Bioactive natural products opportunities and challenges in medicinal chemistry

Preface This single volume entitled Bioactive Natural Products: Opportunities & Challenges in Medicinal Chemistry is an endeavor to underline how nat-ural product research continues to

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BIOACTIVE NATURAL PRODUCTS

Opportunities and Challenges in Medicinal Chemistry

To All those who are working globally with bioactive natural products for the cause of human

welfare

Unlike other books with a similar title, this edited volume covers not onlysecondary metabolites from natural product sources and their derivatives,but also a significant amount of what might best be covered under therubric of alternative medicine or even functional food stuffs In addition,

it also contains excellent chapters on the methodologies of production of

“natural products that will be drug molecules in their own right” Thusthere are chapters by well-known experts on not only classical fermenta-tion processes using microbes, but also on the methodologies involved inplant tissue culture This latter system is one that is not often referred to

Thus in this volume, as a result of a careful juxtaposition of whatmight be called “classical natural product-based drug discovery” wherepure single compounds or their close chemical relatives, are used as eth-ical pharmaceutical agents, with commentaries on the history and use ofagents found in “functional foods and alternative therapies”, the readerwill have a more nuanced understanding of the role that natural

vii

products, in the widest sense of the term, has had upon the discovery anddevelopment of agents — be they single agents, or validated mixtures,that can be utilized to maintain the health of people from all areas ofthe world.

David J Newman

Wayne, Pennsylvania, USA

June, 2011

Preface

This single volume entitled Bioactive Natural Products: Opportunities &

Challenges in Medicinal Chemistry is an endeavor to underline how

nat-ural product research continues to make significant contributions in thedomain of discovery and development of new medicinal entities; the pres-ent book brings together a total of fourteen articles contributed by eminentnatural product chemists from several countries in response to my per-sonal invitation I am most grateful to the authors for their generous andtimely response in spite of their busy and tight schedules with academics,research, and other responsibilities

Nature stands as an inexhaustible source of novel chemotypes andpharmacophores; natural products present in the plant and animal king-dom offer a large diversity of chemical structures which are the result

of biosynthetic processes that have been modulated over the millenniathrough genetic effects Interest in obtaining biologically active com-pounds from natural sources has recently spiked due to their lowtoxicity, availability from renewable sources, complete biodegradabil-ity, and in most cases, low cost as well Bioactive natural products areproving to be a rich source of novel therapeutics The search for bioac-tive molecules from nature (plants, animals, microflora) continues toplay an important role in fashioning new medicinal agents With theadvent of modern techniques, particularly the rapid improvements inspectroscopic as well as accompanying advances in high-throughputscreening techniques, it has become possible to have an enormousrepository of bioactive natural compounds, thus opening up excitingnew opportunities in the field of new drug development to the pharma-ceutical industry

Medicinal chemistry of bioactive natural products spans a wide range

of fields, including isolation and characterization of bioactive compoundsfrom natural sources, structure modification for optimization of their

activity and other physical properties, and also total and semi-synthesisfor a thorough scrutiny of structure–activity relationship (SAR) It hasbeen well documented that natural products played crucial roles in mod-ern drug development, especially for antibacterial and antitumor agents;however, their uses in the treatment of other epidemics such as AIDS, car-diovascular, cancerous, neurodegradative, infective, and metabolicdiseases have also been extensively explored The need for leads to solvesuch health problems threatening the world population makes all naturalsources important for the search of novel molecules, diversified andunique structural architectures of which inspired scientists to pursue newchemical entities with completely different structures from known drugs This book, which comprises a variety of fourteen chapters written byactive researchers and leading experts in natural products chemistry onbiologically active natural products, brings together an overview of cur-rent discoveries and trends in this remarkable field The introductory bookeditorial (Chapter 1) attempts to assess the impacts and opportunities ofbioactive natural products in ongoing drug discovery programmes; newdrugs launched during the last decade, originating from terrestrial plants,terrestrial microorganisms, marine organisms, and terrestrial vertebratesand invertebrates are summarized categorically (as per disease area) inthis article In addition, this overview incorporates natural products, semi-synthetic natural products and natural product-derived compounds thatare being presently evaluated in clinical trials or are in registration high-

