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Chapter 1
1.1 Introduction
Natural products (NPs) extracted from speckled life forms of plants, animals,
marine organisms or micro-organisms are the evolutionary shaped molecules with
profound medicinal significance. The biosynthetic engine of nature produces myriad
NPs in almost incredible chemical diversity with distinct biological properties. These
NPs are by and large stereochemically complex with diverse functional groups that
explicitly interact with biological targets thus make them valuable as health products
or structural templates for drug discovery. Rightly said by Aristotle that “Nature does
nothing without purpose or uselessly” the world of plants, and indeed all natural
sources, represents a virtually untapped pool of novel drugs awaiting imaginative and
progressive organisation. In early 1900s, when the synthetic chemistry was at infancy
stage, more than 80% drugs/medicines were generally obtained from plants. Over the
past centuries the countries like USA, China, India, Egypt, and Greece etc., emerged
with different plant based traditional medicine systems. The continuous growth in the
knowledge of plant, animal, and microbial species lends support to constant discovery
of novel secondary metabolites from these sources. Even today 80% of the world’s
population mainly uses traditional medicines developed from plant-based compounds
for health care and therapeutic purposes (World Health Organisation, 2008). The
significant contribution of these plant-derived drugs to medicine even in present era of
science and technology is also evident by the immense therapeutic potential of
Morphine, Quinine, Digitalis, Atropine, Reserpine, Vincristine, Vinblastine etc.
The exploration of natural product sources associated with anti-cancer and
other biological properties are studied for several principal reasons. NPs present
unmatched chemical diversity and structural complexity. Several useful drugs viz.,
Quinine, Morphine and Penicillin used against malaria, dulling pain and infectious
diseases respectively were all nature based. Further they increase our understanding of
the genetics and biosynthesis of natural products and possibly lead to the discovery
and better understanding of the disease process and pathways underlying. Apart from
this natural products can go straight from hit to a drug in comparison to synthetic
drugs. Thus there is a continued interest in the investigation of NPs extracted from
living organisms to search for bio-active compounds [1-4]. Natural product based
modified drugs are also accumulating steadily in the market. In this backdrop the
present work was planned to achieve the following objectives; 1) structural
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modification of various natural products 2) subsequent biological evaluation of these
molecules for development of anti-cancer and anti-microbial lead molecules.
1.2 Plants as source of anti-cancer agents
Cancer is the most feared disease second only to heart disease as a leading
cause of death in most of the developed countries including United States. Cancer can
affect people at all ages, even foetus, but the risk for the more common varieties tends
to increase with age [5]. Cancer causes about 13% of all deaths. Although surgery and
radiation therapy are key weapons to fight against cancer, chemotherapy also plays an
important role and is the only essential and possible approach for disseminated
cancers. Cancer chemotherapy is aimed at using selective and more appropriate drugs
that can kill malignant tumour cells or render them benign without effecting normal
cells. Cancer chemotherapy was in practice since 1940 when nitrogen mustard and
folic acid antagonist drugs were used. Since then, cancer drug development has gone
up into a multi-billion dollar industry. As a result of this ongoing research, a number
of clinically useful and market-approved natural product based drugs are available.
Today, this strategy remains an essential route to new pharmaceuticals. Towards the
end of 19th century and till date US approved a number of plant-derived compounds as
anticancer drugs.
The historical isolation of two alkaloids Vinblastine 1 and Vincristine 2 from
the Madagascar periwinkle, Catharanthus roseus G. Don (Apocynaceae) introduced a
new era of the use of plant material as anticancer agents. These two agents first
advanced into clinical use for the treatment of cancer by inhibiting mitotic cell
division [6]. They irreversibly bind to tubulin, thereby blocking cell multiplication
and eventually causing cell death thereby show potential activity against lymphocytic
leukaemia. A series of semi-synthetic analogues of these two important drug
molecules have been developed in due course of time to increase the therapeutic
index. The two semi synthetic analogs such as Navelbine or Vinorelbine (VRLB) 3
and Vindesine (VDS), were synthesised which showed potential activity against
leukaemia’s, lymphomas, advanced testicular cancer, breast cancer, lung cancer and
Kaposi’s sarcoma when treated in combination with other chemotherapeutic drugs.
