PHYTOCHEMISTRY OF ALKALOIDS

Dr. SALWA M.RAWEH

LECTURE IV

4th YEAR OF PHARMACY.

V- Morphinans alkaloids

The oxidative coupling, which is the fundamental

reaction allowing the biosynthesis of BBTHIQ, can
also occur at intra-molecular level. This coupling
takes place between any phenolic OH groups,
between a phenolic OH group and a carbon in
ortho or para to another OH group, or between
two carbon atoms either in ortho or para position
to the OH groups. When this coupling takes place
within a molecule, a large number of combinations
are possible, that is, a large number of skeletons
can be biosynthesised.
Isoquinoline alkaloids are no exception: a
variety of skeletons can derive from a simple
benzyltetrahydroisoquinoline precursor.
However, only one group is of significant
pharmaceutical importance, the morphinans.
This group is biosynthesised via an oxidative
coupling between C-4a and C-10 atoms of a
BTHIQ precursor.
This type of alkaloids is specific to the sole genus
Papaver, from the Papaveraceae family. One plant
is especially important by many respects:
 OPIUM POPPY = PAPAVER SOMNIFERUM L.
(PAPAVERACEAE)
• Botany: The opium poppy is an annual herb,
about 1.5 m high. It bears a large solitary flower; its
colour varies from white, red or purple depending
on the cultivar.
The ovary is superior, unilocular. It results from the
merger of the carpels (8 to 12 of them). The
stigmas form a disk at the top of the capsule.
• Production of the alkaloids: Opium is obtained by
incision of the unripe capsule and harvest of the latex
coagulated on its surface. Morphinan alkaloids can
also be extracted from the straw of the poppy; this is
currently the chief licit source for these
• Composition of opium: Opium contains more than
30 alkaloids, the major constituents are:
- Morphine, 10-12% w/w, chief component.
- Codeine (3-O-methylmorphine), 1-4%.
- Thebaine (3,6-O-dimethyl-dehydromorphine), 0.2-
2%.
- Other isoquinoline alkaloids of various structures.
substances.
• Uses of the opium alkaloids:
- Morphine is the most powerful analgesic. It is used as
sulphate salt in tablets (10 to 60 mg/tablet), sustained
release capsules (20 to 100 mg/capsule), injectable
ampoules (10 and 15 mg/mL). However, the major part of
the morphine is produced to be converted by semi-
synthesis into derivatives, such as codeine, codethyline,
pholcodine or various morphine antagonists, not to
mention the illegal production of heroine or
diacetylmorphine.
- Codeine, as phosphate salt, is part of the formulation of
numerous antitussive preparations, and in analgesic and
antipyretic combinations with paracetamol.
- Thebaine is converted by semi-synthesis into
various morphinic derivatives.
- Methylnaltrexone bromide is a
-opioid receptor antagonist and used for the
treatment of opioid-induced constipation. It
blocks peripheral opioid receptors activated by
opioids administered for pain relief but does
not have pain-relieving properties and does
not penetrate the blood brain barrier.
VI- Protoberberine alkaloids
Protoberberines are tetracyclic quaternary ammonium
alkaloids, usually intense yellow. The corresponding
tertiary amine alkaloids are the
tetrahydroprotoberberines, which are colourless. The
extra carbon atom originates from the incorporation of
the N-methyl group of the BTHIQ precursor. According to
the orientation of the benzylic ring of precursor, the
protoberberine is substituted in positions 2,3,9,10 or
2,3,10,11.
Protoberberines are quite widely distributed