lighting their mechanism of action Chapter 2 (Matsui et al.) offers an

overview of a new functionality of small peptides in preventing sion and vessel dysfunctions including atherosclerosis Chapter 3 (byFotie) focuses on naturally occurring secondary metabolites that played akey role in the malaria chemotherapy; besides, advances in the total syn-thesis of these compounds and their derivatives along with theirimplications in new strategies for the development of new generation of

hyperten-antimalarial drugs are also discussed Chapter 4 (Scott et al.) provides an

update on naturally occurring bioactive compounds that can inhibit, vate, or modulate the activity of histone deacetylases (HDACs) Chapter

acti-5 (da Silva et al.) summarizes the recent advances on the analytical ods for extraction and quantification of artemisinin from Artemisia annua

meth-plants, and also the biological properties of this natural product highlighting

anti-proliferative structure–activity relationships of a large number (96) ofartemisinin derivatives Chapter 6 (Brahmachari) describes multidirec-tional biological activities exhibited by another promising naturalbioactive compound — andrographolide — the principal bioactive chem-

ical constituent of Andrographis paniculata (Acanthaceae), along with its pharmacokinetics and metabolism Chapter 7 (Mishra et al.) presents a

review on the neuropathology of Alzheimer’s disease and the current state

of research in the use of natural products that may prove effective in the

treatment Chapter 8 (Lozitsky et al.) highlights the use of multi-nutrient

functional peptide complex «GRINIZATION» for the treatment and

pre-vention of viral infections Chapter 9 (Abad et al.) presents an overview

on anti-infective natural bioflavonoids reported since 2005 Chapter 10

(Lawal et al.) reviews anti-Helicobacter pylori activities of compounds of

natural origin Chapter 11 (by Ibezim) deals with the uses and impacts ofnatural remedies for various types of skin ailments Chapter 12(Brahmachari) provides an overview of a wide range of promising antidi-abetic chemical entities of varying structural skeletons isolated fromdifferent natural sources Chapter 13 (Demain and Sanchez) highlightsseveral aspects of process improvement to yield natural products forindustry at the laboratory, pilot plant and factory scales; improvement ofmicrobial strains for overproduction of natural metabolites has been thehallmark of all commercial fermentation processes Finally, Chapter 14

(de Faria et al.) deals with the concept of plant metabolic engineering and

reprogramming along with directional compound trafficking, and alsoprovides examples of promoters for specific gene expression; besides, adiscussion on the advances in the use of cell suspension cultures andtransgenic plants for the cost-effective production of therapeutic drugsand proteins is presented as well

This book encourages interdisciplinary work among chemists, macologists, biologists, botanists, and agronomists with an interest inbioactive natural products This definite volume is also an outstandingsource of information with regard to the industrial application of naturalproducts for medicinal purposes The broad interdisciplinary approachdealt in this book would surely make the work interesting to scientistsdeeply engaged in the research and/or use of bioactive natural products Itwill serve not only as a valuable resource for researchers in their own

phar-fields to predict promising leads for developing pharmaceuticals to treatvarious ailments and disease manifestations, but also motivates youngscientists to the dynamic field of bioactive natural products research.Representation of facts and their discussions in each chapter areexhaustive, authoritative and deeply informative; hence the book wouldserve as a key reference for recent developments in the frontier research

on bioactive natural products, and also would find much utility to the entists working in this area I would like to express my sincere thanksonce again to all the contributors in this volume for the excellent reviews

sci-of bioactive natural products that they have produced It is their tion that makes my effort to organize such a book possible Their masterlyaccounts will surely provide its readers with a strong awareness of currentcutting-edge research approaches being followed in some of the promis-ing fields of biologically active natural products

participa-I would like to express my sincere thanks and deep sense of gratitude

to Dr David J Newman, Chief, Natural Products Branch, NationalCancer Institute, USA for his keen interest in the manuscript

