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Opportunity, Challenge and Scope of Natural Products in Medicinal Chemistry, 2011: 411-431
ISBN: 978-81-308-0448-4
14. Carbohydrate-containing natural
products in medicinal chemistry
1
Hongzhi Cao1, Joel Hwang2 and Xi Chen2
National Glycoengineering Research Center, Shandong University, Jinan, Shandong 250012
P. R. China; 2Department of Chemistry, University of California-Davis
One Shields Avenue, CA 95616, USA
Abstract. Carbohydrates are essential components of many natural
products known for great medicinal importance. The carbohydrate
moieties can increase drug water solubility, decrease toxicity,
and/or contribute to the bioactivity of the natural products. This
review provides a short summary of diverse carbohydratecontaining natural products, recent advances in introducing glycan
diversity to natural products, and their potential application in
medicinal chemistry.
1. Introduction
Carbohydrates are the most abundant biomolecules. They are presented as
free monosaccharides, oligosaccharides, polysaccharides, and as essential
components of glycoconjugates, including glycolipids, glycoproteins or
glycopeptides, and glycosylated natural products. Glycosylated natural
products have been commonly used as antimicrobial drugs and now as
emerging anti-cancer drug candidates. The sugar moieties in many bioactive
natural products do not only increase water solubility thus the bioavailability
of the compounds, but also decrease toxicity. Some glycans are also the
essential components for the bioactivity of the natural products. This review
Correspondence/Reprint request: Dr. Hongzhi Cao, National Glycoengineering Research Center, Shandong
University, Jinan, Shandong 250012, P. R. China. E-mail: [email protected]; Prof. Xi Chen, Department of
Chemistry, University of California-Davis, One Shields Avenue, CA 95616, USA
E-mail: [email protected]
412
Hongzhi Cao et al.
summarizes the diverse carbohydrate-based and glycosylated natural
products that have been used as drugs and those have great drug potential.
Recent advance in developing novel glycosylated natural products by
glycorandomization/glycodiversification is also included in the review.
2. Iminosugars, aminoglycosides and carbohydrate mimics
Iminosugars, also known as azasugars or polyhydroxylated alkaloids, are
a family of naturally occurring carbohydrate mimics. These sugar mimics in
which the ring oxygen is replaced by nitrogen are classified into five
structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines,
pyrrolizidines, and nortropanes [1]. Some representative iminosugar
structures are shown in Figure 1. Nojirimycin (1, Figure 1) [2] was the first
natural iminosugar isolated from Streptomyces roseochromogenes R-468 and
S. lavendulae SF-425 and was shown to be a potent inhibitor of α- and
β-glucosidases from various sources [3]. The chemically more stable 1-deoxy
nojirimycin (DNJ, 2) was also isolated shortly after the discovery of
nojirimycin. So far, many iminosugars have been isolated from natural source
and most of them exhibit specific potent inhibition against different
glycosidases, a class of carbohydrate catabolic enzymes [1-4].
Aminoglycosides are an important group of carbohydrate-based
antibiotics typically containing one aminocyclitol linked to two or more
uncommon monosaccharides. Streptomycin (9, Figure 2) from Streptomyces
griseus was the first aminoglycoside natural product discovered [5].
Streptomycin and many other aminoglycosides (Figure 2) isolated from
natural sources have been widely used as antibacterial agents, especially
against mycobacterium tuberculosis. Recently, aminoglycosides have been
demonstrated to inhibit catalytic RNAs in vitro as well as to interfere with
HIV replication by disruption of essential protein-RNA contacts [6-8].
Figure 1. Structures of representative iminosugars.
413
Carbohydrate-containing natural products in medicinal chemistry
H2N
NH2
NH
HN
OH
OH
HO
NH
H2N
NH CHO
O
H3C
HO
HO
O
HO
HO
H2N
O
NH2
O
HO
OH
O
O OH
NHMe
H2N
O
H2N
NH2
O
HO
OH
O
O OH
NH2
O
H2N
HO
OH
H2N
OH
Streptomycin, 9
H2N
NH2
O
O
H2N
H2N
O
HO
NH2
O
Kanamycin B, 12
H2N
O
HO
H2N
NH2
O
H2N
O
HO
NH2
O
OH
O
HO
OH
Paromomycin, 11
NHCH3
O
NH2
O
OH
Neomycin B, 10
NH2
HO
HO
H2N
O
O
HO
HO
O
O
HO
OH
OH
NH2
O
HO
CH3HN
Gentamicin C1, 13
CH3
OH
O
HO
CH3HN
CH3
OH
Sisomicin, 14
Figure 2. Structures of representative aminoglycosides.
