2016

NPC Natural Product Communications Vol. 11

No. 9
A Survey of the Chemical Compounds of Piper spp. (Piperaceae) and 1403 - 1408
Their Biological Activities
Cai-Peng Xianga, Yan-Ni Shib, Fang-Fang Liub, Hai-Zhou Lia, Ying-Jun Zhangb, Chong-Ren Yangb,c and
Min Xua*
a
Center for Pharmaceutical Sciences, Faculty of Life Science and Technology, Kunming University of Science and
Technology, Chenggong Campus, Kunming, P. R. China 650500
b
State Key Laboratory of Phytochemistry and Plant Resources of West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming, P. R. China 650201
c
Center for Drug Discovery & Technology Development of Yunnan Traditional Medicine,
Yunan Academy of Science, Kunming, P. R. China 650101

xumin8121@hotmail.com

Received: April 20th, 2016; Accepted: June 14th, 2016

The genus Piper is one of the largest genera in the Piperaceae, with most species widely distributed globally, covering all continents. To date, many Piper
species have been scientifically investigated for their chemical diversities and interesting broad spectrum of bioactivities, including central nervous system
(CNS), pesticidal, antifungal and antibacterial effects. This review systematically summarizes the scaffolds of the alkaloids reported, the major chemicals
isolated from Piper spp., and their biological activities. Besides the alkaloids, some neolignans with rearranged skeletons show structural diversities, while the
chalcones, flavonoids and kava-pyrones have some potential activities. Herein, the sesquiterpenes and phenolic compounds from Piper species and their
bioactivities are also surveyed.

Keywords: Piper, Amides, Sesquiterpenes, Phenolic compounds, Biological activities.