I would also like to express my deep sense of appreciation to all of theeditorial and publishing staff members of World Scientific Publishing Co.Pte Ltd., Singapore for their keen interest in publishing the works as well

as their all-round help to ensure the highest standards of publication aremaintained in bringing out the book

Goutam Brahmachari

Santiniketan, June 2011

Contents

Opportunities — An Assessment

Goutam Brahmachari

Toshiro Matsui, Zhengquan Wang and Mitsuru Tanaka

From Quinine to Artemisinin and Beyond

Jean Fotie

of Histone Deacetylases

Michael D Scott, Manas K Haldar and Sanku Mallik

of Potent Anticancer Agents

Daniel L da Silva, Luzia V Modolo, Ilza M O Sousa,Rodney A F Rodrigues, Mary Ann Foglio

and Ângelo de Fátima

Molecule of Pharmaceutical Promise

Goutam Brahmachari

7 Natural Products in Alzheimer’s Disease: 369 Impacts and Prospects

Shri Kant Mishra, Mark C Stahl and Parampreet Singh

«GRINIZATION» for Treatment and Prevention

of Viral Infections

Viktor Lozitsky, Alla Fedchuk, Irina Gomolyako,Ivan Chekman, Anatoliy Bulavka, Galyna Anokhina,Georgiy Donchenko, Sergiy Pozdnyakov, Xeniya Igrunova,Tetyana Grydina, Lidiya Socheslo, Liubov Mudryk,Nataliya Klochkova, Larysa Shytikova,

Valentina Pushkina, Olga Golubovska, Vladimir Shestakovand Anatoliy Pechinka

María José Abad, Luis Miguel Bedoya,Luis Apaza and Paulina Bermejo

Compounds of Natural Origin

Temitope O Lawal, Kapil K Soni, R C Saxena,Bolanle A Adeniyi and Gail B Mahady

of Skin Diseases

Emmanuel C Ibezim

A Retrospective Account of Some Promising Chemotypes

Goutam Brahmachari

Yielding Natural Products for Industry

Arnold L Demain and Sergio Sanchez

14 Plant Cell Culture and Transgenic Plants: 631 The Goldmines for the Production of

Compounds of Pharmacological Interest

Ana Paula de Faria, Ângelo de Fátima,Vagner A Benedito and Luzia V Modolo

List of Contributors

*María José Abad

Department of Pharmacology, Faculty of Pharmacy, University Complutense,Ciudad Universitaria s/n, 28040, Madrid, Spain

Luis Miguel Bedoya

Department of Pharmacology, Faculty of Pharmacy, University Complutense,Ciudad Universitaria s/n, 28040, Madrid, Spain

Vagner A Benedito

Genetics and Developmental Biology Program, Plant and Soil SciencesDivision, West Virginia University, 2090 Agricultural Sciences Building,Morgantown, WV USA

xvii

* Corresponding author

9 Leontovich str., 01601, Kyiv, Ukraine.

Ana Paula de Faria

Grupo de Estudos em Bioquímica de Plantas (GEBioPlan), Departamento

de Botânica, ICB, Universidade Federal de Minas Gerais, Belo Horizonte,

MG Brazil

*Ângelo de Fátima

Grupo de Estudos em Química Orgânica e Biológica (GEQOB),Departamento de Química, ICEx, Universidade Federal de Minas Gerais,Belo Horizonte, MG Brazil

* Corresponding author

*Alla Fedchuk

Laboratory of immune-biological and chemotherapeutical preparations,I.I Mechnikov Ukrainian Anti-Plague Research Institute, Ministry ofHealth of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine

Mary Ann Foglio

Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas,Universidade Estadual de Campinas, Paulínia, SP Brazil

*Gail B Mahady

Department of Pharmacy Practice, UIC PAHO/WHO CollaboratingCentre for Traditional Medicine, University of Illinois at Chicago,College of Pharmacy, 833 South Wood st., Chicago, IL 60612, USA

*Shri Kant Mishra

Professor of Neurology at the Keck School of Medicine, USC.; ClinicalProfessor of Neurology, David Geffen School of Medicine, UCLA.;Director of Neuromuscular Disease, VA Greater Los Angeles & OliveView UCLA Medical Center, 16111 Plummer Street, Sepulveda,California 91343

*Luzia V Modolo

Grupo de Estudos em Bioquímica de Plantas (GEBioPlan), Departamento

de Botânica, ICB, Universidade Federal de Minas Gerais, Belo Horizonte,

MG Brazil

Liubov Mudryk

Laboratory of immune-biological and chemotherapeutical preparations,I.I Mechnikov Ukrainian Anti-Plague Research Institute, Ministry ofHealth of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine

Sergio Sanchez

Departamento de Biología Molecular y Biotecnología, Instituto deInvestigaciones Biomédicas, Universidad Nacional Autónoma de México,México D.F 04510

Daniel L da Silva

Grupo de Estudos em Química Orgânica e Biológica (GEQOB),Departamento de Química, ICEx, Universidade Federal de Minas Gerais,Belo Horizonte, MG Brazil

Kapil K Soni

Department of Pharmacy Practice, UIC PAHO/WHO CollaboratingCentre for Traditional Medicine, University of Illinois at Chicago,College of Pharmacy, 833 South Wood st., Chicago, IL 60612, USA

Natural Products in Drug

Discovery: Impacts and

Opportunities — An Assessment

Goutam Brahmachari*

Nature stands as an inexhaustible source of novel chemotypes and macophores, and has been a source of medicinal agents for thousands ofyears, and an impressive number of modern drugs find their origin innatural products Natural product chemistry has experienced explosiveand diversified growth, making natural products the subject of muchinterest and promise in the present day research directed towards drugdesign and discovery It is noteworthy that natural products are a source

phar-of new compounds with diversified structural arrangements possessinginteresting biological activities Natural products, thus, have played andcontinue to play an invaluable role in the drug discovery process.Recently, there has been a renewed interest in natural products researchdue to the failure of alternative drug discovery methods to deliver manylead compounds in key therapeutic areas such as immunosuppression,anti-infective, and metabolic diseases However, continuing improve-ments in natural products research are needed to continue to becompetitive with other drug discovery methods, and also to keep pacewith the ongoing changes in the drug discovery process Faithful drivesare needed in a more intensified fashion to explore “Nature” as a source

of novel and active agents that may serve as the leads and scaffolds forelaboration into urgently needed efficacious drugs for a multitude of dis-ease indications

Natural products have provided considerable value to the ceutical industry over the past half century In particular, the therapeutic

pharma-1

1

* Corresponding author E-mail: brahmg2001@yahoo.co.in; brahmg2001@gmail.com

areas of infectious diseases and oncology have benefited much fromnumerous drug classes derived from the natural form and as templatesfor synthetic modification About 40 new drugs launched on the marketbetween 2000 and 2010, originating from terrestrial plants, terrestrialmicroorganisms, marine organisms, and terrestrial vertebrates and inver-tebrates are reported, and summarized categorically (as per disease area)

in this article In addition, this review incorporates natural products andnatural product-derived compounds that are being presently evaluated inclinical trials or are in registration highlighting their mechanism ofaction These drugs substances, representative of very wide chemicaldiversity, thus continue to demonstrate the importance of compoundsfrom natural sources in modern drug discovery efforts Hence, theproven natural product drug discovery track record, coupled with thecontinuing threat to biodiversity through the destruction of terrestrialand marine ecosystems, provides a compelling challenge for the globalscientific community to undertake expanded exploration of “Nature” as

a source of novel leads for the development of drugs and other valuablebioactive agents A huge number of natural product-derived compounds

in various stages of clinical development highlight the existing viabilityand significance of the use of natural products as sources of new drugcandidates

“Organic chemistry just now is enough to drive one mad It gives the impression of a primeval tropic forest, full of the most remarkable things, a monstrous and boundless thicket, with no way to escape, into which one may well dread to enter.”