Many natural occurring and synthetic carbohydrate mimics including
iminosugar- and aminoglycoside-based glycosidase inhibitors have been used
as drugs to treat diabetes, viral infections, cancers, and Gaucher disease
(Figure 3) [1-4]. For example, acarbose (15), a pseudotetrasaccharide isolated
from the fermentation broth of the Actinoplanes strain SE 50, was the first
marketed α-glucosidase inhibitor. It was introduced in early 1990s under the
name of GlucobayTM [3]. Two other synthetic carbohydrate mimics, miglitol
(16) and voglibiose (17), have also been introduced to the market as
α-glucosidase inhibitors for the treatment of type II diabetes [4,9].
As α-glucosidase inhibitors, acarbose (15), miglitol (16) and voglibiose (17)
can decrease the carbohydrate digestion rate and reduce postprandial
hyperglycaemia (PPHG).
Neu5Ac2en (20), the dehydrated Neu5Ac, is a transition state analog
inhibitor of sialidases (also known as neuraminidases). To overcome the low
efficiency and poor selectivity of Neu5Ac2en in inhibiting influenza virus
neuraminidases, Relenza (18) and Tamiflu (19) were developed in recent
years as competitive inhibitors against influenza viral neuraminidase [1,4].
These two blockbuster “flu drugs” have played important roles in combating
the recent flu pandemic and epidemics.
414
Hongzhi Cao et al.
Figure 3. Some glycosidase inhibitor-based drugs.
The iminosugar Miglustat (22) was the first market azasugar anticancer
drug. It was also used to treat Gaucher disease by inhibiting the
glycosyltransferase involved in the biosynthesis of glucosylceramide [4,9]. Other
iminosugars, such as naturally occurring swainsonine (5), castanospermine (6),
and a DNJ synthetic derivative (NMDNJ, 21), are current anticancer drug
candidates in ongoing clinic trails. These iminosugars are inhibitors against
catabolic glycosidasees associated with cancer progresses [1,4].
During the course of synthesizing novel inhibitors against glycosidases
and glycosyltransferases, many new synthetic approaches and methods for
iminosugars have been developed. For example, Wong and co-workers
developed a one-pot chemoenzyamtic approach for the synthesis of a
library of iminocyclitols using fructose-6-phosphate aldolase (FSA) [10].
Most recently, the Wong group also developed a two-step chemical synthesis
of iminocyclitols using Petasis-type aminocyclization as the key step [11].
The organocatalytic aldo reaction was also intensively investigated in recent
years for the synthesis of iminosugars [12,13].
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Carbohydrate-containing natural products in medicinal chemistry
3. Saponins
Saponins are a class of glycosylated secondary metabolites that have
been found in various plant species and some marine organisms. Thousands
of saponins have been characterized and they usually can be classified into
steroidal glycosides and triterpenoid glycosides according to their aglycones.
As natural surfactants, saponins have not only been used as detergents or
foaming agents for many years, they have also been used in Africa to kill
infected snails and prevent the transmission of schistosomiasis. Plant saponin
extracts from ginseng, liquorice, horse chestnuts, ivy leaves, quillaia barks,
primula roots, senega roots, sarsaparilla roots and others have been used as
folk medicines [14-16]. The cardiac glycosides include well-known drugs
such as digoxin (23) has been used for many years to treat congestive
heart failure.
O
OH
O
HO
OH
O
O
OH
O
O
O
OH
O
OH
Digoxin, 23
Some recent studies showed that digoxin also has anti-cancer activity and
can be used as a novel cancer therapeutic agent [17,18]. Antimicrobial,
especially antifungal, activities of many steroidal saponins (e.g. 24-29 in
Figure 4) have also been reported [19-25].
Ginseng (Panax genus) is a family of slow-growing perennial plants
belonging to the family Araliaceae. Its root has been used to increase the
quality of life in China and East Asia since ancient time. So far, more than 30
different ginsenosides (Figure 5) have been isolated, and these triterpene
saponins are considered to be the main active compounds in the ginseng
products [26,27]. Accumulated evidences have shown that ginsenosides also
have anti-inflammation [28], anticancer [29-31] anti-diabetic [32,33]
activities, and can prevent neurodegeneration [34,35].
OSW-1 (Figure 6, 34) is a high potent anticancer cholestane glycoside.
OSW-1 and its four natural analogues (35-38) have been isolated from the
bulbs of Ornithogalum saundersiae, a perennial grown in southern Africa
where it is cultivated as a cut flower and garden plant [36]. These cholestane
416
Hongzhi Cao et al.