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Camptothecin (CPT) 4, is a quinoline alkaloid isolated from Camptotheca
acuminata. It is a potential anticancer agent showing topoisomerase-I inhibitor
activity, and cause cell death by DNA damage [7]. It showed poor solubility and
severe toxicity. To overcome these limitations a panel of analogues of CPT were
synthesized. Some of the reputed and most promising analogues like topotecan 5,
irinotecan 6, (CPT-11), 9-amino camptothecin (9-AC), lurtotecan and rubitecan
worked well by inhibiting DNA topoisomerase-I which plays a major role in various
DNA functions like replication and transcription [8]. However, CPT itself is too
insoluble to be used as a drug but its modified analogs, namely, topotecan 5 and
irinotecan 6 have been developed as effective drugs.
Phodophyllotoxin 7 is another important anti-cancer compound obtained from
Podophyllum peltatum in 1944 [9]. It was initially used therapeutically as a purgative
and in the treatment of venereal warts [10]. An extensive research was initiated on
this molecule particularly in its chemical synthesis and bio-evaluation. Later in 1974,
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this molecule has come up with a promising anticancer activity by binding
irreversibly to tubulin [11]. Etoposide 8 and Teniposide 9 are the two important
modified analogs of Phodophyllotoxin out of a range of analogues synthesized. These
analogues showed cell death activity by inhibition of topoisomerase II, thus
preventing the cleavage of the enzyme-DNA complex and arresting the cell growth
and therefore useful in the treatment of various cancers [12,13].
The discovery of paclitaxel (Taxol, 10) from the bark of the Pacific Yew,
Taxus brevifolia Nutt (Taxaceae) is another evidence of the success in natural product
drug discovery. An extract of T. brevifolia was discovered to possess an excellent
anticancer property in 1963, and its active component paclitaxel (Taxol 10) was
isolated and characterized only few years latter [14,15]. It was reported to bind
irreversibly with β-tubulin, thus promoting microtubule stabilization [16]. This
tubulin-microtubule equilibrium is essential for cell multiplication, and its
stabilization causes programmed cell death [17]. Paclitaxel was the first compound to
be discovered to promote microtubule formation. Since then it has been used in the
treatment of several types of cancer particularly for ovarian and breast cancers as well
as non-small cell lung tumours [18]. The structure of Paclitaxel is highly complex and
it was very difficult to have ever been produced synthetically prior to its discovery.
Hence combinatorial chemistry would have ever led to the discovery of paclitaxel.
However, the structural complexity of molecule made it a good candidate for
combinatorial modifications to produce a panel of analogues [19]. An extensive and
targeted research was started on this molecule by many groups around the globe for
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both semi- and total synthesis in view of its complex structure, unique activity and
low bioavailability.
There is a long list of bioactive compounds available in the literature that has
been isolated from plant sources. Out of them a good share is currently in clinical
trials or preclinical trials or undergoing further investigation e.g. flavonoids (12, 13,
14, 15), sesquiterpenoid lactones (16, 17, 18, 19) and many others.
1.3 Sesquiterpeniods in cancer chemotherapy
Sesquiterpene lactones (SLs) constitute a large and diverse group of
biologically active plant chemicals that have been identified in several plant families
such as Asteraceae, Canthaceae, Anacardiaceae, Apiaceae, Euphorbiaceae, Lauraceae,
Magnoliaceae, Menispermaceae, Rutaceae, Winteraceae and Hepaticeae etc [20].
With over 3000 different structures these compounds are reported to be present in
greatest numbers in the family Asteraceae [21]. Sesquiterpene lactones are diverse
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and unique class of natural products of plant terpenoids. They are important
constituent of essential oils, which are formed from head-to-tail condensation of three
isoprene units and subsequent cyclization and oxidative transformation to produce cis-
or trans-fused lactones. These secondary compounds are primarily classified on the
basis of their carbocyclic skeletons into pseudoguainolides, guaianalides,
germanocranolides, eudesmanolides, heliangolides and hyptocretenolides etc., (Fig-
6). The suffix "olide" refers to the lactone function, a germanacranoride which is
related to the ten-membered carbocyclic sesquiterpene, germacrone. However, SLs
exhibit variety of other skeletal arrangements. An individual plant species generally
produces one skeletal type of SLs concentrated primarily in the leaves and flower
heads. These compounds exhibit a wide range of biological activities. An important
feature of SLs is the presence of a γ-lactone ring (closed towards either C-6 or C-8)
containing in many cases, and α-methylene group. Among other modifications, the
incorporation of hydroxyls or esterified hydroxyls and epoxide ring are common. A
few SLs occur in glycoside form and some contain halogen or sulphur atoms [22].