Wöhler (1835)

1 Introduction

Almost two centuries had elapsed after Wöhler’s historical comment cited

in his letter to Berzelius in the year 1835 on the ongoing development of

organic chemistry; his “monstrous and boundless thicket” is now

suffi-ciently more dense and complex than ever and quite forbidding tostrangers! Natural products chemistry, a vital section of organic chemistry,

has also undergone an explosive growth in its own course and has alreadyestablished itself as a distinct discipline Mother Nature now stands as an

Nature’s terrestrial flora and fauna have formed the basis of cated traditional medicine systems that have been in existence forthousands of years — such an intrinsic dependence of human beings onNature has invoked tremendous interest in the scientific world, which ulti-mately led to the isolation of a vast number of chemical agents with the

challenge of determining the structures of ever more complicated naturalproducts From the late 19th century until today, generations of naturalproduct chemists have applied their skills and intellect to many tens ofthousands of molecules of natural origin, encouraged by a society that val-ues many natural products for their life-giving or life-enhancing properties.Although ~200 000 natural compounds derived from natural sources such

as plants, animals or microorganisms are currently known, this figure iswith small variety regards to the widen of natural resources; only about5–15% of nearly 250 000 higher plants and less than 1% of the microbialworld have been explored so far chemically — the vast majority of these

dis-covery, thus, appears to be a tale of justifiable hope The pragmaticoptimism currently placed on natural products in search of new drugs andlead molecules has recently been aptly expressed as “The world of plants,and indeed all natural sources, represent a virtually untapped reservoir of

By the 20th century, natural products began to provoke some chemists interested in understanding the way in which compounds weremade that eventually initiated the concepts of biosynthetic pathways for dif-ferent kinds of natural products In the early 20th century, very fewresearchers associated with the emerging departments of clinical biochem-istry, pharmacology, toxicology, microbiology and cell biology becamemotivated to work with some specific natural products, but the study of nat-ural products as a group was still largely confined to chemistry departments

bio-By the mid 20th century, some cell biologists and physiologists screened afew natural products (viz colchicine, atropine, nicotine, digoxin, etc.) asexperimental tools that influenced or disrupted cell functions in specific

ways However, it was the discovery of antibiotics that offered the study ofnatural products a great boost in microbiology departments and ensured that

Due to multidirectional promising aspects, the interest in natural

use of botanical products among members of the general public throughself-medication than never before The use of herbal drugs is once moreescalating in the form of complementary and alternative medicine

atten-tion to phytomedicines as a form of alternative therapy by the healthprofessions; in many developing countries of the world, there is still amajor reliance on crude drug preparation of plants used in traditional med-

(WHO) estimates that approximately 80% of the world’s population reliesmainly on traditional medicine, predominantly originated from plants, for

remedies is noteworthy; in the US alone, in 1997, it was estimated that

sales of herbal remedies were worth of £75 million in 2002, an increase

out in other countries, such as Australia and Italy, also suggest an

In India and China, the Ayurvedic and Chinese traditional medicine tems respectively are particularly well developed, and both have providedpotential for the development of Western medicine Throughout our evo-lution, the importance of natural products for medicine and health hasbeen enormous; the past few years have seen a renewed interest in the use

sys-of natural compounds and, more importantly, their role as a basis for drugdiscovery The modern tools of chemistry and biology — in particular, thevarious “-omics” technologies — now allow scientists to detail the exactnature of the biological effects of natural compounds on the human body,