O
O
HO
O HO
O
HO
HO
O
OH
O
O
OH
HO
O
O
HO
HO
O
O
OH
O
HO
HO
O
OH
TTS-12, 24
HO
O HO
O
HO
HO
HO
O
OH
O
O
OH
HO
O
O
HO
HO
O
O
O
OH
O
HO
HO
OH
TTS-15, 25
O
O
OH
O
O
OH
O
HO
HO
HO
O
O
HO
HO
Dioscin, 26
HO
OH
29
O
OH
O
HO
O HO
O
HO
HO
O
OH
O
HO HO
HO
HO
O
O
OH
O
OH
O
HO
O
HO
O
O
OH
OH
OH
O
Aginoside, 27
HO
HO
HO
HO
O HO
O
OH
O
HO
HO
O
O
OH
HO
HO
O
OH
O
O
OH
O
HO
O
HO
O
OH
OH
CAY-1, 28
Figure 4. Structures of representative antimicrobial saponins.
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Carbohydrate-containing natural products in medicinal chemistry
OH
O
HO
HO
O
HO
HO
OH
OH
OH
O O
HO
HO
HO
O
RO
O
HO
HO
OR
30, R = Rha, Ginsenoside Re,
HO 31, R = Glc, Ginsenosied Rg1
32, R = H, Ginsenoside Rh2
33, R = Glc, Ginsenoside Rg3
Figure 5. Structures of some representative ginsenosides (30–33).
glycosides exhibited extremely potent cytotoxicity against human
promyelocytic leukemia HL-60 cells with IC50 between 0.1 and 0.3 nM.
OSW-1, the major constituent, exhibited high potent activity against
various malignant tumor cells, including leukemia, mastrocarcinoma, lung
adenocarcinoma, pulmonary large cell carcinoma and pulmonary squamous
cell carcinoma. The cytotoxicity is 10-100 fold more potent than some wellknown anticancer agents in clinical use, such as mitomycin C, cisplatin,
camptothecin, adriamycin and taxol [37].
Due to its unique structure and exceptional highly potent anticancer
activity, OSW-1 has been an attractive synthetic target for organic chemists.
Three groups have reported the total synthesis of OSW-1. All of these
synthetic approaches utilized a convergent strategy that glycosylated the
aglycone acceptor with disaccharide donor to realize the coupling (Figure 7).
The most challenging part of the total synthesis was the synthesis of aglycone
O
OH
O
AcO
R1O
HO
HO
34, R1 = H, R2 = p-methoxybenzoyl, OSW-1
35, R1 = H, R2 = 3,4-dimethoxybenzoyl
O
36, R1 = H, R2 = (E)-cinnamoyl
O O OH 37, R1 = Glc,R2 = p-methoxybenzoyl
38, R1 = Glc,R2 = (E)-cinnamoyl
OR2
Figure 6. OSW-1 and its analogs.
418
Hongzhi Cao et al.
(a) Hui and Yu's synthesis (1999)
O
O
35%
39
O
OH
OH
3 steps
9 steps
HO
O
O
54%
30%
40
TBSO
2 steps
41
TBSO
OSW-1
(b) Jin's synthesis (2001)
O
O
66%
39
TBSO
O
OH
OH 3 steps
OAc 2 steps
7 steps
HO
O
O
58%
74%
42
41
TBSO
OSW-1
(c) Guo's gram scale synthesis (2008)
O
O
HO
39
O
O
4 steps
3 steps
37%
41%
TBSO
40
TBSO
O
OH
OH
3 steps
41%
41
OSW-1
Figure 7. Total synthesis of OSW-1 (34).
acceptor. It was achieved from commercially available 5-androsten-3β-ol-17one (39) in all three reports. The Hui and the Yu groups reported the first
total synthesis of OSW-1 (34) in 1999 (Figure 7, path a) [38]. In their
synthesis, the side chain elongation was realized by employing sequentially
Wittig olefination, Ene reaction, Dess-Martin oxidation, Grignard addition,
PDC oxidation, and protection of keto with ethylene glycol to give the key
diene intermediate 40. The diene 40 was subjected to OsO4 to afford the
corresponding 16α,17α diol intermediate in moderate yield, which was
converted to the natural aglycone as the acceptor for the next glycosylation
step by reversing the 16α-OH to 16β-OH through an oxidation-reduction
process. Finally, the OSW-1 (34) was constructed from commercially
available dehydroisoandro-sterone, L-arabinose, and D-xylose in 14 linear
steps with a total yield of 6%.