Majority of SLs are associated with cytotoxic activity (κB and P388 leukaemia in
vitro) and activity against in vivo P388 leukaemia.
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The first sesquiterpeniods with potential antitumor activity were vernolepin 20
and vernomenin 21 (Fig-7). These were isolated from Vernonia hymenolepis by
Kupchan and colleagues in 1968 [23] as tumour inhibitors against KB cells and
Walker intramuscular carcinosarcoma at appreciable doses.
The discovery of Vernolepin and its antitumor properties was the impetus for a
decade of intensive searching for cytotoxic and anti-cancer active sesquiterpenoid
lactones during the 1970s. A large number of active agents were isolated from plants,
primarily from Asteraceae. A majority of the hundreds of compounds evaluated were
cytotoxic, and a small number have shown activity in-vivo against P-388 leukaemia
and other tumour systems. Some other antitumor sesquiterpenoid lactones include the
following compounds (Fig-8) with different skeletal types [24].
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1.3.1 Anticancer sesquiterpenoid lactones in clinical trials
The SL drugs presently in clinical trials are parthenolide 16 from Tanacetum
parthenium and artemisinin 17 from Artemisia annua L and Thaipsigargin 19 from
Thiapsia (Apiaceae), and a panel of their synthetic derivatives. Artemisinin derived
drugs are promising for laryngeal carcinomas, uveal melanomas and pituitary
macrodenomas as indicated by clinical evidences. Some of these drugs and are in
phase I-II trials against lupus nephritis and breast, colorectal and non small cell lung
cancers (Table-1). Thaipsigargin derived drugs are undergoing phase-I clinical trials
for breast, kidney and prostate cancer treatment. The orally bioavialable parthenolide
analogue, dimethyl amino-parthenolide, or LC-1 is at present in phase I against acute
myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and other blood
and lymph node cancer.
Table-1: List of some sesquiterpeniods in cancer clinical trials
Sesquiterpenoid lactones in cancer clinical trials
SL or derivative Cancer or inflammation Clinical trials Reference
Parthenolide (16) AML, ALL and other body lymph tumors Phase I Clinical trials [25]
Artemisinin (17)Lupus nephritisMetastatic breast cancerColerectal cancer
Phase I Clinical trials [26]
Thaipsigargin (19) Advanced solid tumours Phase I Clinical trials [27]
Atresunate (31)
Non small lung cancerMetastatic uveal cancerLaryngeal squamous cellCarcinoma
As lead molecules[28][29][30]
Artemether (32) Pituitary macrodenomas As lead molecules [31]
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1.3.2 Mechanism of action of sesquiterpenoid lactones
Effective cancer treatment is through elevation of tumour load and inhibition
of cancer stem cells which are concerned in cancer clinical degeneration and
treatment resistance. SLs in cancer clinical trials have properties that enable them to
target tumour and cancer stem cells while sparing normal cells [32-34]. The selectivity
of thiapsigargin, artemisinin and/or parthenolide towards tumour cells are attributed to
their ability to target the sarco/endoplasmic reticulum calcium ATPase (SERCA)
pump [35], particularly proteases secreted by cancer cells [36], high iron content and
cell surface transferrin receptors [37-38], nuclear factor-(NF-κB) signalling [39-40],
MDM2 degradation and p53 activation [41], angiogenesis [42], metastasis [43] and
epigenetic mechanism [44-45] as shown in (Fig-10).
Fig 10: Mechanism of action of SLs (taken from Ref: [46])
But most of the anticancer SLs inhibit the NF-κB pathway (Fig-11) e.g
Parthenolide and artemisinin are established NF-κB inhibitors and render cancer cells
sensitive to chemotherapy. Parthenolide was found to directly modify the NF-κB, p65
subunit or to suppress the activity of upstream IκB kinase complex leading to the
stabilization of the NF-κB inhibitors IκBα and IκBβ. The nucleophillic attack by
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parthenolide occurs through α-methylene-γ lactone ring and epoxide moieties that
target specific nucleophiles but not others. Several artemisinin type compounds also
inhibit NF-κB activity. Normal cells are usually not sensitive to these SLs because
their basal NF-κB activity is often low.
