activity comparable or superior
to that of GA.125 Mechanistic studies indicated that compound
46 was able to induce programmed cell death and arrest cell
cycle growth in the G2/M phase as well as regulate apoptotic
related proteins and cellular caspase-3 activity. The mode of
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Table 8. Biological Activities of Simplified Analogues of

Sanglifehrin A
PPIase
TR-FRET Cyp A functional assay HCV genotype 1b
compounds binding Kd (nM) Ki (nM) replicon EC50 (nM)
143 25 16 600
144 65 65 240
145 2600 795 4500
146 64 14 320
147 11 4 36
148 24 7 87
149 48 4.3 620
cyclophilin A 17 6.7 170

Figure 30. Structural simplification of caprazamycin B.

Figure 31. Structural simplification of militarinone D.

bacteria strains than sanguinarine (Table 6). Mechanism

Figure 29. Structural simplification of anguinomycin.
action of compound 46 was consistent with the apoptotic
induction effects of GA. In contrast, compound 47, which was
obtained both the A and B rings were removed, was
substantially less effective.
3.3.1.5. Structural Simplification of Sanguinarine.
Sanguinarine (48, Table 6) is a benzo[c]phenanthridine
alkaloid which displayed moderate antibacterial activity against
a broad range of Gram-positive bacteria.128 It was validated as
a filamenting temperature-sensitive protein Z (FtsZ, an
antibacterial target)129 inhibitor that can alter the Z-ring
formation and function of FtsZ.130 To further improve the
antibacterial activity, Ma et al. simplified the skeleton of
sanguinarine to synthesize a series of 5-methyl-2-phenyl-
phenanthridium derivatives (Table 6).128 Compounds 49, 50,
and 51 displayed better activity against sensitive and resistant
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studies revealed that these analogues exhibited strong cell
division inhibitory activity and obvious inhibition on B. subtilis
FtsZ polymerization, indicating that they inhibited the
bacterial proliferation by interfering the function of bacterial
FtsZ.
3.3.1.6. Structural Simplification of Dynemicin. The
violet dynemicin (52, Figure 10), a cyclic 10-membered
enediyne NP isolated from the fermentation broth of
Micromonospora chersina. M956-1,131,132 exhibited strong in
vitro activity against Gram-positive bacteria and significant in
vivo potency against Staphylococcus aureus Smith infection in
mice (i.p., PD50 = 0.13 mg/kg) with low toxicity. In addition,
dynemicin demonstrated highly potent antitumor activity
against a variety of cancer cell lines and significantly prolonged
the life span of mice with P388 leukemia or B16
melanoma.131,133 Structurally, dynemicin contains an anthra-
quinone and a 10-membered ring with a 1,5-diyn-3-ene bridge.
The mechanism of its antitumor activity involves intercalation
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Figure 32. Structural simplification of bistramide A (A) and the binding mode of bistramide A (B, PDB code: 2FXU) with monomeric actin.
Figure 33. Structural simplification of withaferin A by FOS.
Figure 34. Structural simplification of rakicidin A.
of the anthraquinone core into DNA and triggering of a
Bergman reaction, generating highly reactive benzenoid
diradicals, causing DNA damage (Figure 10).134,135 Guided
by the mechanism, structural simplification was focused on
mimics of dihydroquinoline epoxides spanned by an enediyne
bridge (red part in compound 52) while retaining the
antitumor activity and reducing the molecular complexity.
The simplest analogue, 53, was synthesized by Wender et al. in
only seven steps and maintained the antitumor activity of the
parent compound.135,136 Nicolaou et al. removed the A and B
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rings of dynemicin and incorporated a phenylsulfone ethylene
carbamate moiety on the nitrogen atom. The resulting
simplified analogue, 54, was highly active with an IC50 value
of 20 fM against Molt-4 T-cell leukemia cells.134
3.3.1.7. Structural Simplification of Merrilactone A.
Sesquiterpenoid NPs, such as merrilactone A (55, Figure
11)137 and anislactone A/B (56),138 possess a variety of
biological activities.139 Structurally, merrilactone A is a
sesquiterpene dilactone consisting of two γ-lactones and an
oxetane ring, and it displayed intriguing neurotrophic activity
in primary cultures of fetal rat cortical neurons.137 Although
nonpeptidic small molecules with neurotrophic activity are
considered to have potential for the development of
therapeutic agents against neurodegenerative diseases such as
Alzheimer’s and Parkinson’s diseases, the drug development of
merrilactone A was hampered because of its structural
complexity as well as the poor yields and high costs of
obtaining it from its natural source.139 Thus, the structural
simplification of merrilactone A was performed by Tiefen-
bacher’s group to reduce its complexity while maintaining its
neurotrophic activity. By simplifying the scaffold of merrilac-
tone A, analogues 57 and 58 showed neurite outgrowth activity
comparable to that of the reference drug jiadifenolide.140
Compared with the 17−26 steps required for the total
synthesis of merrilactone A, compounds 57 and 58 can be
synthesized in just 6−8 steps with high yields from commercial
materials.141,142
3.3.1.8. Structural Simplification of Pyripyropene A.
Pyripyropene A (59, Figure 12), isolated from the culture
broth of Aspergillus f umigatus strain FO-1289, is a strong and
selective inhibitor of sterol O-acyltransferase 2 (SOAT2) (IC50
= 0.07 μM),143−145 which is an important target for the
treatment of hypercholesterolemia and atherosclerosis.146,147
In the pursuit of new cholesterol-lowering or antiatheroscler-
otic agents, Nagamitsu’s group reported the first total synthesis
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Figure 35. Structural simplification of spongistatins.
of pyripyropene A in 2011. 148 Then, the structural
simplification was performed to give new A ring-simplified
pyripyropene A analogues based on the results of the SAR
studies. Among these simplified analogues, 60 showed
excellent SOAT2 inhibitory activity (IC50 = 0.07 μM) with
high isozyme selectivity over SOAT1, and its activity was
comparable to that of natural pyripyropene A.147 60 was
considered to be the most potent and selective synthetic
inhibitor of SOAT2 and an attractive candidate for further
development.
3.3.1.9. Structural Simplification of Pladienolide B.
Pladienolide B (PB, 61, Figure 13) contains a 12-member
macrolide ring with an extended epoxide-containing side
chain.149 It acted by targeting the SF3B1 subunit of
spliceosome and displayed potent antiproliferative and tumor
suppressive activity when assayed in both cell culture and
xenograft models.149,150 To investigate the importance of the
epoxide-containing side chain, Maier et al. reported a
simplified analogue bearing a phenyl substituted side chain
(compound 62).151 However, it was inactive up to 4 μg/mL in
a cellular proliferation assay against L929 mouse fibroblasts.