within the families known to contain
isoquinoline alkaloids, e.g. Berberidaceae,
Menispermaceae, Ranunculaceae,
Annonaceae, Papaveraceae, etc. Yet,
protoberberines are often further
metabolised by the plants, hence leading to
a variety of structures, which are more or
less specific of some genera or families.
Some common protoberberines are shown
below:
In spite of interesting pharmacological properties
displayed by some protoberberines, these
compounds do not play any major role in
therapeutics. Yet, they are worth to be mentioned
since they are frequently found in plants used as
traditional remedies
. Two examples of plants used in traditional Malay •
medicine are given below:
TREE TURMERIC, MENGKUNYIT (= MERKUNYIT,
SEKUNYIT, KEKUNYIT, TUBA KUPAK): COSCINIUM
BLUMEANUM MIERS. (MENISPERMACEAE) .
This plant is a long and strong woody climber, •
with large peltate leaves. The cross section of the
stem is bright yellow (hence its name), due to the
presence of large amounts of protoberberines
(palmatine, jatrorrhizine) and
tetrahydroprotoberberines (columbamine). In
addition this plant contains bitter
furanoditerpenes.
In vitro, protoberberines are shown to have good •
antibacterial, antifungal, antivibrio and anti
protozoa properties. This may justify the
traditional usage of this plant to treat wound
and scurf as well as in after-birth treatment.
PATAWALI: TINOSPORA CRISPA MIERS. •
(MENISPERMACEAE):
This plant is a much smaller climber than the •
former one, with an irregular spotted stem. It is
commonly cultivated in gardens as medicinal
plants.
The cross section of the stem is also yellow and its
composition is similar to that of mengkunyit. The
stem is used in powdered form topically as
disinfectant (in combination with sulphur), or
internally as decoction to treat stomach-ache,
fever, gonorrhoea, intestinal worms, and diabetes
mellitus. This latter indication was supported by
experimental studies on the hypoglycaemic effect
of the alkaloid extract on rats.
In vitro, protoberberines are shown to have good antibacterial,
antifungal, antivibrio and anti protozoa properties. This may
justify the traditional usage of this plant to treat wound and
scurf as well as in after-birth treatment.
 PATAWALI: TINOSPORA CRISPA MIERS.
(MENISPERMACEAE):
This plant is a much smaller climber than the former
one, with an irregular spotted stem. It is commonly
cultivated in gardens as medicinal plants. The cross
section of the stem is also yellow and its composition
is similar to that of mengkunyit. The stem is used in
powdered form topically as disinfectant (in
combination with sulphur), or internally as decoction
to treat stomach-ache, fever, gonorrhoea, intestinal
worms, and diabetes mellitus. This latter indication
was supported by experimental studies on the
hypoglycaemic effect of the alkaloid extract on rats.
The traditional Chinese medicine also makes use of
a number of protoberberine-containing drugs. Let us
mention two of them:
HUANG-LIAN: COPTIS SINENSIS, AND
OTHER COPTIS SPP. (RANUNCULACEAE):
The crude drug is the rhizome, which is very rich in
berberine (5-8% dry weight). It is recommended for
 SANKEZHEN, CI-HUANG-LIAN: BERBERIS
SOULIENA AND OTHER BERBERIS. SPP.
(BERBERIDACEAE):
The roots of this plant, like all Berberidaceae
members, are very rich in berberine and other
protoberberines.
It is logically used as antiseptic. The crude drug
contains also few BBTHIQ which may be responsible
for the hypotensive properties of this plant. dysentery