Piper, comprising more than 2000 species, is the largest genus in
the family Piperaceae, with most species growing in the tropics,
although some extend into the subtropical zone [1]. Most Piper
species are famous due to their delicious taste and biological
activities [2]. For example, the fruits of P. nigrum are one of the
important flavorings in the world [3].The leaves of P. betle have
been used as a wrap for foods by local minorities [4]. The roots and
rhizomes of P. methysticum, known as kava, are used as a beverage
to relieve pain and reduce stress by people living in the South
Pacific tropical islands. In Germany, kava (P. methysticum) is a
very popular herbal preparation for the treatment of anxiety[5].
Systematic phytochemical investigations of the genus Piper have
been made since the 1960s [6, 7]. The secondary metabolites from
Piper plants, not only because of their promising bioactivities, but
also their novel skeletons, attracted natural product chemists to
study this genus. To date, almost 400 structural and biologically
diverse compounds have been isolated from the genus. Most of
them are alkaloids, lignans, flavones, chalcones, phenylpropanoids
and kava-pyrones.
A review of piperidines and their occurrence in Piper species was
published almost 30 years ago [8]. Since then, more than 200 papers
have appeared relating to the secondary metabolites and their
bioactivities of more than 70 Piper species, for example, P. longum
[9, 10], P. methysticum [11-14], and P. betle [15-17]. In addition,
some publications summarized the chemical and biological
characteristics of the amides of Piper spp. [2, 18]. However, none
gave a general insight into the chemical constituents of the genus
Piper and their biological activities.
As part of our comprehensive efforts to search for compounds from
Piper plants and their biological activities [19, 20], herein were
viewed the compounds that have been reported in the literature from
1939 until Dec. 2015, concerning the chemistry of the genus Piper
and their biological activities. All structures of the compounds are
shown in the Supplementary, Figures 1–13, and their names and the
corresponding plant sources are compiled in Supplementary Tables
1–7.
Alkaloids
Various amide alkaloids from Piper species bear isobutyl,
pyrrolidine, dihydropyridone, piperidine and benzylamine moieties.
In addition, some aristolactams and dimeric amides were isolated
from Piper species (Supplementary, Tables 1–6 and Figures 1–7).
These alkaloids have generated interest as a result of their potent
biological activities, e.g. insecticidal, antibacterial, and anti-
depressive.
Isobutyl-type
As the major alkaloids in Piper plants, the isobutyl-type featured in
an amide unit bearing an isobutyl group mainly relate to two types,
aliphatic chain amides and isopentyl amides (Figure 1). Both types
showed potential biological activities, especially insecticidal
properties against the fourth instar larvae of Aedes aegypti [21-23],
female adults of Culex pipiens pallens and A. aegypti [24].
Moreover, some of them exhibited mild activity against
Mycobacterium tuberculosis H37Ra [25] and an anti-HIV effect on
ΔTat/RevMC99 virus and the 1A2 cell line system [26]. The amide
group and the aliphatic chain could be the key domain for the
insecticidal activities of the compounds, while the methylenedioxy
phenyl unit might be a synergistic group. Several isobutyl-type
amides weakly inhibited cell proliferation of breast cancer (MCT-7)
and human leukemia (HL-60) cell lines and displayed major
apoptosis-inducing effects [27, 28]. Among them, the isopentyl
amides possessed more biological diversities than that of amides
only bearing a long chain. The isopentylamides showed potential
inhibition of Bacillus subtilis, B. sphaericus and Staphylococcus
1404 Natural Product Communications Vol. 11 (9) 2016
aureus amongst Gram-positive bacteria, Klebsiella aerogenes and
Chromobacterium violaceum amongst Gram-negative bacteria [29],
and Candida tropicalis [30] and Cladosporium sphaerospermuma
[31] amongst fungi, as well as antileishmanial activities [32], while
it exhibited low toxic effects to Vero cells and macrophages.
Moreover, the isopentyl amides may be used for the treatment of
atherosclerosis, because of their inhibition of cholesterol
esterification in HepG2 cells in the ACAT (cholesterol
acyltransferase) enzyme assay system using rat liver microsomes
[33]. The isopentyl amides also showed antidepressant and
antinociceptive effects in forced swimming, open field, acetic acid
writhing and formalin tests in KM mice [34]. It is reported that the
isopentyl amides with the longer aliphatic chain significantly
inhibited ethanol induced gastic lesions at a dose of 25 mg/kg, p.o.,
while the ones with the shorter aliphatic chain inhibited
indomethacin-induced gastric lesions at the same dose [35]. Among