The results highlighted the central role of the epoxide-
containing side chain for binding. After removal of the 3-
hydroxy group and the methyl groups at positions 10, 16, 20,
and 22 in PB, simplified derivative 63 was inactive against
several human cancer cell lines at the concentration up to 20
μM.152 In contrast, the aryl analogue 64 with a truncated side
chain displayed moderate antitumor activity (A549 cell line,
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IC50 = 1.5 μM).23,153 Furthermore, Burkart et al. reported
C18−C19 cyclopropyl derivative 65, which displayed
improved stability and effectively mimicked the apoptotic
and splicing activity of PB.154 It showed potent inhibitory
activity against HCT116 cell line (IC50 = 42.9 nM), which was
slightly less active than PB (IC50 = 24.8 nM). The results
indicated that the C18−C19 epoxide moiety was not essential
for the spliceosome activity.
Compound 66 lacking the 6-OH group demonstrated
potent inhibitory activity against the mutant SF3B1 pancreatic
cancer cell line (GI50 = 8.1 nM), high binding affinity to the
SF3b complex (IC50 = 4.0 nM), and inhibition of pre-mRNA
splicing.155 Moreover, NP herboxidiene (67, Figure 13) could
be seen as a simplified analogue of PB, whose 12-member
macrolide ring was replaced by the 6-member tetrahydropyran
ring.156 Herboxidiene displayed potent inhibitory activity
against several human cancer cell lines (e.g., Hela cell line,
IC50 = 14.7 nM). However, analogue 68, a hybrid molecule
from herboxidiene and PB, was totally inactive (IC50 > 20
μM), which highlighted the central role of the methyl
substituent in the tetrahydropyran ring and the hydroxyl
group in the side chain.156
3.3.1.10. Structural Simplification of Melicobisquino-
linone B. Melicobisquinolinone B (69, Figure 14) containing
the pyranoquinolone structural motif exhibited potent
antitumor activities and was investigated as a potential
anticancer agent.157−159 The MCRs have the advantages of
environmental friendliness, atom economy, and efficient
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Figure 36. Structural simplification of spongistatins.

Table 9. Antitumor Activity of Simplified Spongistatin acts by the inhibition of topoisomerase I (Top1).160 The total
Derivatives (IC50, nM) synthesis of campotothecin requires more than 15 steps due to
its five conjugated planar rings. The investigation of
human cancer cell line paclitaxel 166 174 175
camptothecin analogues identified two clinically useful agents,
MIP101 colon 200 0.1 0.08 587
topotecan161 and irinotecan,162 that can be employed for the
HCT116 colon 0.3 0.05 0.02 407
treatment of colon and ovarian cancer, respectively.163
1A9PTX22 47 0.03 0.007 >632
Magedov et al. developed a one-step multicomponent
1A9 1 0.03 0.007 >632
A549 6 0.07 0.04 >632
condensation of various aminoheterocycles (77), aldehydes
(76), and 1,3-indanedione (78) that facilitated the synthesis of
various heterofused indenopyridines (Figure 15).110 These
construction of molecules in only one or two synthetic steps. analogues (79) mimicked the A−D rings of campotothecin,
Magedov et al. developed a three-component reaction of
and the dihydropyridine moiety could be transformed to the
pyridine (70) with malononitrile (72) and various aromatic
planar indenopyridine skeleton (80) via an intracellular
aldehydes (71) to efficiently construct a library of compounds
with pyrano[3,2-c]pyridone and pyrano[3,2-c]quinolone scaf- oxidation. These simplified derivatives displayed broad-
folds (73, Figure 14).109 Most derivatives displayed sub- spectrum antitumor activity. For example, compound 81
micromolar or low micromolar inhibitory activities against showed better inhibitory activity toward HeLa, Jurkat, and
HeLa cells. Generally, pyrano[3,2-c]quinolones were more MCF-7 cells than campotothecin (Table 7).110 Interestingly,
potent than pyrano[3,2-c]pyridines.109 Compound 74 showed mechanism studies revealed that these analogues inhibited
potent inhibitory activity against HeLa cells with a GI50 value topoisomerase II (Top2) instead of Top1. These results
of 47 nM and significantly induced the apoptosis of Jurkat cells indicated that the structural simplification of NPs may result in
at a concentration of 5 μM. Mechanistic studies revealed that a change in the molecular target.
these compounds induced cell cycle arrest in the G2/M phase 3.3.1.12. Structural Simplification of Yohimbine.
and blocked in vitro tubulin polymerization. Yohimbine (82, Figure 16) is an indole alkaloid derived
3.3.1.11. Structural Simplification of Campotothecin. from the bark of the Pausinystalia yohimbe tree with diverse
Campotothecin (75, Figure 15) is a classic antitumor NP that biological activities.164 It was identified as an inhibitor of
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Figure 37. Structural simplification of migrastatin (A) and the binding mode of analogue 185 with fascin (B, PDB code: 3O8K).
phosphatase Cdc25A by Waldmann’s group.41 The pentacyclic
scaffold of yohimbine was sequentially truncated into simpler
compounds by a chemistry-based rule165,166 called “structural
classification of natural products” (SCONP).41 As a result, a
scaffold tree of yohimbine was obtained in which complex
scaffolds become smaller step by step (Figure 16A). The
simpler scaffolds in the scaffold tree may retain the bioactivity
of the more complex compounds, which can be used for
structural simplification. For example, the simplified tetracyclic
scaffold 85 showed similar phosphatase Cdc25A inhibitory
activity (IC50 = 20.3 μM) to yohimbane (IC50 = 22.3 μM).167
In contrast, analogue 86 was inactive against Cdc25A and was
identified as a mycobacterial protein tyrosine phosphatase B
(MptpB) inhibitor.167 Moreover, analogue 87 showed potent
activity against the HeLa cervical cancer cell line (IC50 = 0.8
μM) and arrested the cell cycle at the G2/M phase.168 In
addition to the inhibitory activity against MptpB,41 additional
simpler tetrahydrocarbazole (88) and indole (89) derivatives
were inhibitors of vascular endothelial growth factor receptors
2 (VEGFR-2).169 The results also indicated that over
simplification might lead to the change of the binding target.
3.3.1.13. Structural Simplification of Withanolide A.
Withanolide A (90, Figure 17) is steroid-like NP with diverse
bioactivities.170 The trans-hydrindane/dehydro-δ-lactone frag-
ment was thought to be the essential pharmacophore.