 SANKEZHEN, CI-HUANG-LIAN: BERBERIS

SOULIENA AND OTHER BERBERIS. SPP.
(BERBERIDACEAE):
The roots of this plant, like all Berberidaceae
members, are very rich in berberine and other
protoberberines. It is logically used as antiseptic. The
crude drug contains also few BBTHIQ which may be
responsible for the hypotensive properties of this
plant. and various bacterial infections.
VII- Aristolochia alkaloids
The Aristolochiaceae form a small and very primitive
family of Dicots (7 genera and 400 species). It is
comprised of herbs or woody vines with heart-shaped
leaves and medium to large, often bizarre and foul-
smelling flowers. This family contains specific
isoquinoline alkaloids, which can be looked upon as
catabolites of some common isoquinoline alkaloids, i.e.
the aporphines.
Aristolochic acids are a family of carcinogenic, mutagenic,
and nephrotoxic compounds commonly found in the
Aristolochiaceae family. Exposure to aristolochic acid is
associated with a high incidence of uroepithelial
tumorigenesis, and is linked to urothelial cancer.
In August 2013, two studies identified aristolochic acid
mutational signature in upper urinary tract cancer patients
from Taiwan. The carcinogenic effect is found to be the most
potent found thus far, exceeding the amount of mutations in
smoking-induced lung cancer and UV-exposed melanoma.
Exposure to aristolochic acid may also cause certain types of
liver cancer.
No major drug was ever derived from these structures, but a
series of incidents happened in the 90’s in Europe and North-
America.
It first started in Belgium. From 1990 to 1992, a private clinic
ran slimming programmes and administered to patients tablets
allegedly based on TCM (actually these tablets incorporated
plant powder, not plant extracts), together with fenfluramine
and/or acetazolamide. Over 100 patients got intoxicated and
suffered from end- stage renal failure and urothelial tract
carcinoma (about half of them). This nephropathy was then
referred to as Chinese Herbal Nephropathy (CHN). Analytical
and toxicological studies revealed that the culprit was
aristolochic acid (generic term for aristolochic acids and
aristolactams), which is able to denature the nucleic acids and
form aristolactams–DNA adducts, such as 7-(deoxyadenosine-
N6-yl)-aristolactam I.
- Aristolochia fangchi Y.C. Wu ex L.D. Chow & S.M.
Hwang
= Guang fang ji (or Kwangbanggi) 关防己.
= Kou-boui (or Mokuboi) 日语.
- Stephania tetrandra S. Moore
= Fen fang ji , Fang ji root 粉防己.
= Han fang ji 汉防己.
= Kanboi (or Fun-boui) 日语发音.
The vernacular names are close and confusion is easy,
especially if a non-specialist handle these plants.
Furthermore, it seems that in TCM, these plants
(together with Clematis spp., Mufangji 木防己) are
collectively denominated Fang ji (防己)and can be
interchanged with various species collectively
denominated Mu tong (木通). In practice, a number
As a result, similar problems occurred in UK (2
cases following an eczema treatment), and in France
(1994) then in Japan (1998 and 2000, several cases
were reported to occur as a result of taking
aristolochic containing herbs.
The US Food and Drug Administration (FDA)
answer to the problem was quite mild for few years,
as it just recommended the herbal companies to
recall voluntarily suspect products. In the late 90’s,
preparations in the USA and Canada were found to
contain aristolochic acid.
In May 2000, the FDA placed an import alert on 63
herbs that "contain, may contain, or may be
adulterated with aristolochic acid." Furthermore, the FDA
took the position that these herbs would be
automatically detained and would be released only if
an analytical examination proved that the herbs were
free from aristolochic acid. The only allowed
analytical method involves the use of LC/MS/MS,
with a detection limit set at 0.5 ppm at most. As a
result of this regulation, many valuable herbs and
formulas were taken off the market. Canada followed
promptly:
Health Canada Notice, 001-105 October 5, 2001

Advisory: Health Canada advises consumers about

additional products that could contain aristolochic acid.

OTTAWA - Health Canada is advising consumers not to use

products labelled to contain Bragantia, Diploclisia,
Menispermum, Sinomenium, Vladimiria souliei and Soussurea
lappa. Recent evidence obtained from the U.S. Food and Drug
Administration and the Australian Therapeutic Goods
Administration has led Health Canada to suspect that these
herbs are being used interchangeably with Aristolochia in
Traditional Chinese Medicine products.
There have been numerous international reports of death or injury from •
kidney failure due to ingestion of products found to contain aristolochic
acid. Other countries, including the United States, Australia and
member states of the European Union, have taken regulatory action to
address the risk of aristolochic acid to consumers.