Jin and co-workers developed a new strategy for steroselective
introduction of the aglycone side chain via 1,4-addition of α-alkoxy vinyl
cuprate to 17(20)-en-16-one steroid to give the intermediate 42 (Figure 7,
pathway b) [39,40]. In Jin’s synthesis, a new strategy was developed to
introduce the 16β,17α diol to avoid using toxic OsO4. The total synthesis was
finished in 10 linear steps with a 28% overall yield.
419
Carbohydrate-containing natural products in medicinal chemistry
Recently, Guo and co-workers reported gram-scale synthesis of OSW-1
(34) (Figure 7, pathway c) [41]. In their synthesis, an efficient new approach
was developed to elongate the steroid side chain to give the key diene
intermediate 40 in 4 steps with a 37% total yield. Then, following the similar
approach as described by Hui and Yu, the OSW-1 was synthesized in 10 linear
steps in a 6% overall yield. Structure-activity relationship studies of OSW-1
analogues revealed that a new 23-oxa-analogue of OSW-1 had much more
potent antitumor activity than its parent OSW-1 [42]. Recently, a biotinylated
OSW-1 was successfully synthesized for cell targeting studies [43].
Other than the anti-cancer activity of some saponins such as OSW-1 and
its analogs described above, some saponins such as QS-21Aapi and QS-21Axyl
has been used as the potent immunoadjuvants for vaccine. The saponin
extracts of South American tree Quillaja saponaria Molina have long been
used as foaming agents in beverages. Recently, the extracted saponins attract
tremendous attention for its immunological adjuvant activities and have been
used as a critical adjuvant component in many vaccine therapy trials [44].
QS-21A (the 21st fraction from Reverse Phase-HPLC) was the minor
constituent which comprised two isomeric triterpene glycoside saponins
QS-21Aapi (43) and QS-21Axyl (44) (Figure 8) [45].
These
two
complex
triterpene-oligosaccharide-normonoterpene
conjugates consist of a quillaic acid as a central lipophilic core, a branched
trisaccharide, a linear tetrasaccharide, and an extended glycosylated diester
side chain (Figure 8). QS-21Aapi (43) and QS-21Axyl (44) have a β-D-apiose
and a β-D-xylose, respectively, as the terminal saccharide residue on the
linear tetrasaccharide substructure. Unfortunately, obtaining sufficient
quantities of these natural products in pure form is a daunting project due to
their low abundance.
O
OH
O
O
HO
O
HO
HO
O HO
O
OH
HO OH
O
HO
CO2-
OH
O
O
O
O
O
HO
O
CHO
OH HO
O
O
HOO
HO
OR
O
OH
OH
OH
OH
O
43, QS-21Aapi R=
HOOOH
44, QS-21Axyl R= HO
O
OH
OH
Figure 8. Structures of QS-21Aapi (43) and QS-21Axyl (44).
O
OH
420
Hongzhi Cao et al.
The synthesis of the fully protected branched trisaccharide and the linear
tetrasaccharide components of QS-21Aapi were reported by Zhu et al. [46].
The total synthesis of QS-21 Aapi (43) [47], QS-21Axyl (44) [48], QS-7-Api
[49] was successfully accomplished by Gin and his co-workers. The total
synthesis of QS-21 Aapi (43) was achieved in 2006 by judicious choice of the
coupling protocols and protecting patterns (Figure 9) [47]. A convergent
coupling strategy was used for conjugating four building blocks including a
branched trisaccharide (45), a quillaic acid acceptor (46), a tetrasaccharide
fragment (47), and an acyl chain (48) (Figure 9). The glycosyl acceptor, a
30-carbon triterpene quillaic acid ester (46), was prepared by acid-mediated
hydrolysis of natural semipurified QS saponins followed by selective
protection.
In Gin’s total synthesis, most of the glycosidic linkages were constructed
with sulphoxide-mediated dehydrative glycosylation (Ph2SO-Tf2O) method
using hemiacetal donors. The steroselective coupling between branched
trisaccharide α-imidate (45) and the quillaic allyl ester (46) was achieved
using a less common B(C6F5)3 Lewis acid as the promoter. The coupling of
linear tetrasaccharide (47) and acyl chain (48) under Yamaguchi conditions
provided the complex sugar ester in 90% yield. This sugar ester was then
converted to its α-imidate and coupled with the acid of glycosylated quillaic
acid triterpene to give the fully protected QS-21Aapi. QS-21Aapi was finally
achieved after global deprotection [47].