Waldmann’s group developed the concept of BIOS, which
integrates computational and synthetic tools to design and
synthesize bioactive simplified NP analogues.113,171 To reduce
the structural complexity of withanolide A, an efficient BIOS
method was developed for the synthesis of trans-hydrindane
dehydro-δ-lactone derivatives (91).172 Cell-based assays
indicated that four withanolide analogues act by inhibiting
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Hedgehog (Hh) signaling. Among these analogues, compound
92 was proven to bind to the SMO protein (Ki = 57 nM) with
low cytotoxicity. The same group further constructed a
compound library of substituted δ-lactones 93.173 Several
withanolides, particularly vinylogous urethane analogues,
displayed significant potency in inhibiting the Wnt/β-catenin
pathway. Compound 94 was the most potent withanolide
(IC50 = 0.11 μM) and interfered with the Wnt pathway by a
novel tankyrase-independent mechanism. Interestingly, its
simplified analogue, 95, retained the ability to inhibit the
Wnt reporter gene (IC50 = 4.5 μM), although it was 40-fold
less active. The novel and potent inhibitors of the Hedgehog
signaling pathway and the Wnt/β-catenin pathway were
promising lead compounds for drug discovery.
3.3.2. Structural Simplification by Removing Chiral
Centers. 3.3.2.1. Structural Simplification of Podophyl-
lotoxin. Podophyllotoxin (96, Figure 18), a well-known NP
isolated from the roots of Podophyllotoxin peltatum, displays
good in vitro antitumor activity.174 However, the total
synthesis of podophyllotoxin is challenging due to its complex
structure. The C ring of podophyllotoxin contains four chiral
centers, and the facile epimerization of the C-2 position
converts the compound into its inactive cis-acetone isomer in
vivo.175 The structural modification of podophyllotoxin was
focused on its semisynthetic derivatives. Hitotsuyanagi et al.
designed and synthesized structurally simplified podophyllo-
toxin analogues containing the 4-aza-2,3-dehydro-4-deoxypo-
dophyllotoxin scaffold, which could be easily synthesized
because of the elimination of the chiral centers.176 Interest-
ingly, these derivatives retained the good antitumor activity of
their parent compound.176 For example, compound 97
displayed potent antitumor activity against the P-388 leukemia
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Table 10. Selected Examples of Structural Simplification of Complex NPs

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Table 10. continued

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Table 10. continued

cell line with an IC50 value of 0.00182 μg/mL, which makes it mL). Using multicomponent synthesis, Magedov et al.
2-fold more potent than podophyllotoxin (IC50 = 0.0043 μg/ synthesized analogues bearing a dihydropyridine pyrazole
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scaffold.177 Compared with podophyllotoxin, the A ring and
the chiral centers were removed. A one-step multicomponent
reaction enabled a highly efficient construction of the library of
analogues and elucidation of the SARs. These simplified
derivatives displayed good in vitro antitumor activities. For
example, compound 98 had an IC50 value of 0.02 μM and 0.01
μM against the HeLa and MCF-7 cancer cell line, respectively,
which were comparable to that of podophyllotoxin. Moreover,
it showed an antiapoptotic effect comparable to that of
podophyllotoxin against the Jurkat leukemia cell line.
Mechanism studies revealed that compound 98 inhibited
tubulin polymerization and disrupted the formation of mitotic
spindles in dividing cells at concentrations as low as 5 nM,
which was similar to podophyllotoxin. Molecular docking
results revealed analogues 97, 98, and podophyllotoxin
adopted a similar binding mode with tubulin (Figure
18).177,178
3.3.2.2. Structural Simplification of Taxuspine X.
Paclitaxel (Taxol) and its derivative docetaxel are widely
used anticancer agents for the treatment of ovarian, breast, and
lung cancer. These compounds have potent antitumor activity
via binding to β-tubulin. However, broad clinical application
resulted in significant multidrug resistance (MDR), which was
a significant obstacle for the success of chemotherapy in
different types of cancers.179,180 One major mechanism of
MDR is the overexpression of P-glycoprotein (P-gp), a well-
known trans-membrane ABC transporter, which effluxes a
variety of chemotherapeutic drugs out of tumor cells.180−182
Taxuspine X (99), a Taxol analogue that was isolated from the
Japanese yew Taxus cuspidate, was proven to be a potent MDR
reversing agent.183−185 However, 99 was isolated in very poor
yields from the natural source, and the total synthesis was
limited by intrinsic difficulties and high costs. To explore the
biological potential of taxuspine analogues, Botta et al.
performed structural simplification studies (Figure 19).186,187
Simplified diterpenoid 100 was synthesized through a ring-
closing metathesis approach. However, its significant structural
complexity still represents a synthetic challenge, partly due to
the presence of six stereocenters. Therefore, further structural
simplification was conducted to obtain additional simplified
analogues 101 and 102. Compound 101, bearing a benzoyloxy
moiety on C13 of the taxane skeleton, was proven to be an
efficient P-gp inhibitor (IC50 = 7.2 μM).
3.3.2.3. Structural Simplification of Cortistatin A.
Cortistatin A (103, Figure 20), a novel antiangiogenic steroidal
alkaloid isolated from an Indonesian marine organism, showed
potent and selective antitumor activity against human umbilical
vein endothelial cells (HUVECs).188 Compound 103 also
significantly inhibited in vitro migration and tubular formation
of HUVECs induced by vascular endothelial growth factor
(VEGF) or basic fibroblast growth factor (bFGF).188 There-
fore, this compound is expected to be a promising
antiangiogenic lead compound. Kobayashi et al. designed and
synthesized simplified analogues by reducing the number of
chiral centers and removing a bridged ring (Figure 20).189,190
Although compound 104 (IC50 = 0.035 μM) was less active
than cortistatin A in the inhibition of HUVECs, it showed
potent in vivo antiangiogenic and antitumor activities by oral
administration. After introduction of an amide side chain on
the scaffold, acetamide analogue 105 displayed a highly potent
activity against HUVECs (IC50 = 0.0026 μM) as well as an
excellent selectivity for KB3−1 cells (IC50 = 8.2 μM).190
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3.3.2.4. Structural Simplification of Bryostatin 1.