them, two isobutyl-type amides, pellitorine (1) and guineensine (2)
(Figure 1), are the ones with the strongest activities and most
biological diversity. Moreover, leatispiamide A (3) and laetispicine
(4) (Figure 1) showed a significant antidepressant-like effect at a
dose of 60 mg/kg. The double bond from the benzene ring and
conjugated double bond located at 2–3 and 4–5 in the molecular
structure were necessary for its antidepressant activities [34].
Figure 1: The skeletons of isobutyl-type amides and the active amides.
Pyrrolidine-type
Pyrrolidines were the other typical major chemical constituents of
Piper spp., which featured in an amide unit bearing either a pyrrole
or tetrahydropyrrole group (Figure 2). Compared with isobutyl
amides, few pyrrolidines showed insecticidal properties. However,
some of them have antituberculosis and antiplasmodial activities
[25]. They also showed antibacterial activities against B. subtilis, B.
sphaericus, S. aureus (Gram-positive bacteria), K. aerogenes and C.
violaceum (Gram negative bacteria) [29], and antifungal activities
against C.sphaerospermuma [31], e.g. piperamine (5). Moreover,
tricholeine (6) from P. nigrum inhibited cytochrome P450 2D6
(CYP2D6) in human liver microsomes [36].Chaplupyrrolidones A
(7) and B (8) contain a 5-oxygenated-Δ3-2-pyrrolidone moiety,
which revealed potent inhibition of α-glucosidase [37]. 1-(m-
Methoxycinnamoyl) pyrrolidine (9) and cinnamopyrrolidide (10)
displayed the most potent inhibition activity of platelet aggregation
induced by collagen [38]. Furthermore, it was reported that
piperlongumine could result in cancer cell death through the
MEK/ERK pathway [39], or trigger autophagic cell death through
the ROS-p38 pathway [40].
Piperidine-type
Piperidines were a new group of alkaloids that emerged in 1819
following the isolation of piperine from the fruits of P. nigrum. To
date, hundreds of piperidine-type amides have been isolated. Very
recently, a review of piperidine-type amides from Piper was
focused on the chemical and biological characteristics [18].The
piperidine-type amides showed structural and biological diversities
(Figure 3). These bioactivities were generally in two areas: as
pesticides for agricultural use [24, 41, 42], and as medicines to
fight Infections [31, 43], tumors/inflammation, obesity/diabetes,
depression and other human and animal physiological disorders
Xiang et al.
Figure 2: The skeletons of ofpyrrolidine-type amides and active ones.
[18, 27]. Among them, 8,9-dihydropiplartine (11) had potential
activities as an antifungal agent against C. sphaerospermuma with
an MIC value of 0.1 µg, which was stronger than that of the positive
control (MIC 0.5 µg) [31]. The conjugated double bonds of the
piperidine ring might be the synergistic group for its antifungal
activities. However, for the activity of gastric lesions protection, the
conjugated double bonds of the aliphatic chain were likely to be the
key structure. For example, (E,E)-piperidine (12), (E,E,E)-
dehydropipernonaline (13) and pipernonaline (14) significantly
inhibited indomethacin-induced gastric lesions at a dose of 25
mg/kg, while piperanin (15) significantly inhibited ethanol-induced
gastric lesions at the same dose [35]. 3β,4α-Dihydroxy-1-(3-
phenylpropanoyl)-piperidine-2-one (16) possessed a remarkable
inhibitory activity against the secretion of hepatitis B virus surface
antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) with a
selectivity index value of 16.4 and an IC50 value of 0.21 mM [44].
Piperodione (17) was found to enhance the neurite outgrowth of
NGF-mediated PC12 cells at concentrations ranging from 0.1 to 10
μM [45]. Besides, two amides, piperine and 4,5-dihydropiperine
were isolated from P. capense, which is traditionally used as a sleep
inducing remedy in South Africa. Both of them showed moderate
affinity for the benzodiazepine site on the GABAA receptor with
IC50 values of 1.2 mM and 1.0 mM, respectively. Preliminary SAR
analysis suggested that the carbon chain must contain no less than
four carbons, and that a conjugated double bond, adjacent to the
amide group, is necessary for binding to the receptor and that the
amine part should be bulky [46].
Figure 3: The skeletons of piperine-type amides and active ones.
Dimeric amides
Dimeric amide alkaloids, normally possessing a cyclohexene ring,
were one of the novel compounds in Piper plants (Figure 4). The
biosynthetic hypothesis of the dimers was proposed by an
intermolecular Diels-Alder reaction from the corresponding
monomeric amides [47]. To date, around 36 amide dimers have
been reported from Piper spp. Compared with amide oligomers, the
dimers showed weak insecticidal and antibacterial activities [48, 49].
However, some of the dimers showed potential activity for
inhibition of drug metabolism. For example, dipiperamides D (18)