Fig 11: NF-κB cell signalling pathway (taken from) Ref: [47]
Besides anticancer activity SLs show a broad spectrum of other biological
properties e.g., anti-inflammatory [48], anti-bacterial [49], anti-malarial [50], antiviral
[51], anti-fungal [52].
1.3.3. Structural-activity relationships (SAR) of sesquiterpene lactones
The biological activity of SLs can be affected by three major chemical
properties viz., 1) alkylating centre reactivity 2) side chain and lipophilicity 3)
molecular geometry and electronic features.
1.3.3a Alkylating centre reactivity
It is commonly believed that the bioactivity of SLs is mediated by alkylation
of nucleophiles through their β or γ-unsaturated carbonyl structures, such as α-
methylene-γ-lactones or α,β-unsaturated cyclopentenones. These structural elements
react with nucleophiles especially the cystiene sulfhydryl groups by Michael-type
addition. Therefore, it is widely accepted that thiol groups such as cystiene residues in
proteins, as well as the free intracellular GSH, serve as the major targets of SLs. In
essence, the interaction between SLs and protein thiol groups or GSH leads to
reduction of enzyme activity or causes the disruption of GSH metabolism and vitally
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important intracellular redox homeostasis. The relationship between chemical
structure and bioactivity of SLs has been studied in several systems, especially with
regard to cytotoxicity. It is believed that the exo methylene group on the lactone is
essential for cytotoxicity as structural modifications such as saturation or addition to
the methylene group resulted in the loss of cytotoxicity and tumour inhibition.
However, it has also been shown that the factor responsible for the cytotoxicity of SLs
might be the presence of the O=C-C=CH2 system, regardless of lactone or
cyclopentenone. It was latter demonstrated that the presence of additional alkylating
groups greatly enhanced the cytotoxicity of SLs. Furthermore, it was established that
the α-methylene-γ-lactones and α, β-unsaturated cyclopentenone ring (or α-epoxy
cyclopentenone) present in SLs is essential for their in vivo anti-tumour activity.
Further it has been confirmed by various published reports that the spectrum of
biological activities displayed by SLs is due to presence of either α-methylene-γ-
lactones or α, β-unsaturated cyclopentenone ring.
1.3.3b Side chain and lipophilicity
In general, higher lipophilicity can facilitate penetration through cell
membrane, thereby increasing the SLs cytotoxicity in vitro but steric hindrances set
up a threshold limit. Moreover higher lipophilicity is often associated with lower drug
bioavailability in vivo. In bi-functional helanalin 33 and maxicanin I 34 analogues, the
increased lipophilicity due to lipophilic chain ester and liphophilic conjugated ester
group at C-6, enhanced cytotoxicity aganist Ehrilish ascites both in vitro and in vivo
[53]. However there was a size optimum of lipophilic ester groups beyond which SLs
toxicity decreased. In contrast to this, within the mono-functional 11α-13-
dihydrohelanalin 35, cytotoxicity was directly proportional to the size of the ester side
chain at C-6. Although, larger groups can increase lipophilicity, these moieties,
beyond a size limit, cause steric hindrance on to the exocyclic methylene group,
preventing it from approaching its target.
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The number and position of H-bond acceptors do influence SLs cytotoxicity.
Non covalent interaction, such as hydrogen bond formation between oxygen atoms in
SLs and amino acid residues adjacent to the target protein, can precede alkylation and
increase SLs bioactivity. In addition chemical environment around the target
sulfhydryl groups which are SLs Michael addition sites is important for bioactivity.
1.3.3c Molecular geometry and electronic features
Conformational flexibility effects SLs bioactivity to a very great extent.
Flexible bi-functional helanalins with 7,8- cis fused lactone ring, were more toxic than
rigid maxicanin I derivative with 7,8-trans-fused lactone ring [54]. Within 2,3-
dihydrohelanalin 36, 37 derivatives flexibility accounted for five fold differences in
cytotoxicity between two compounds having identical structures but one bearing
carbonyl group, instead of hydroxyl group at C-4.