Chikungunya virus (CHIKV) is an arbovirus of the Alphavirus
genus that has been spreading rapidly.191 Currently, there is no
effective therapy to treat CHIKV infections, and the only
medications (i.e., the anti-inflammatory drugs) can be used to
alleviate the symptoms. PKC modulators were reported to
inhibit CHIKV virus-induced cell death, representing a
promising therapeutic choice to treat CHIKV infection.192−194
Bryostatin 1 (106, Figure 21) is a marine NP bearing a
polyacetate backbone which was originally isolated from the
bryozoan Bugula neritina.195 It is a great challenge for the total
synthesis of bryostatin 1 because of the complex scaffold
(nearly 55 synthetic steps).196 Bryostatin 1 was proven to be a
potent pan-conventional and novel PKC isoform modulator
(PKC δ binding affinity Ki = 1.1 nM). However, it was inactive
in inhibiting CHIKV virus-induced cell death.191 Wender’s
group designed the simplified analogues of bryostatin 1 by
removing several chiral centers (Figure 21).191 Compared with
bryostatin 1, synthetic routes of simplified analogues 107 and
108 were significantly shortened (∼30 steps). Interestingly,
compounds 107 and 108 displayed potent activity in the
CHIKV cell protective assay with an EC50 value of 0.13 μM
and 0.8 μM, respectively.191 Moreover, compound 108
displayed no observable toxicity (CC50 > 50 μM). In 2014,
Wender et al. reported a new class of simplified analogues in
which the complex A/B-ring system of bryostatin 1 was
replaced with simple salicylate-derived fragments (109, Figure
21).197,198 These analogues retained potent affinity (nano-
molar) for PKC isoforms, whereas the synthetic route was
greatly shortened to 23−25 steps. Analogue 109 displayed
good protective activity (EC50 = 1.4 μM) and lower toxicity
(CC50 > 50 μM). SAR study of various substitutions attached
to the hydroxyl group revealed that methoxyl analogue 110
displayed good protective activity and lower toxicity (CHIKV
EC50 = 2.2 μM, CC50 > 50 μM). However, compound 110
displayed a lower affinity to PKC (PKCδ Ki = 1.0 μM),
indicating that there might be a PKC-independent mechanism
for evading CHIKV-mediated cell death. This structural
simplification study provided a good starting point for the
design of new drugs for the treatment of CHIKV infections.
3.3.2.5. Structural Simplification of Cyclopamine 1.
The steroidal alkaloid cyclopamine 1 (111, Figure 22) was
isolated from Veratrum californicum and proven to be
responsible for craniofacial birth defects.199,200 Subsequently,
mechanism studies revealed that cyclopamine 1 blocked the
Sonic Hedgehog (SHH) signaling pathway by binding to 7-
transmembrane protein Smoothened (SMO).201,202 Despite its
teratogenicity, cyclopamine 1 showed highly potent activity
against a number of human cancers and holds great promise
for cancer chemotherapy.203−205 However, its poor aqueous
solubility and acid lability hampered its further develop-
ment.206,207 To address these limitations, Dahmane et al.
explored the SAR of cyclopamine 1 by structural simplifica-
tion.207 First, replacement of the C-nor-D-homo steroidal
system with the androstane ring and aromatization of rings A
and F generated simplified analogue 112 as well as the C-17
epimer 114. The C-3 deoxy compound 113 was also prepared.
Biological evaluations demonstrated that simplified analogues
112−114 showed comparable SHH inhibitory activities with
improved metabolically stability.208
3.3.2.6. Structural Simplification of Carolacton.
Carolacton (115, Figure 23) is a NP isolated from
myxobacterium Sorangium cellulosum.209 It was unable to
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affect the viability of planktonic bacteria but effectively kills
pathogen Streptococcus mutans biofilm cells at low nanomolar
concentration.210,211 Earlier SAR work revealed that mod-
ifications of the 12-member macrolide ring were not
tolerated.212,213 Thus, Wuest et al. applied DTS to synthesize
16 simplified carolacton-inspired analogues (Figure 23).214 1,3-
Disubstituted aryl motifs were rationally selected to mimic the
trisubstituted olefin side chain. Among them, compound 120
inhibited the formation of biofilms at concentrations at the
concentration of 63 μM, and compound 121 exhibited a
similar effect on S. mutans biofilms at concentrations as low as
500 nM. The results highlighted that 1,3-disubstituted aryl
motifs could be used as an bioisosteric substitution of the
trisubstituted olefins, which significantly reduced the synthetic
difficulty while maintaining the structural integrity.
3.3.2.7. Structural Simplification of Promysalin.
Promysalin (122, Figure 24) is a NP produced by Pseudomonas
putida, and displays potent inhibitory activity against
Pseudomonas aeruginosa at nanomolar concentrations,215
while Gram-positive bacteria show no susceptibility to it.216
Promysalin acts by a unique mode of action that it could
inhibit the production of pyoverdine (a siderophore) in P.
putida KT2440, which can actively chelate Fe3+ for its end use
in enzymatic processes and is essential for the growth of
Pseudomonads. Wuest et al. synthesized 16 promysalin
analogues utilizing DTS (Figure 24).217 Several analogues
displayed comparable inhibitory activity against P. aeruginosa
to promysalin. For example, the simplified analogue 126,
obtained by removing the hydroxyl group in the side chain,
displayed potent inhibitory activity against P. aeruginosa strains
PAO1 and PA14 with an IC50 value of 5.8 μM and 0.035 μM,
respectively. The results determined the key structural features
responsible for bioactivity and highlighted the central role of
the intramolecular hydrogen-bonding network for binding with
iron.
3.3.3. Structural Simplification by Truncating Un-
necessary Substructures. 3.3.3.1. Structural Simplifica-
tion of Chaetocin. Chaetocin (127, Figure 25), a NP isolated
from the genus Chaetomium, is the first reported inhibitor of
protein lysine methyltransferase G9a (PKMT G9a).218 It is a
dimer composed of symmetric structures that contain eight
chiral centers. Due to the structural complexity and functional
group density, the total synthesis of chaetocin is highly
challenging. In the structural simplification of chaetocin,
Fujishiro et al. synthesized monomeric derivatives to
investigate the importance of the dimeric structure for the
activity (Figure 25).219 Interestingly, monomeric derivative
128 was a more potent PKMT G9a inhibitor (IC50 = 3.3 μM)
than chaetocin (IC50 = 7.2 μM). Further removal of the indole
moiety of analogue 128 afforded structurally simplified bicyclic
compound 129, which retained the PKMT G9a inhibitory
activity (IC50 = 5.2 μM) of the parent compound. Compared
with chaetocin, the structure of compound 129 was greatly
simplified and its toxicity was also significantly lower.