and E (19) inhibited the drug metabolizing enzymes cytochrome P
450 (CYP) 3A4 and CYP4503A4 with IC50 values of 0.79 and 0.12
µM, respectively [50]. Nigramide G (20) and pipercyclobutanamide
A (21) exhibited potent cytotoxic activity against colon (COLO-205)
Chemical compounds of Piper spp.
cancer cell lines with IC50 values of 0.018 and 3.10 mg/mL,
respectively [51]. Pipercyclobutanamide A (21) showed inhibition
of CYP450 2D6 with an IC50 value of 0.34 µM [36]. The results
suggested that Piper plants could enhance the bioavailability of
foods and drugs as a carminative. Further results suggested that the
dimeric amides inhibited the growth of cancer cells and induced
apoptosis, at least in part, through the Akt/MAPK pathway [52].
Figure 4: The skeletons of amide dimers and the active amide dimers.
Other amides
Other amides reported from Piper plants exhibited toxicity to fourth
instar larvae of A. aegypti, e.g. pipzorine (22) [23], homopellitorine
(23), pipyahyine (24) and pipnoohine (25) [42, 53]. Moreover,
taiwanamide B (26) and Z-N-feruloyltyramine (27) exhibited potent
inhibition of platelet aggregation induced by collagen [38].
Figure 5: The skeleton of other-type amides and active ones.
Aristolactam-type
Aristolactam-type alkaloids were, typical compounds found in
Aristolochia spp., also isolated from Piper plants. Tabopda et al.
suggested that the two aristolactam-type alkaloids, cepharadiones A
(28) and B (29), found in some Piper plants, could be considered as
chemotaxonomic markers of the genus [54]. Until now, almost 20
aristolactam-type alkaloids have been reported in Piper, some of
them exhibited cytotoxic activities, e.g. cepharadione A (28), a
naturally occurring DNA damaging agent [55]. Furthermore, 3-
demethoxypiperolactam C (30) showed HIV-1 activity inhibition
[26]. Noraristolodione (31), piperolactam E (32) and piperolactam
B (33), at doses of 100 µg/mL, exhibited stronger anti-platelet
aggregation activities induced by arachidonic acid than 4-
allylcatechol and eugenol [56].
Figure 6: The skeletons of aristolactam-type alkaloids and active alkaloids.
Natural Product Communications Vol. 11 (9) 2016 1405
Sesquiterpenes
Sesquiterpenes were the main constituents of the essential oils of
Piper species. Some novel sesquiterpenes have been isolated from
Piper plants including capentin (34), from the roots of P. capense
[57], nudibaccatumone (35) from P. nudibaccatum, a novel trimer
comprising a phenylpropanoid and two sesquiterpene moieties [58],
and ishwarol (36) from P. amalago [59, 60]. β-Caryophyllene oxide
(37) from black pepper (P. nigrum) inhibited human prostate (PC-3)
and breast cancer cell (MCF-7) growth and induced apoptosis
through the suppression of the PI3K/AKT/mTOR/S6K1 pathways
and ROS-mediated MAPKs activation [61].
Figure 7: Novel sesquiterpenes from Piper spp..
Phenolic compounds
Some phenolic compounds have been isolated from Piper species,
including lignans, neolignans, chalcones, flavonoids, flavonones,
phenylpropanoids, benzoic acid derivatives and kava-pyrones.
Among them, the lignans and neolignans showed structural
diversities, while chalcones, flavonoids and kava-pyrones showed
some potential activities. To date, more than three types of lignans
and neolignans have been reported in Piper. Further oxidation of
the propane chains, together with additional oxygen ring formation
can lead to several hydroxy-, oxy-, andoxo- forms of each of the
types (Supplementary, Table 7 and Figure 11). It is noteworthy that
some rearranged neolignans of the macrophyllin-type bicycle [3.2.1]
octanoid neolignans (Figure 8) have been reported from Piper, e.g.
kadsurenin L (38) [62], puberulins A-C (39–41) and piperkadsin C
(42), bearing C-8 bridged to C-3' and C-5' [63]. In addition,
piperwalliol A (43), with an additional aromatic ring, was reported
from a Piper species, which represented the first example
possessing a 5/6/5/6 ring system [20]. Although the phenolic
compounds from Piper showed biological activities, including
larvicidal [64, 65], anti-inflammatory [66], anti-platelet aggregation
[67, 68], anti-tuberculosis [69], antifungal [70] and antibacterial [4,
71-74] activities, these were mostly either weak or mild.
Figure 8: The neolignans from Piper species.
Of the chalcones, flavokawains A-C (44–46) from P. methysticum,
commercially known as kawa-kawa, hold promising anti-cancer
effects. Experimental data indicated that flavokawains A (44) and B
(45) were involved in the arresting of the cell cycle in several
cancer cell lines [75]. Furthermore, several novel dihydrochalcones,
adunctins A-E (47–51), were isolated from P. aduncum, which
featured substitution by a cyclized monoterpene [76].
Figure 9: The monoterpene-substituted dihydrochalcones from Piper species.
1406 Natural Product Communications Vol. 11 (9) 2016 Xiang et al.