Perusal of literature has witnessed that stereochemistry of SLs plays an
important role in defining their anti-tumorigenic properties. Studies of structurally
related pseudoguanolides showed that β-OH isomer (parthenin 30) at C-1 are active
than α-OH equivalent (hymenin 35) [55]. In summary, the differences in activity
among individual SLs may be explained by differences in the number of alkylating
elements, lipophilicity, molecular geometry, and the chemical environment of the
target sulfhydryl group.
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1.4 Natural products as anti-infective agents
Today, infectious diseases are the second major cause of death worldwide and
third leading cause of death in economically advanced countries [56]. Bacterial
pathogens are responsible for several serious diseases. Resistant strains to antibiotics
in clinical use pose great threat to mankind. The ability of bacteria to deceive any kind
of conventional therapy has become apparent and pathogens resistant to one or more
antibiotics are emerging and spreading worldwide [57]. The discovery of vancomycin
resistant S. aureus (VRSA) and multi resistant S. aureus has evoked worldwide
response. Thus, novel antibacterial drugs with broader spectrum of activity are
urgently needed. There is long list of herbs known to be used for many infectious
diseases such as Acacia, Garlic, Turmeric, Neem, Ginger, Clove, Plum and
Pomegranate etc. The extracts from most of these herbs have been screened in quest
for potential and safer antibacterial agents [58-63]. The majority of antibacterial
agents that are in use today find their origin in natural products or their semi-synthetic
variants. More than 75% of new chemical entities that entered in the market between
1984 and 2004 were based on natural product lead structures [64].
β-Lactams were the first class of antibiotics used as therapeutic treatment
against bacterial infections by inhibiting the final step of the bacterial cell wall
biosynthesis [65]. The most important mechanism of this inhibition is the inhibition of
the terminal peptidoglycan cross-linking. Penicillin was the first antibiotic of this
group discovered by Fleming from the cultures of Penicillium notatum in 1928. Since
then this group has been of central importance among many groups of synthetic and
medicinal chemists [66-67]. Production of β-lactamases by bacteria neutralizes the
effect of β-lactam anti-bacterials by hydrolyzing the β-lactam ring which is required
for antibacterial activity. There are four distinct classes of β-lactamases, of which
class-A enzymes are the most common. In order to counter the hydrolysis by β-
lactamases, some antibiotics are administered in combination with a β-lactamase
inhibitor drug. For example, amoxicillin is administered in combination with
clavulanic acid, itself also a β-lactam (oxapenam). The major thrust areas in research
on β-lactams have been the development of new stereo selective methodologies to
construct the β-lactam ring, and structural modifications in compounds, especially
carbapenems and cephems with known activity, to design and develop new molecules
with 1) a broad spectrum of activity, especially against resistant strains and 2) least
side effects. Later on various other antibacterials were isolated from micro-organism
as given in (Fig-15).
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Although, the discovery of antibiotics completely eradicated mankind from infectious disease but their indiscriminate use has led to the development of multi drug-resistant pathogens. More than 80% of S. aureus strains worldwide are resistant to penicillin [68] and methicillin [69]. Efforts are being made to search the reliable methods to control vancomycin-resistant Enterococci (VRE), vancomycin-resistant Streptococcus aureus (VRSA) and methicillin-resistant S. aureus (MRSA). Thus there is a need to design and develop novel highly effective anti-infective agents in general and anti- mycobacterials in particular. Plant derived antibacterials have always been a source of novel therapeutics. Plants are known to produce enormous variety of small molecule antibiotics, generally classified as phytoalexins. But most of these small molecules have weak antibiotic activity, several orders of magnitude less than common antibiotic produced by bacteria and fungi. In spite of the fact that plant derived antibacterials are less potent, plants fight infections successfully. Hence it becomes apparent that plants adopt a different paradigm (synergy) to combat infections.
Fig 15: Different anti-bacterial agents
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1.5 Phenylpropanoids and their biological importance
The Phenylpropanoid (PPs) are a diverse family of organic compounds that
are synthesized by plants from the amino acid phenylalanine through shikimic acid
pathway [70]. Their name is derived from the six-carbon, aromatic phenyl group and
the three-carbon propene tail of cinnamic acid, which is synthesized from
phenylalanine in the first step of phenylpropanoid biosynthesis. These are a group of
water soluble natural products widely distributed in plant kingdom, most of which are
isolated from medicinal plants. Structurally they are characterised by cinammic acid
and hydroxy phenyl ethyl meoties attached to β-glucopyranose through ester and
glycosidic linkages respectively. Rhamanose, xylose, apiose etc., may be attached to
the glucose residues which in most cases form the core of the molecule.