3.3.3.2. Structural Simplification of Largazole. Larga-
zole (130, Figure 26) is a depsipeptide NP that was isolated
from cyanobacterium Symploca sp. by Luesch and co-workers
in 2008.220 It displayed potent HDAC1 inhibitory activity with
an IC 50 value of 0.0137 μM and exhibited potent
antiproliferative activity and selectivity for cancer cells. In the
crystal structure of HDAC8 in complex with largazole thiol
(136, Figure 26B), the thiol side chain inserts into the binding
pocket and chelates the zinc in the active site with its thiol
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group.221 The macrocyclic depsipeptide subunit locates
outside the binding pocket and forms mainly hydrophobic
interaction with surrounding residues.221 Nan’s group
performed a structural simplification of largazole in which
the −CH2CONHCH2− group and the C7-methyl group were
eliminated to afford ring-opened analogue 131 (Figure 26).222
Compared with largazole, analogue 131 displayed decreased
HDAC1inhibitory activity, but it was more potent against
HDAC3 and HDAC6. A typical HDAC inhibitor has three
essential pharmacophoric features, namely, a recognition cap
group, a hydrophobic linker, and a zinc-binding group (ZBG).
Therefore, the long side chain of compound 131 was replaced
with the classic hydroxamic acid ZBG to afford a series of
analogues 132.222 Disappointingly, these hydroxamic acid
analogues displayed significantly reduced HDAC1 inhibitory
activity (IC50 values of 2.45−9.69 μM). Further structural
simplification, including the replacement of the chiral L-valine
moiety with a carbon chain linker, was conducted to afford
analogue 133, which displayed significantly improved inhib-
itory activity.222 Furthermore, analogue 134, containing a 2,2′-
bisthiazole moiety instead of the 2,4′-bisthiazole moiety,
showed a 2-fold increase in activity compared to that of
compound 133. Further structure modification of 134 afforded
analogue 135 via the introduction of a hydrophobic cyclo-
propyl group to the thiazole ring, and 135 displayed HDAC1
inhibitory activity (IC50 = 0.07 μM) comparable to that of
lagazole.222 Moreover, analogue 135 displayed potent and
broad-spectrum inhibitor activity against various HDAC
isoforms except HDAC7 and HDAC9. The simplified structure
of 135 has a smaller molecular weight and showed favorable
pharmacokinetic profiles characterized by high Cmax (7.04 μg/
mL) and AUC0‑t (12.07 μg·h/mL) values and excellent
absolute bioavailability (F% = 118.7%) in mice (20 mg/kg,
P.O.).222 Moreover, this compound showed in vivo efficacy in
ameliorating clinical symptoms of experimental autoimmune
encephalomyelitis (EAE) mice when administered orally. The
simplified largazole derivatives are currently under preclinical
evaluation for the treatment of various tumors.
3.3.3.3. Structural Simplification of Lobatamide C.
Lobatamide C (137, Figure 27) belongs to a unique class of
NPs with a common benzolactone core structure and a highly
unsaturated enamide side chain.223 This compound displayed
highly potent inhibitory activities against the NCI’s 60 cell-line
human tumor screen (mean panel GI50 values = 1.6 nM) along
with unique cellular response profiles.223 Mechanism studies
revealed that the salicylate enamide macrolides potently
inhibited mammalian vacuolar-type (H+)-ATPases (V-AT-
Pases), which are proton-translocating pumps ubiquitous in
eukaryotic cells.224−226 To clarify the minimal pharmacophores
required for V-ATPase inhibition, Porco et al. designed and
synthesized acyclic lobatamide analogues via opening the
lactone ring (Figure 27).227,228 Biological assays indicated that
simplified salicylate enamide analogue 138 displayed potent
inhibitory activity toward V-ATPase with an IC50 value of 0.1
μM.227 Analogue 139, with a steric prenyl substituent, showed
slightly higher activity (IC50 = 60 nM).228 The results
indicated that the simplification of lobatamide C was feasible
and that acyclic salicylate enamide V-ATPase inhibitors
required further optimization.
3.3.3.4. Structural Simplification of Sanglifehrin A.
Sanglifehrin A (SFA, 140, Figure 28), an immunosuppressive
NP isolated from Streptomyces sp. A92-308110,229,230 exhibited
high affinity (Kd = 6.9 nM) to cyclophilin A and inhibited the
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peptidyl-prolyl cis−trans isomerase (PPIase) activity of cyclo-
philin A (Ki = 12.8 nM) in a cell-free assay.231 It was
investigated as a potential treatment for hepatitis C virus
(HCV). However, SFA has a complex molecular structure
consisting of a 22-membered macrocycle bearing a nine-carbon
tether at the 23 position terminated by a highly substituted
spirobicyclic moiety, which poses a tremendous challenge for
the synthesis of new analogues. The crystal structure of SFA-
cyclophilin A complex revealed that the 22-membered
macrocycle scaffold formed a hydrogen bond network with
residues Gln63, Arg55, His126, and Asn102 (Figure 28B).232
In contrast, the terminal substituted spirobicyclic moiety was
oriented out of the binding domain, indicating that it was
unnecessary for the binding activity.232 For the structural
simplification of SFA, Wagner et al. performed the selective
oxidative cleavage of the C26C27 exocyclic double bond to
afford the spirolactam fragment and macrolide 141 (Figure
28).233 Biological assays indicated that macrolide 141
displayed potent binding affinity for cyclophilin (Kd = 29
nM), which was slightly less active than SFA, indicating the
macrocyclic portion of SFA was the key fragment for the
activity. Moreover, the removal of the C24 polyketide side
chain eliminated the immunosuppressive activity. Further
degradation studies afforded analogue 142, which has an
allylic alcohol side chain, and it displayed improved binding
affinity for cyclophilin (Kd = 5.7 nM).
On the basis of analogue 142, Schultz et al. performed a
further step-by-step structural simplification study (Figure 28,
Table 8).234 After analyzing the cocrystal structure of 142 with
cyclophilin A, they envisioned that the C23 and C14 side
chains and the two hydroxyl groups might be unnecessary
(Figure 28C).233 Therefore, the C23 and C14 side chains were
removed, and the two hydroxyls were methylated to afford
simplified analogue 143. This compound displayed potent
binding affinity for cyclophilin A (Kd = 25 nM) and sub-
micromolar antiviral activity in the HCV replicon cellular assay
(EC50 = 600 nM). Similar to 142, analogue 143 retained the
hydrogen bonding interaction with residues Arg55, Gln63,
Asn102, and His126 (Figure 28D).234 Furthermore, the C14
to C17 stereocenters were investigated using analogues 144−
145, which were synthesized in only a few steps. Biological
assays indicated that the chiral centers at C16 and C17 were
not essential for the activity. Subsequent replacement of the
C18−C21 diene unit with a styryl group led to potent
analogues 146 and 147. Analogue 147 displayed the most
potent binding affinity for cyclophilin A (Kd = 11 nM) and
sub-micromolar antiviral activity in the HCV replicon cellular
assay (EC50 = 36 nM). The crystal structure of analogue 147 in
complex with cyclophilin A displayed a novel binding mode in
which the m-tyrosine (m-Tyr) residue was displaced into the
solvent (Figure 28F).234 On the basis of this observation, they
further simplified the scaffold and replaced the m-Tyr with an
alanine to afford analogues 148 and 149. Analogue 148
displayed an excellent binding affinity for cyclophilin A (Kd =
24 nM) with potent cellular activity (EC50 = 87 nM),
confirming that the m-Tyr residue was unnecessary in these
new analogues. The binding mode of compound 148 was
similar to that of SFA, whose macrocycle moiety formed
hydrogen bonds with residues Asn102, Arg55, and Gln63
(Figure 28G).234 After removal of the C14 to C17 stereo-
centers of compound 148, analogue 149 only showed a 2-fold
decrease in binding affinity, and its cellular activity was
retained.