BnO
BnO
O
BnO
BnO
CO2Me
AcO
O
O
OBn
O
OO
CO2All
OH
NH
BnO
CCl3
OBz
HO
46
CHO
45
H
OH
BnO
TIPSO
O
O
O
O
O
O
O BnO
O
O
Ph
OO
HO
OBn
OBn
TBSO
O
TBSO
O
O
O
TBSOO
TBSO
47
OTBS
48
Figure 9. Structures of four building blocks for the synthesis of QS-21Aapi (43).
421
Carbohydrate-containing natural products in medicinal chemistry
The total synthesis of the other two QS saponins, QS-21Axyl (44) [48]
and QS-7-Api [49], were also accomplished by the same group using a
similar approach. Most recently, Gin and his co-workers designed and
synthesized several amide-modified, non-natural QS-21 analogs [50]. These
synthetic saponins were chemically stable and exhibited similar or even
better immunopotentiating effects in in vivo assays with GD3-KLH
melanoma conjugate vaccine. The highly convergent synthesis of these novel
non-natural saponins provides new avenues for searching and identifying
improved molecular adjuvants for specifically tailored vaccine therapies.
Some other saponins have been isolated and characterized with significant
biological activities such as anticancer, anti-infection, anti-fungi etc. Because of
the lengthy steps of protection/deprotection and sometimes low yields and low
stereoselectivity in the glycosidic coupling processes suffered in saponin
synthesis, only a small portion of these natural products have been synthesized.
For example, two complex triterpene saponins, Lobatoside E (49) [51] and
Candicanoside A (50) [52] both exhibited potent anticancer activity, have been
recently synthesized by Yu’s group (Figure 10). However, many others, such as
Avicin D (Figure 10, 51) [53] which also exhibited potent anticancer activity, are
still attractive total synthetic targets that have not been synthesized.
O
HO
O
HO
HO
HO
O
O
O
O
O HO
O
OH
OH
OH
O
HO
O
O
HO
O
O
OH O
O
O
O
HO
HO OH
OH
HO
HO
HO
O
O
O
OH
O
HO
HO
OH
Anticancer
Total Synthesized in 2008
Lobatoside E (49)
Anticancer
Total Synthesized in 2007
Candicanoside A (50)
O
O
O
HO
O
HO
HO
OH
O
O HO
HO
OH
O
OH
O
HO
O
O
O
NHAc
OH
O
O
O
O
O
HOO
O
OH
O
OH
HO
O
HO
HO OH
HO
OH
OH
O
OH
OH
OH
OH
Anticancer
(To be synthesized)
Avicin D (51)
Figure 10. Structures of three bioactive complex triterpene saponins.
422
Hongzhi Cao et al.
4. Glycosylated macrolides
Many microlides produced by bacteria have sugar moieties and have
excellent activity against Gram-positive bacteria. Many of them such as
erythromycin A (52), oleandomycin, spiramycin, josamycin, tylosin, and
midecamycin have been successfully used in clinic for years [54,55].
In addtion, cytotoxic tetraene macrolide CE-108 (53) [20-56], a secondary
metabolite of Streptomyces diastaticus 108, and amphotericin B (54) [57] are
good candidates for broad-spectrum antifungal drugs. Most recently, a new
18-membered macrolide glycoside, biselyngbyaside (55) from marine
cyanobacterium Lyngbya sp., has been reported to exhibit uncommon broadspectrum antitumor activity in a human tumor cell line panel [58].
5. Glycosylated cyclic peptides
Cyclic polypeptides have been considered as potential antimicrobial
agents for pharmaceutical, preservation, cleaning, and disinfection uses [59].
Most of these cyclic polypeptides are of microbial origin and many have
carbohydrate moieties. Many of these glycosylated cyclic peptides, such as
O
HO
HO
HO
OH
NMe2
HO
O
O
O
O
OH
O
O
HO
OH
OH
HO
(antibacterial)
Erythromycin A, 52
O
OH
NH2
(Antifungal)
CE-108, 53
OH
OH
O
OH
O
OMe
O
O
HO
O
O
HO
O
OH
OH
OH
OH
O
OH
O
O
HO
(Antifungal)
Amphotericin B, 54
O
NH2
OH
O
HO
HO
MeO
O
O
O
OMe
OH
(antitumor)
Biselyngbyaside, 55
Figure 11. Structures of representative glycosylated macrolides.