PPs are found throughout the plant kingdom serving essential components of a
number of structural polymers. They provide protection from ultraviolet radiations,
defence against herbivores and pathogens, and mediate plant-pollinator interactions as
floral pigments and scent compounds. An almost ubiquitous feature of plant responses
to incompatible pathogens or to elicitors is the activation of PPs metabolism in which
PAL (phenylalanine ammonia lyase) catalyses the first committed step of the core
pathway of general PP metabolism. Branch pathways lead to the synthesis of
compounds that have diverse defensive functions in plants such as cell wall
strengthening and repair (lignin and suberin), anti-microbial activity (furanocoumarin,
pterocarpan and isoflavonoids phytoalexins), and signalling (salycilic acid) [71]. The
resulting phenolics are often converted into more reactive species by phenol oxidases
and peroxidases [72-73]. There are several PPs-based mechanisms of defence against
pathogens, for example, construction of structural lignin containing barriers
preventing the pathogen penetration into the plant tissues. Another mechanism is the
use of phytoalexin and scopoletin, which could act as broad-range antibiotics.
Additionally, scopoletin being an efficient peroxidase substrate may act as scavenger
of reactive oxygen species and thus prevent, or reduce, oxidative damage to infected
plant cells [74]. PPs exert direct antimicrobial activity and also serve in signalling and
chemotaxis to both pathogenic and symbiotic microorganisms [75].
PPs and their derivatives present in plants are associated with appreciable
defensive role. Plant-derived PPs are among the most common biologically active
compounds displaying large number of medicinal properties viz., antioxidants, UV
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screens, anticancer, anti-virus, anti-inflammatory, wound healing and antibacterial
[76-77]. Additionally, these molecules are of immense importance in cosmetic and
perfume industries [78]. Their chemical synthesis is complex and expensive.
Although in order to increase specificity and activity, natural PPs sometimes are
subjected to chemical modifications. An example of first phenylpropanoid glycoside
isolated was verbascoside also known as acteoside 44 from Verbascum sinuatum.
Further strategies are on way to explore the anti-microbial activity of this important
molecule. Consequently, present work is also aimed to make its potent anti-fungal
analogues.
1.6 Carbohydrate based natural products in medicinal chemistry
Carbohydrates are the most abundant biomolecules. They are present as free
monosaccharides, oligosaccharides, polysaccharides, nucleosides, nucleotides, nucleic
acids and as essential components of glycoconjugates, including glycolipids,
glycoproteins or glycopeptides, and glycosylated natural products.
Nucleosides are elemental building blocks of biological systems that show an
ample range of biological activity [79]. The chemical investigation of nucleosides was
for the first time started by an American scientist Werner Bergmann in 1951[80]. He
first isolated unusual nucleosides spongothymidine 45 and spongouridine 46 (Fig-17)
and then a series of similar compounds [81-82] from the sponge Cryptotethia crypta
collected near the coast of Florida. These molecules contained arabinose residues,
instead of the ribose and deoxyribose residues observed in most compounds of this
class. Those investigations stimulated the appearance of the anti-metabolite
conception in pharmacology. Anti-metabolites are the active substances of drugs,
which are characterized by a significant similarity to, and structural difference from,
human metabolites. Anti-metabolites participate in the biosynthesis of some
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biopolymers, more often, of DNA, and inhibit its exhibiting antitumor and antiviral
properties. Bergmann’s discovery was followed by the development of two arabino-
nucleoside drugs: arabinoadenine 47 and arabinocytosine 48 (Fig-17), which was
used in clinical practice as antitumor and antiviral drugs for decades. Several other
drugs of a nucleoside nature (azidothymidine, acyclovir, etc) differ from ordinary
nucleosides in other structural features. For instance, azidothymidine has an azide
group in its monosaccharide residue, while acyclovir is characterized by an open
furanose cycle.