as well as to uncover possible synergies, which holds much promise for

Natural products, thus, have been the major sources of chemicaldiversity as starting materials for driving pharmaceutical discovery over

natural product derivatives have been successfully developed for clinical

prod-uct medicines have come from various source materials includingterrestrial plants, terrestrial microorganisms, marine organisms, and ter-

products in modern medicine has been described in a number of earlier

A comprehensive review of natural products in clinical trials, “RecentNatural Products Based Drug Development: A Pharmaceutical Industry

of discussions have been published that describe natural product-derivedcompounds in clinical trials by organism type, compound class and/or

present chapter is aimed, particularly, to highlight the impact and tunities of natural products in modern drug discovery programsdelineating the approved natural product-based drugs launched during theperiod 2000 to 2010, and also natural product-based drug candidatesundergoing clinical evaluation

oppor-2 Natural Products in Traditional Medicine:

A Historical Perspective in Brief

Natural products (including plants, animals and minerals) have been thebasis of treatment of human diseases History of medicine dates backpractically to the existence of human civilization Modern medicine sys-tem has gradually developed over the years by scientific and observationalefforts of scientists; however, the basis of its development remains rooted

in traditional medicine and therapies, prevailing throughout the world forthousands of years, which continue to provide mankind with new remedies.Plant-based medicines initially dispensed in the form of crude drugs such

serve as the basis of novel drug discovery The plant-based indigenousknowledge was passed down from generation to generation in variousparts of the world throughout its history and has significantly contributed

to the development of different traditional systems of medicine

The history of traditional medicine in India can be traced to theremote past Multidirectional therapeutic uses of various plants in tradi-

tional way are known in India since the Vedic times as Ayurvedic and

Unani systems of medicine The lore of any country man is built upon the

experience of generations, often of centuries and the data upon which it isbased have often been obtained at a price in human lives which no mod-ern research worker would ever dream of considering The earliest

mention of the medicinal use of plants is found in the Rig Veda, perhaps

the oldest repository of human knowledge, having been written between

4500 and 1600 BC “Susruta Samhita” which was written not later than

1000 BC contains a comprehensive chapter on therapeutics and “Charaka

Samhita”, written about the same period, gives a remarkable description

of the materia medica as it was known to the ancient Hindus During the centuries that have gone by, the materia medica of the indigenous system

of medicine has become explosive and heterogeneous

The “Nei Ching” is also one of the earliest health science anthologies,

nat-ural products in medicine were written in cuneiform in Mesopotamia on

agents continue to exist in one form or another to this day as treatments forvarious ailments Chinese herb guides document the use of herbaceous

Medica” has been repeatedly documented over centuries starting at about

the Ming Dynasty entitled “Pen-ts’as kang mu” in AD 1596, which records

these documents is the Ebers Papyrus, which documents nearly 1000

dif-ferent substances and formulations, most of which are plant-based

entitled “De Materia Medica” in approximately AD 100, and this is still a

very well-known European document on the use of herbs in medicine.However, it should not go unrecognized that it was the Arabs who wereresponsible for maintaining the documentation of much of the Greek andRoman knowledge of herbs and natural products and expanding that infor-

Besides, various types of societies and botanical clubs held meetings andpublished different types of communications to educate the general peoplewith regard to the availability of natural products and how they could be

helpful to an individual’s health Samuel Thompson’s “Thompson’s New

Guide to Health” was also one very popular publication For a variety of

reasons, the interest in natural products continues to this veryday.16,17,19,20–22,83,84

In many developing countries of the world, there is still a majorreliance on crude drug preparation of plants used in traditional medicines

dif-ferent institutions are aware of the changing trends of herbal medicationsand a number of useful texts on the analysis, uses, and potential toxicities

of herbal remedies have appeared recently, which serves as useful guides

in pharmacy practice The history of medicine includes many ludicroustherapies Nevertheless, ancient wisdom has been the basis of modernmedicine and will remain as one important source of future medicine andtherapeutics The future of natural products drug discovery will be moreholistic, personalized and involve the wise use of ancient and modern ther-apeutic skills in a complementary manner so that maximum benefits can be