423
Carbohydrate-containing natural products in medicinal chemistry
OH
H2N
HO
OH HO
Cl
O
O
HO
HO
HO
O
O
O
Cl
HO
HO
Cl
O
O
H
N
N
H
HN
O
O
OH
OH
HO
NH2
H H
N
H2N
HO
O
O
H
N
HN
N
H
N
N
H
O
NH
O
HO
NH2
O
O
O
HO
OH
HO
OH
O
H
N
S+
O
H
N
N
H
Vancomycin, 56
NH2
OH
OH
O
OH
O
OH
Teicoplanin, 57
OH
NH2
H
N
O
N
H
Cl
O
AcHN
O
NH2
O
O
H
N
N
H
O
HO
OH
O
O
O
O
HO
O
O
H
N
O
HO
O
H
H H
N
O HO
H O
H O
HO
N
H
H H
N
O
H
OH
O O
N
H
OH
OH
O
OH
OH
O
O
NH2
N
O
HO
H
N
S
H
N
NH N
Bleomycin, 58
S
HO
H
N
O
N
H
O
NH
H2N
O
O
HO
HO
HO
N
O
O
R
OH
O
NH2
HN
H
N
O HO
N
H
O
O
O
O
O
O
O
R = OH, Hassallidin A, 59a
R = L-Rhamnose, Hassallidin B, 59b
Figure 12. Structures of some glycosylated cyclic peptides.
vancomycin (56), teicoplanin (57), bleomycin (58) and ristocetin etc., are
very important antibiotics and some of them have been considered as the last
resort for treating multiple resistant bacteria infections (Figure 12) [60].
Hassallidins A (59a) [61] and B (59b) [62] isolated from a cyanobacterium
Hassallia sp., have shown broad-spectrum antifungal activity. Compared to
hassallidin A, hassallidin B has an extra rhamnose attached to the 3-hydroxyl
group of the acyl chain and was shown to have increased water solubility
without decreasing its potent antifungal activity [20,62].
6. Cyanogenic glycosides
Cyanogenic glycosides are secondary metabolites widely distributed
in more than 2500 plant species. They comprise a sugar moiety, mostly
D-glucose, beta-linked to an alpha-hydroxynitrile type aglycone. The sugar in
some cases can also be gentibiose, primeverose or others, and the aglycones
can be aliphatic or aromatic compounds (Figure 13) [63,64]. Cyanogenic
glycosides can release hydrocyanic acid (HCN) upon hydrolysis. They are
believed to participate in defense mechanisms of many plants against
different phytopathogens [63,65].
424
Hongzhi Cao et al.
HO
HO
HO
CN
O
CH3
O
OH
HO
HO
HO
O
OH
CO2H
HO
HO
HO
OH
Cynocardin, 62
NC
HO
HO
HO
O
O
NC
O
O
OH
OH
CO2H
HO
HO
OH
Lithosperm, 64
Tryglochinin, 63
NC
O
O
OH
Aciapetalin, 61
CN
O
O
OH
CH3
Linamarin, 60
HO
HO
HO
HO
HO
HO
NC
O
OH
65
Figure 13. Structures of some cyanogenic glycosides.
7. Glucosinolates
Glucosinolates are sulfur-rich secondary metabolites of plants
which contain beta-D-thioglucose and sulpholated oxime moieties (Figure
14) [66-68]. The glucosinolates share some common features with
cyanogenic glycosides, such as similar biosynthetic pathway at the early
stages and both can be hydrolyzed to generate toxic degradation products in
plant defense. The biosynthesis of glucosinolates comprised three steps, sidechain elongation of precursor amino acids, formation of the core
glucosinolate structure, and side-chain decoration. The biological activity of
glucosinolates is not limited to protection against various pathogens and
weeds in case of plants, and recently studies demonstrated it has antifungal,
antibacterial, antioxidant, antimutagenic and anticarcinogenic effects [69-73].
HO
HO
HO
N
O
S
OH
OSO3-
HO
HO
OH
HO
N
OSO3-
O
S
H
N
N
HO
HO
HO
O
Glucobrassicin, 67
S
OH
OH
Sinalbin, 66
OSO3-
Sinigrin, 68
Figure 14. Structures of some glucosinolates.
8. Other carbohydrate-containing natural products
Other carbohydrate-containing major secondary metabolites which have
recently been identified as potent antimicrobial agents or dietary supplements
include antifungal glycosylated flavonoid 69, antimicrobial glycosylated
iridoids (monoterpenoids) 71 and 73, antimicrobial glycosylated lignan 74,
and antibacterial glycosylated terpenoid 72 (Figure 15) [20,74-76]. In
addition, flavonol glycoside rutin (70, from buckwheat and rue) and the
flavanone glycoside hesperidin from Citrus peels have been used as vitamin P
in dietary supplements [5].