(http://www.napra.ca/docs/0/310/312.asp) •

TCM practitioners and herbal companies protested with •

notably the following arguments:
Guang Fang Ji has been in use in traditional Chinese •
medicine for several hundred years. It had always been used
as a water decoction. The Merck index states that
aristolochic acid is insoluble in water, which could
explain why there have not been reported cases of toxicity in
TCM decoctions or products made from traditional water
decoctions. As the Belgium slimming regimen used the Guang
Fang Ji in raw powdered form, the Aristolochic Acid
was present and absorbed by the patients, and may have,
along with the Although the clinic thought that what it was
administering Ji, it is evident that the clinic was not using or
preparing the herb in a traditionally prescribed manner.
was Han Fang Ji (Stephania tetrandra) and Ji, it is evident
that the clinic was
not using or preparing the herb in a traditionally prescribed
not Guang Fang prescription drugs, caused kidney manner.
failure. As a company, we feel that this situation underscores
the
) need for more research and a better understanding on the
part of regulating agencies, industry and practitioners. Many
herbs containing toxic substances have therapeutic merit and
have been used safely and effectively throughout Chinese
medicinal history through correct processing, preparation,
administration, dosage and diagnostics. With the growing use
of traditional Chinese medicines worldwide, comes the inevitable
growth in research and use of Chinese herbs outside the realm
of TCM.
Although TCM itself is an ever-changing art and science, it is essential
that correct identification of species and traditional processing and use
must be taken into account. In our efforts to “modernize” and to make
TCM more scientific or find new applications for it, we must also be
diligent in our efforts to maintain a complete understanding of
traditional Chinese
herbal medicine.

(http://www.mayway.com/aristo.shtm
Conclusion:
1. TCM credibility was badly damaged.
2. Western countries have taken one more opportunity to
raise protectionist barriers.
3. Scientific names are the best denomination for herbal
products.
4. Traditional usage does not mean absolutely safe usage.
5. If tradition is to be invoked, there is an increased risk to
not abide strictly to it.
6. One more example of the necessity to conduct in-depth
studies on herbal remedies: Herbs should be considered as
real drugs and be given the same attention as the so-called
modern drugs.
VIII- Amaryllidaceae alkaloids

The Amaryllidaceae family (Monocots) comprises

75 genera and 1100 species, mostly from tropical
regions.
It is chemically characterised by specific alkaloids,
the Amaryllidaceae alkaloids, of which c.a. hundred
are known. One is of interest, galanthamine (or
galantamine). The biosynthesis of these compounds
is very similar to that of regular benzylisoquinolines.
It differs mainly by the loss of one additional carbon
atom from the phenylalanine precursor. Depending
on the folding of the norbelladine
intermediate, the intramolecular phenolic oxidative
coupling would lead to several skeletons.
Galanthamine Pharmacological investigations
showed that galanthamine is a reversible
competitive cholinesterase inhibitor. It is also a pre-
synaptic nicotinic receptor stimulant. is obtained by
ortho-para coupling.
Snowdrop (Galanthus nivalis) and related plants
from Europe were used in folk medicines for ages
for neuromuscular relief, muscular soreness.
In monasteries, the snowdrop was used as a
wound healer and for digestive problems. This
prompted investigations by Eastern Europe
chemists who isolated galanthamine first from
Galanthus woronowii in 1952 , in 1954 from G.
nivalis. Galanthamine was later found in
numerous Amaryllidaceae, including the daffodil
(Narcissus It binds specifically on the
"galanthamine binding site" and triggers an
allosteric modification of the receptor which
induces an increased release of acetylcholine.
pseudonarcissus).
Galanthamine was first commercialised in the
Eastern European countries(1960’s) under the
name Nivaline® with indications for myasthenia
and neuromuscular dystrophies as well as in
anaesthesiology. It was then extracted from

*In the Odyssey, Homer's epic celebration of heroic memory, Hermes, god of the travellers, gives to Odysseus a plant named
“Molly” which should protect him from being intoxicated by the beverages offered by the sorceress Circe. His crew, who
were not protected believed they were transformed into pigs. Translated into modern pharmacology, this evokes an
atropinic poisoning. The antidote would naturally be a plant with anticholinergic activity. Among the various possible ones,
the snowdrop is a likely hypothesis as it fits the description given by Homer : “Its root was black, and its flower was as with
as milk.”