In 1939, the narcotic properties of kawa-kawa (P. methysticum)
were first observed, which also as an intoxicating beverage widely
consumed by the indigenous peoples of the islands of the South
Pacific [77]. Kava-pyrones were shown to be the major active
compounds, e.g. kavain (52), methysticin (53), dihydrokavain (54),
and dihydromethysticin (55) [78]. It was reported that the
kavapyrones, (+/-)-kavain (52) and (+)-methysticin (53) inhibited
voltage-operated Na+-channels in rat CA1 hippocampal neurons
[79]. Kavain (52) could also affect the voltage-dependent Ca2+
channel [80]. Furthermore, in 1994, it was reported that kava-
pyrones might mediate the sedative effects in vivo through effects
on GABAA receptor binding sites [78], while it had been reported
that the neuropharmacological activities of kava resin and pyrones
did not appear to be explained by any significant interaction with
GABA or benzodiazepine binding sites [81]. Kavain (52) and
dihydromethysticin (55) might enhance the effects of the anxiolytic
serotonin-1 A agonist ipsapirone and active NMDA receptors
and/or voltage-dependent Ca2+ channel [82]. P. methysticum extract
(containing 30% kavalactones) exhibited anxiolytic effects, of
which dihydrokavain (54) was the major active constituent
attenuating separation-induced distress vocalizations [83].
Figure 10:The active chalcones and pyrones from Piper species.
Other compounds
Furthermore, a few piperolides and cyclopentendiones have been
isolated from Piper spp. [84]. Among them, the cyclopentendiones
showed strong antifungal activities, of which coruscanone A (56),
isolated from P. coruscans, exhibited significant activity against
Candida albicans and its azole-resistant strains and may serve as a
template for a new class of antifungal agents [85, 86]. The
piperolides, 4,6-dimethoxy-5-E-phenylbutenolide (57) and 4,6-
dimethoxy-5-Z-phenylbutenolide (58), also showed antifungal
activities against Cladosporium cladosporioides and C.
sphaerospermum, while the E configuration had higher activity than
the Z configuration [87].
Figure 11: Other compounds from Piper species.
Conclusion: Except for insecticidal, antibacterial, antidepressive,
antifungal and cytotoxic activities, the amides from Piper possessed
bioavailability-enhancing activity with various structurally and
therapeutically diverse drugs [88, 89]. Therefore, the amide
alkaloids are the predominant constituents of Piper spp. which have
attracted attention as one of the hot research topics from both
natural products and synthetic chemists. In addition, the phenolic
compounds from Piper plants showed an interesting skeleton, e.g.
the rearranged neolignan and the dihydrochalcones fused with a
cyclized monoterpene. A few of the phenolic compounds also
showed promoting activities. For example, the kava-pyrones might
affect both GABAA and NMAD receptors, as well as sodium and
calcium channels. However, the mechanisms of many active
chemical compounds from Piper spp. are still unclear. As one of the
important plant resources, new research strategies should be further
explored to find the new and active chemical compositions of Piper
spp. to use in agriculture as pesticides and in medicine as drug leads.
The mechanism of actions of bioactive compounds in Piper spp.
should also be further investigated.
Acknowledgments - This work was supported by the NSFC
81273408, the National Science and Technology Support Program
of China (2013BAI11B02), and the Fourteenth Candidates of the
Young Academic Leaders of Yunnan Province (Min XU,
2011CI044).

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