425
Carbohydrate-containing natural products in medicinal chemistry
MeO2C
O
HO
HO
OH
HO
OH
O
HO
O
OH
HO
HO
HO
O
OH
O
73
O
H
O
O
O
AcO O
O
O
71
H
CO2H
OH
72
O
O
OH
OMe HO
OH
O
HO
H OH
AcO
OMe
HO
O
H OH
O
HO
O
OH HO
HO
HO
O
O
rutin, 70
69
O
O
OH
O-Glc-Rha
OH
OH
HO
HO
HO
OH
O
MeO
OMe
OH
74
OH
OMe
HO
HO
O
O
O
OH
OH
OH
O
hesperidin, 75
Figure 15. Some glycosylated flavonoids, iridoids, lignans & terpenoids.
9. Current advances in glycosylated natural products:
Glycorandomization/glycodiversification
Many glycosylated naturally occurring antibiotics and its synthetic
analogs are widely used in the clinic for the treatment of various human
diseases such as antibacterial, anticancer, antifungal, antiparasite drugs,
etc [77,78]. These antibiotics can be classified to macrolides, enediynes,
anthracyclines, coumarins, non-ribosomal peptides, aminoglycoside, polyenes,
aureolic acids, and others, according to their specific architectures.
The emergence of pathogenic bacteria that are resistant to multiple
antibiotics represents a growing threat to human health and has given
additional driving force for the search for novel antibiotic drugs [79-81].
Fewer and fewer new drugs have been found in target screening programs
during the past two decades, and scientists have started to look for new
technologies to generate new compounds. Accumulating evidence has shown
that the sugar moiety of many antibiotics play pivotal roles in drug targeting
and activity. Alteration of the carbohydrate structures of drugs, therefore, will
have profound effect to their molecular targeting and organism specificity.
Recently, Thorson’s group reported a promising new glycoengineering
(glycorandomization or glycodiversification) strategy for drug development by
quick accessing a library of diverse natural product analogs [82,83]. One example
is glycoengineering of vancomycin using a promiscuous glucosyltransferase GtfE
and an expanded pool of NDP-sugars (Figure 16) [84,85]. Vancomycin (56), a
glycosylated natural product from Amycolatopsis orientalis, is considered the last
defense against infections caused by methicillin-resistant Gram-positive bacteria.
Two glycosyltransferases, GtfE and GtfD, are involved in the vancomycin
biosynthetic pathway to stepwisely add L-vancosaminyl-1,2-D-glucosyl
disaccharide to the 4-hydroxyphenylglycine of the heptapeptide vancomycin
aglycone (Figure 16a) [86].
426
Hongzhi Cao et al.
OH
H 2N
a) Glycosylation steps in the vancomycin biosynthetic pathway
O
HO
R
OH
vancomycin
aglycone
O
O
dTDP-Glc
dTDP-vancosamine
GtfE
HO
HO
O
GtfD
vancomycin
aglycone
O
O
vancomycin
aglycone
b) Glycoengineering and futher chemical diversification of vancomycin (Thorson, 2003)
R1
R
O
OH
O
NDP-sugars
vancomycin
aglycone
R2
alkynes
vancomycin
aglycone
GtfE
N
OH
O
O
vancomycin
aglycone
HN
N
H
O
O
vancomycin
aglycone
OH
O
N
H
O
H
N
O
N
H
H
N
NH2
O
HO
N
O
H
N
HO
OH
O
Cl
HO
O
O
Click-chemistry
Cl
OH
HO
HO
N
OH
OH
Figure 16. Glycoengineering of vancomycin.
Previous studies have shown that GtfD and GtfE have flexible substrate
specificity [86,87]. Thorson and his co-worker further exploited these
properties and found that 21 of the 23 TDP-sugars generated through
chemoenzymatic synthesis were utilized by GtfE to give a library of novel
vancomycin analogs (Figure 16, Path way B). The vancomycin analog which
has an azidosugar moiety (6-azido-6-deoxy-glucopyranose) can be further
modified in the presence of alkynes via “Click-Chemistry” to generate 39
additional vancomycin derivatives. One of the new compounds displayed
improved antibiotic activity against Staphylococcus aureus and Enterococcus
faecium (Figure 16) [84,85].
