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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.

[2]. Butler, M.S., 2005. Nat. Prod. Rep. 22, 162-195.

[3]. Newman, D.J., Cragg. G.M., 2007. J. Nat. Prod.70, 461-477.

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