Extensive modifications have been made to both the heterocyclic base and the
sugar moiety in order to avoid the drawbacks shown by nucleosides or analogues in
certain applications, mainly due to enzymatic degradations. For example it has been
proven that: a) replacement of the oxygen in the sugar portion of the nucleoside with a
methylene unit results in carbocyclic nucleoside analogues which are highly resistant
to phosphorylases, b) simple replacement of the furanose ring-oxygen with a sulphur
atom leads to promising antiviral or antitumor nucleosides, such as 4′- thiothymidine
and 2′-deoxy-4′-thiocytidine and has stimulated the synthesis of this class of
nucleosides. It has also been reported that 4′-thio-Cl-IB-MECA, a 4′-
thioribonucleoside, exhibits a higher binding affinity to the human adenosine A3
receptor than the parent compound, C) attachment of fluorine atoms on sugar moieties
of nucleoside analogues can impart potent anticancer and antiviral activity [83] e.g.,
Gemtacibine 49, d) replacement of nucleobases in oligodeoxynucleotides by designed
surrogates like aromatic bases have been introduced frequently to confer new
functions to DNA, i.e., molecular interactions in DNA-DNA and DNA-protein
recognition processes. Also, deoxynucleoside analogues constitute an important class
of antimitotic drugs used in the treatment of hematological malignancies [84]. This
family includes a number of pyrimidine analogues, such as the sugar-modified
analogue cytosine arabinoside (cytarabine, araC), which is extensively used in the
treatment of acute leukaemia, purine analogues like 6-mercaptopurine, thioguanine, as
well as 2-chloro deoxyadenosine (cladribine,CdA) and 2-fluoroadenine-β-D-
arabinoside (fludarabine). Fludarabine and cladribine have mostly been used in the
treatment of low-grade hematological malignancies, with an apoptotic effect on non-
dividing cells [85]. These therapeutic compounds mimic physiological nucleosides in
terms of uptake and metabolism and are incorporated into nucleic acids.
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Fig 17: Bioactive Nucleosides
1.7 Aims and outline of the thesis
The aim of the research presented in this thesis is the development of a novel
natural product based anticancer and anti-infective agents.
In Chapter 2, the design and synthesis of sesquiterpenoid lactone “santonin”
for anticancer activity has been presented. While exploring the cytotoxic activity of
santonin, it was found that modification of its core skeleton generated new
compounds with promising cytotoxicity. This evoked interest in us to modify this
sesquiterpenoid lactone to generate new compounds with better cytotoxicity. In this
direction, novel spiro analogues of this natural product were developed via 1,3-dipolar
cyclo-addition reactions with nitrile oxides and nitrones. Furthermore, studies were
also carried out by opening the lactone ring of santonin in order to make out its effect
on cytotoxicity. All the synthesised compounds were subjected to preliminary
screening against cancer cells. Most active compounds were taken for further studies.
In Chapter 3, the design and synthesis of sesquiterpenoid lactone “parthenin”
for anticancer activity has been presented. While exploring the cytotoxic activity of
parthenin, it was found that α, β-unsaturated cyclo-pentenone ring was necessary for
its cytotoxicity. Thus in order to examine the effect of exo-methylene group on
cytotoxicity we became interested in modification of α,β-unsaturated double bond of
cyclo-pentenone ring with a view to understand its SAR. In this direction, novel
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triazole analogues of this natural product were developed following click chemistry
approach. All the synthesised compounds were subjected to preliminary screening
against cancer cells. Most active compound was taken for further studies.
In Chapter 4 Section A, structural modification of phenylpropanoid glycoside
viz., “acteoside” has been presented. Acteoside has attracted much attention and is
considered as potential anti-microbial and anti-oxidant agent. But drawback with this
molecule is its low bioavailability owing to its low solubility. Thus in order to increase its bioavailability within the lipid membranes with a view to derive
improved structures from this glycoside with proper hydrophilic-lipophilic balance
(HLB), novel semi-synthetic analogues of this glycoside were developed through
random and lipase catalysed regio-selective acylation approach and screened for
antifungal activity. The resulting compounds are studied for their synergistic
interaction with antifungal drug AmB.
In section B of chapter 4, synthesis and pharmacological activities of
nucleoside mimics from glycal has been presented. Owing to the wide range of
biological activity of nucleosides, synthesis of N-glycoside has been generated from
glycals and their anti-bacterial and anti-cancer activity has been presented in this
section.
1.8 References
[1]. Cragg, G.M., Kingston, D.J.I., Newman, D.J., 2005. CRC Press: Boca Raton,
FL.
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