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3.3.3.5. Structural Simplification of Anguinomycin.
The polyketide NPs of the leptomycin family have attracted
substantial interest from chemists and biologists because of
their highly complex structure and excellent antitumor
activity.235,236 Unfortunately, drug development of leptomycin
B (150, Figure 29) failed in phase I clinical trials due to
toxicity to patients.237 In contrast, two related compounds,
anguinomycins C and D (151 and 152), showed excellent
antitumor activities at low nanomolar concentrations and
induced apoptosis in pRB-inactivated tumor cells while only
inducing growth arrest in normal cells.235,236 A mechanism
study revealed that these antitumor antibiotics inhibited the
nuclear export receptor chromosome region maintenance 1
(CRM1).238−240 Gademann et al. investigated the importance
of the polyketide side chain for the antitumor potency. After
the side chain was replaced with a simpler linear terpene,
compound 153 displayed similar activity in blocking
nucleocytoplasmic transport.241 Further reducing the length
of the polyketide side chain led to the very simple analogue
154, which effectively blocked nuclear export at 25 nM.241 The
simplicity, good synthetic accessibility, and excellent activity of
compound 154 make it a particularly attractive candidate for
further development.
3.3.3.6. Structural Simplification of Caprazamycin B.
Caprazamycin B (CPZ-B, 155, Figure 30), a nucleoside NP
extracted from the culture broth of the actinomycete
Streptomyces sp. MK730−62F2,242 demonstrated excellent in
vitro antimicrobial activity against both drug-susceptible and
multidrug-resistant Mycobacterium tuberculosis strains with low
toxicity to mice at single doses up to 200 mg/kg.242 CPZ-B was
a new member of the 6′-N-alkyl-5′-β-O-aminoribosoyl-C-
glycluridine class of antibiotics, which act by targeting
phospho-MurNAc-pentapeptide translocase (MraY) to block
the formation of lipid I and peptidoglycan biosynthesis.243−247
On the basis of its excellent biological properties, CPZ-B was
expected to be a promising antibacterial drug candidate.
However, the total synthesis of CPZ-B remains challenging.
Only recently have Takemoto et al. reported a 23-step total
synthesis for the related compound caprazamycin A.248 This
fact, combined with its extremely poor water solubility,
hampered the clinical development of this compound.249
Therefore, Matsuda et al. reported the rational simplification of
CPZ-B through FOS.247 First, the diazepanone ring of CPZ-B
was proven to be nonessential for the antibacterial activity.
Then, the diazepanone and aminoribose units were replaced
with an oxazolidine moiety to give oxazolidine analogue 156
(Figure 30). Biological evaluation revealed that compound 156
showed good antibacterial potency against drug-susceptible S.
aureus, E. faecalis, and E. faecium and drug-resistant bacterial
strains (e.g., MRSA and VRE strains) with MIC values ranging
from 2 to 16 μg/mL.247 Compound 156 can be synthesized in
just 12 steps, which makes it a good candidate for further
development.
3.3.3.7. Structural Simplification of Militarinone D. A
number of pyridone alkaloids with diverse bioactivities and
pharmaceutical relevance have been isolated from entomopa-
thogenic Deuteromycetes fungi. Among these compounds,
militarinone D (157, Figure 31) was discovered from a
mycelial extract of the entomopathogenic fungus Paecilomyces
militaris. (RCEF 0095) and identified through activity-directed
fractionation.250,251 Militarinone D showed potent neurito-
genic activity in PC-12 cells and significantly induced neurite
outgrowth in the absence of a nerve growth factor
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(NGF).251−253 In 2011, Gademann et al. reported a unified
approach for the stereoselective total synthesis of pyridine
alkaloids and evaluated their neuritogenic activities in a
standardized assay with PC-12 cells.254 The results revealed
that neither the side chain length nor the absolute
configuration was the essential pharmacophore. Therefore,
Gademann’s group synthesized truncated analogue 158 by
deleting the side chain, and this compound showed neurite
outgrowth activity comparable to that of militarinone D at 20
μM.255
3.3.3.8. Structural Simplification of Bistramide A.
Bistramide A (159, Figure 32) is a marine-derived NP isolated
from the ascidian Lissoclinum bistratum.256−258 In addition to
highly potent antitumor activity against A549 lung cancer cell
lines, bistramide A was also confirmed to alter the voltage
dependence of muscle twitch tension and inhibit Na+
conductance.259,260 Initially, bistramide A was thought to
selectively activate PKC δ.261 However, Kozmin et al. proved
that actin was the primary target of bistramide A.261,262
Structurally, bistramide A can be divided into three parts,
namely, C(19)−C(38) lipophilic subunit A, C(13)−C(18)
hydrophilic subunit B, and C(1)−C(13) reactive subunit C
(Figure 32A).263 The X-ray crystal structure of the actin-
bistramide A complex revealed that subunits A and B spanned
the entire deep binding cleft of actin through an network of
hydrogen bonds and van der Waals interactions (Figure
32B).264 In contrast, subunit C was oriented out of the binding
domain and faced to the solvent. Subunit C was proved to be
unnecessary for the binding affinity and could be trun-
cated.263,265 Thus, simplified analogue 160 was designed,
which simultaneously retained the G-actin affinity and reduced
the structural complexity of the parent compound.263
3.3.3.9. Structural Simplification of Withaferin A. The
withanolides constitute a class of NPs characterized by an
ergostane skeleton with a modified side chain in which carbons
22 and 26 are oxidized to form a δ-lactone.170 To date, over
600 members of this family have been isolated and
characterized, and they have shown a broad range of biological
activities including anti-inflammatory, antitumor, antimicrobial,
and immunoregulatory activities as well as antifeedant and
insecticidal activity.170,266 Withaferin A (161, Figure 33) was
the first withanolide analogue isolated from Withania somnifera
Dun (Solanaceae) by Lavie in 1965.267 The compound was
reported to trigger apoptosis and largely suppress cell
migration/invasion in MDA-MB-231 human breast cancer
cells depending on the inhibition of STAT3 phosphoryla-
tion.268 Withacnistin (162, Figure 33), a C18-functionalized
derivative of withaferin A, was also identified as a potent
STAT3 inhibitor and induced regression in breast tumor
cells.268,269 Considering their potent inhibitory activities
against STAT3, withaferin A and withacnistin were inves-
tigated as potential lead compounds for antitumor drug
discovery. The FOS approach was applied to synthesize
simplified withaferin A analogues with maintained or improved
biological activity.270 After truncating of the δ-lactone side
chain, compound 163 showed STAT3 inhibitory activity
(more than 50% inhibition of STAT3 phosphorylation at 1
μM) comparable to that of compound 161 in MDA-MB-231
breast cancer cell lines.