The glycodiversification strategy has been recently employed by the
same group in generating calicheamicin analogs. A new reversible reaction
mechanism catalyzed by the glycosyltransferases (GTs) was discovered
during the course of their studies (Figure 17) [88]. Calicheamicin (Figure 17,
77) is a member of the enediyne family of antitumor antibiotics isolated from
Micromonospora echinospora. Thorson and his co-workers demonstrated
427
Carbohydrate-containing natural products in medicinal chemistry
A) Glycosylation step catalyzed by CalG1 in the Calicheamicin biosynthetic pathway
O
HO
O
HO
MeSSS
O
I
O
S
H
O N
HO
OMe OH
HO
OMe
O
H
NHAc HO
MeO
O
OTDP
O
CalG1
B) Modification Calicheamicin by in vitro glycodiversification
I
O
S
OMe OH
HO
NHAc
MeSSS
O H
N
HO
76
OMe
O
O
HO
MeO
OH
O
OMe OH
OMe
O H
N
HO
O
R
O
OH
Calicheamicin, 77
O
O
S
OTDP
O
CalG1
OH
MeSSS
O
I
H
NHAc
H
HO
O
O
S
O
OH
HO
I
OH
76
MeSSS
O
R
O
O
OMe OH
O
O H
N
HO
O
NHAc
H
O
OH
OMe
Calicheamicin derivatives with non-natural sugar moiety
C) Modification Calicheamicin by reverse glycosyltransferase reaction
I
O
S
OMe OH
HO
NHAc
MeSSS
O
O H
N
HO
O
H
O
HO
O
HO
R
O
O
I
S
OTDP
O
CalG1
OH
MeSSS
R
O
OMe OH
O
O
O H
N
HO
O
NHAc
H
O
OH
OMe
OMe
Calicheamicin derivatives with non-natural sugar moiety
O
OTDP
HO
MeO
OH
CalG1
TDP
O
HO
MeSSS
O
I
OMe OH
O
O
HO
MeO
OH
O
S
OMe
O H
N
HO
O
NHAc
H
O
OH
77
Figure 17. Glycoengineering of calicheamicin by in vitro glycodiversifation and
reverse glycosyltransferase reaction.
that ten different TDP-sugars can be utilized by calicheamicin
glycosyltransferase CalG1 to give calicheamicin derivatives with different
sugars (Figure 17, Pathway B). Quite interestingly, when TDP-3-deoxy-α-Dglucose was incubated with CalG1 in the presence of calicheamicin (77), a
calicheamicin derivative with the sugar moiety being replaced by 3-deoxy-αD-glucose was identified (Figure 17, Pathway C). Close investigation
revealed that CalG1 catalyzed a reverse glycosyltransferase reaction in the
presence of TDP to generate TDP-sugar and deglycosylated calicheamicin as
a glycosyltransferase acceptor for producing the final derivative (76) [88].
More than 70 different calicheamicin derivatives were generated by this
CalG1 catalyzed reverse reaction from 8 calicheamicin derivatives and 10
CalG1 recognized TDP-sugars. This GTs catalyzed reverse reaction was
demonstrated to be a novel approach for the “aglycone exchange” reaction
and can be applied for the synthesis of NDP-sugars [88]. Calicheamicin
aminopentosyltransferase (CalG4) and vancomycin GTs (GtfD and GtfE)
were also shown to catalyze reversible reactions in this study, suggesting that
reversibility may be a general property of GTs involved in glycosylation of
natural products in vitro [88].
428
Hongzhi Cao et al.
10. Prospective and conclusion
Finding drugable carbohydrate-containing natural products remains an
ongoing process. With the increasing interests in the field of carbohydrates
and the rapid advance of the powerful tools including chemical synthetic
strategies, cheomenzymatic methods, and glycodiversification strategies, it is
now possible to expand the existing repertoire of carbohydrate-containing
natural products to find new drugs that can be used to protect human health
and to combat and treat diseases. Nevertheless, developing more efficient and
more economic synthetic approaches for synthesizing carbohydratecontaining natural products remains to be a great challenge and thus an active
area of research for years to come.
Acknowledgements
We are grateful for financial supports from Shandong University (to
H.C.), the National Science Foundation of China (No. 20902087 to H.C.), the
University of California-Davis (to X.C.), the National Institutes of Health
(R01GM076360 and U01CA128442 to X.C.), the National Science
Foundation (CAREER Award 0548235 to X.C.), Alfred P. Sloan Foundation
(to X.C.), and the Camille & Henry Dreyfus Foundation (to X.C.). X.C. is an
Alfred P. Sloan Research Fellow, a Camille Dreyfus Teacher-Scholar, and a
UC-Davis Chancellor’s Fellow.
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