3.3.3.10. Structural Simplification of Rakicidin A.
Tumor hypoxia is a common feature of most tumors and is
highly correlated to poor prognosis of cancer patients owing to
its multiple contributions to chemo-resistance, radio-resistance,
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and metastasis.271,272 Rakicidin A (164, Figure 34) is a
macrocyclic depsipeptide isolated from culture broth of
Micromonospora sp. strain R385-2.273 In 2011, Ashihara’s
group demonstrated that rakicidin A exhibited selective growth
inhibitory activity against hypoxic cancer cells and inhibited
the proliferation of imatinib-resistant, hypoxia-adapted chronic
myelogenous leukemia (HA-CML) cells by inducing apopto-
sis.274 Structurally, rakicidin A is a cyclic depsipeptide
consisting of 4-amino-penta-2,4-dienoic acid (APD, red in
Figure 34), 3-hydroxy-2,4,16-trimethylheptadecanoic acid,
sarcosine, and β-hydroxyasparagine (β-HOAsn) moieties.
This compound belongs to the APD-containing cyclolipodep-
sipeptide (APD-CLD) class of NPs with five chiral centers.275
Due to its structural complexity and unique biological activity,
rakicidin A is of particular interest for both synthetic and
medicinal studies. Chen et al. reported the first total synthesis
of rakicidin A and determined that the absolute configuration
of rakicidin A is 2S,3S,14S,15S,16R.276 SAR studies revealed
that the APD functionality was essential for the biological
activities of rakicidin A.276−279 Guided by the SAR, Poulsen et
al. synthesized simplified analogue 165 by pruning the β-
HOAsn side chain and the C14 and C16 methyl groups, and
this derivative showed potent and selective growth inhibition
under hypoxic conditions with a GI50 value of 352 nM.279
Although the potency was 10-fold lower, compound 165
showed better hypoxic selectivity (>67-fold) than rakicidin A.
3.3.3.11. Structural Simplification of Spongistatins.
The spongipyran NPs, such as spongistatin 1 (166, altohyrtin
A, Figure 35) and spongistatin 2 (167, altohyrtin C, Figure
35), are a unique family of bis(spiroacetal) macrolides which
were isolated from marine sponges in the early 1990s.280−283
They displayed exceptional cytotoxicity against a wide range of
human cancer cell lines, acting by interfering with tubulin
polymerization.284 Spongistatin 1 had an average IC50 of 0.13
nM against the panel of 60 cancer cell lines, which was thought
to be the most potent antiproliferative agent ever discov-
ered.285 Although it shows great promise in cancer chemo-
therapy, the extreme scarcity of natural supply and synthetic
difficulty have halted its further preclinical development. In
order to obtain SAR and identify the spongipyran pharmaco-
phore, several groups devoted their efforts to simplify this
highly complex NP. Smith et al. reported two simplified
analogues (compounds 168 and 169) bearing the F ring and
the C44−C51 triene side-chain.286 However, these analogues
only displayed micromolar inhibitory activity against several
human cancer cell lines. Furthermore, the same group
synthesized the AB-spiroacetal spongistatin derivatives 170
and 171.287 Neither of them had significant cytotoxic or
antitubulin activity. Smith et al. synthesized two diminutive
derivatives of spongistatin 1 (172 and 173, Figure 35).285
Analogue 172 displayed no significant cytotoxic activity (IC50
> 1 μM). In contrast analogue 173 displayed potent cytotoxic
activity against U937 (IC50 = 60 nM) and MDA-MB-435 (IC50
= 83 nM).
A less drastic simplification of spongistatin 1 was performed
by Paterson et al.288 After dehydration at E-ring C35 position,
compound 174 (Figure 36) showed enhanced cytotoxicity at
the low picomolar level (Table 9), whereas truncation of the
side-chain at C46 (compound 175, Figure 36) resulted in an
obvious decrease of the activity (Table 9).288 The SAR
revealed that E-ring modification could be tolerated instead of
F-ring side-chain truncation. Furthermore, Wagner et al.
synthesized several structurally simplified analogues containing
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Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews
only part of the spongistatin structure.289 However, truncation
of C1−C28 (176 and 177) and replacement of the two
spiroketals and their associated functionality by a simple alkane
linker (lactone 178) led to loss of the activity. Similarly,
replacing C, D rings or E, F rings by the alkane linker (179 and
180) also resulted in weak cytotoxicity (Figure 36).
3.3.3.12. Structural Simplification of Migrastatin.
Tumor metastasis is one of the main causes of death in cancer
patients. Migrastatin (181, Figure 37), a novel 14-membered
lactone isolated from Streptomyces sp. MK-929−43F1, showed
moderate antimetastatic activity (IC50 = 29 μM) against 4T1
mouse breast tumor cells.290,291 Despite the modest potency,
Danishefsky and co-workers envisioned that migrastatin could
be used as a lead compound to discover more potent
antimetastatic and antiangiogenic agents. They reported the
first total synthesis of migrastatin and then performed
structural simplification studies using the DTS approach
(Figure 37).292−295 After removal of the glutarimide side
chain, simplified analogues 183 and 184 were 1000-fold more
potent than migrastatin. These compounds significantly
inhibited cell migration in 4T1 mouse breast cancer cells
with IC50 values of 22 nM and 24 nM, respectively.
Interestingly, these analogues did not show any cytotoxic or
antiproliferative activity up to 20 μM.292 On the basis of
analogue 183, further structural simplification was performed
by modifying the ester group. Analogues 185 and 186 retained
potent antimetastatic activity in MDA-MB-435 breast cancer
cells with an IC50 value of 0.10 μM and 0.37 μM, respectively.
Moreover, 186 showed good in vivo potency by significantly
reducing the metastasized MDA231 cells (87%) in a pretreated
mice group. It could not attenuate tumor growth, which
indicated the inhibition was not related to cytotoxicity.295 To
elucidate its mechanism of action, Chen et al. demonstrated
that migrastatin analogues targeted actin-bundling protein
fascin to block tumor metastasis using an affinity protein
purification approach (Figure 37B).296
3.3.4. Recent Examples of Structural Simplification.
Besides the case studies described above, examples of
structurally simplified NPs reported in recent years are
summarized in Table 10.
4. CONCLUSIONS AND PERSPECTIVES
The design of “low-fat” drug-like molecules by structural
simplification represents a powerful strategy in drug discov-
ery.25−27 Structural simplification is particularly useful in NPs-
based drug development because NPs are challenging for
direct drug development because of their complex structures,
abundant chiral centers, difficult total syntheses, and
unfavorable ADMET profiles. The structural simplification of
NPs has yielded several marketed drugs highlighting its utility
in drug development. Recently, numerous NPs with extremely
complex structures, particularly marine NPs, have been shown
to possess highly potent biological activities. These NPs usually
have a MW greater than 1000 and more than 5 chiral centers,
which pose great challenges in total synthesis and drug
development. Structural simplification of these extremely
complex NPs is highly desirable. Another important area for
structural simplification is the development of new anti-
bacterial agents, which require three-dimensionality, but
complex structures are difficult to synthesize and commerci-
alize. Although progress has been made, successful examples of
structural simplification are rather limited, and more medicinal
chemistry efforts need to be devoted in this important field.
AE
Review
Besides DOS, DTS, and FOS, the development of new
highly efficient synthesis methods,111,309 such as chemical or
molecular editing310 and dynamic strategic bond analysis,311
will provide a deep understanding of SAR and biological
functions of complex NPs, and lay an important foundation for
structural simplification. These types of approaches are
particularly useful in the development of antibacterial NPs,
which require three-dimensionality to retain the activity.312,313
They offer a new opportunity to solve the difficulty in
synthesizing complex structures and their simplified analogues.
Moreover, new technologies are still highly desirable for
improving the efficiency of structural simplification. In
particular, the BIOS strategy employs biologically relevant
structural information encoded in complex NPs to guide the
simplification of NP structures.171 Computational tools for the
fragmentation of NPs enable hierarchical structuring, visual-
ization, and analysis of complex structures and bioactivity data,
and the identification of simplified scaffolds with desirable
activities. The resulting NP fragments have been proven to be
a rich source of bioactive molecules.4
Ideally, structural simplification should identify less
complicated molecules that retain the biological activity of
the parent compound. However, simplified molecules were
often less active than the lead compound at the molecular or
cellular level. Thus, the success of structural simplification
needs to be evaluated in terms of the balance between the
synthetic accessibility, in vitro activity, in vivo potency,
physicochemical properties, PK profiles, and so on. For most
simplified molecules, reoptimization is required to improve the
efficacy and drug-likeness. More importantly, reductions in
structural complexity will lead to simplified analogues with new
bioactivities and new targets. Target identification by chemical
biology approaches is important for drug development. With
the advancement of synthetic, computational, and biological
approaches, structural simplification will play an increasingly
important role in drug discovery and contribute to improving
the efficiency and success rate of drug development.
AUTHOR INFORMATION
Corresponding Author
*Phone/Fax: +86 21 81871239. E-mail: shengcq@smmu.edu.
cn.
ORCID
Shengzheng Wang: 0000-0002-2383-2673
Chunquan Sheng: 0000-0001-9489-804X
Author Contributions
#
S.W. and G.D. contributed equally to this perspective.
Notes
The authors declare no competing financial interest.
Biographies
Shengzheng Wang received his bachelor’s degree in pharmacy (2009)
and Ph.D. in medicinal chemistry (2014) from Second Military
Medical University. Since 2014, he has been a lecturer in the
Department of Medicinal Chemistry, School of Pharmacy, Fourth
Military Medical University. His research interests include antitumor
drug discovery and organocatalysis.
Guoqiang Dong received his bachelor’s degree in pharmacy (2008)
and Ph.D. in medicinal chemistry (2013) from Second Military
Medical University. Since 2013, he has been a lecturer in the
Department of Medicinal Chemistry, School of Pharmacy, Second
DOI: 10.1021/acs.chemrev.8b00504
Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews Review

Military Medical University. His current research is focused on the bFGF basic fibroblast growth factor
modification and scaffold hopping of natural products and multi- V-ATPases vacuolar-type (H+)-ATPases
targeting antitumor drugs. SFA Sanglifehrin A
Chunquan Sheng received his bachelor’s degree in pharmacy (2000) HCV hepatitis C virus
and Ph.D. in medicinal chemistry (2005) from Second Military FtsZ filamenting temperature-sensitive protein Z
Medical University, after which he worked as a faculty member in the CHIKV Chikungunya virus
same university. From 2014 to 2015, he worked as a visiting scholar at CRM1 chromosome region maintenance 1
Department of Chemistry and Chemical Biology in University of New CPZ-B caprazamycin B
Mexico, USA. He is currently Professor and Director of Department MraY phospho-MurNAc-pentapeptide translocase
of Medicinal Chemistry and the Vice Dean of School of Pharmacy, NGF nerve growth factor
Second Military Medical University. Professor Sheng’s research HA-CML hypoxia-adapted chronic myelogenous leukemia
interests mainly include rational drug design and natural products- APD 4-amino-penta-2,4-dienoic acid
inspired drug discovery focusing on antifungal and antitumor agents. β-HOAsn β-hydroxyasparagine
He was supported by several talent programs in China including APD-CLD APD-containing cyclolipodepsipeptide
National Outstanding Young Scholarship (NSFC) and Young Chang SOAT sterol O-acyltransferase
Jiang Scholar (MOE). SHH sonic hedgehog
SMO smoothened
PB pladienolide
ACKNOWLEDGMENTS Top topoisomerase
This work was supported by the National Natural Science MptpB Mycobacterium tuberculosis protein tyrosine phos-
Foundation of China (Grants 81725020 to C.S. and 21602252 phatases B
to S.W.), the National Key R&D Program of China Hh hedgehog
(2017YFA0506000 to C.S.), and the Hong Kong Scholars
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AO DOI: 10.1021/acs.chemrev.8b00504
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