The use of natural products as medicine has invoked the isolation ofactive compounds; the first commercial pure natural product introduced

for therapeutic use is generally considered to be the narcotic morphine (1),

aspirin (2), based on a natural product salicin (3) isolated from Salix alba,

was introduced by Bayer in 1899 This success subsequently led to the

isolation of early drugs such as cocaine, codeine, digitoxin (4), quinine (5),

HO

3 Natural Products: The Inherent Potentiality

The most striking feature of natural products in connection to their lasting importance in drug discovery is their structural diversity that is stilllargely untapped Most natural products are not only sterically more com-plex than synthetic compounds, but differ also with regards to the

vol-ume of the chemical space and display a broader dispersion of structuraland physicochemical properties than compounds issued from combinato-

endeavors adopted in recent times for synthesizing complex structures

the chemical scaffolds found in natural products are still absent in today’s

O

OH

O

OH O

H

MeO

N

N O

O

Pilocarpine (6)

activities of a wide variety of natural products have propelled many coveries in chemical and biological sciences, and provided therapeuticagents to treat various diseases as well as offered leads for the develop-ment of valuable medicines.

dis-The history of pharmacognosy is, in part, defined by the ever ing catalog of naturally occurring, biologically active compounds thathave been discovered and characterized It has been estimated that about

chemical potential of plants is however, still largely unexplored Chemicaldiversity has only been analyzed in about 5–15% of all land plants, andeven here only the most abundant compounds have been well character-ized Hence, there remains an unprecedented possibility for the discovery

of novel chemicals that may find diverse uses from pharmaceuticalsthrough fine chemicals Natural products, thus, continue to be a majorsource of biologically active compounds that may serve as commerciallysignificant entities themselves or may provide lead structures for thedevelopment of modified derivatives possessing enhanced activity and/orreduced toxicity

Even though combinatorial synthesis is now producing molecules thatare drug-like in terms of size and property, these molecules, in contrast to

Natural compounds such as brefeldin A, camptothecin, forskolin and

Analysis of the properties of synthetic and natural compounds compared

to drugs revealed the distinctiveness of natural compounds, especiallyconcerning the diversity of scaffolds and the large number of chiral cen-tres This may be one reason why ~50% of the drugs introduced to themarket during the last 20 years are derived directly or indirectly from nat-

In chemical biology, natural products play an important role to date complex cellular mechanisms, including signal transduction and cellcycle regulation, leading to the identification of important targets for ther-

natural products, or new natural product-like small molecules in thefields of genomic and proteomics for the rapid identification of largenumbers of gene products for which the small molecule modulators will

be of both biological and medicinal interest.99–103Besides, the tion of cell biology and high throughput technology has led to thedevelopment of various cellular assays in which small molecule libraries

The reason for the lack of lead compounds from synthetic libraries insome therapeutic areas such as anti-infectives, immunosuppression,oncology, and metabolic diseases may be due to the different chemical

This difference in chemical space makes natural products an attractivealternative to synthetic libraries, especially in therapeutic areas that have

a dearth of lead compounds Natural products have been used also as

product pharmacophores are well represented in lists of “privileged tures”, which make them ideal candidates for building blocks for

con-stitute a prolific source of novel lead compounds or pharmacophores formedicinal chemistry, and hence, natural products should be incorporatedinto a well-balanced drug discovery program Besides their potential aslead structures in drug discovery, natural products also provide attractivescaffolds for combinatorial synthesis and act as indispensable tools for the

4 Natural Products in Drug Discovery: Success, Constrains and New Approaches for Remedies

4.1 A Success Story

Mother Nature still continues to be a resource of novel chemotypes andpharmacophores, and an impressive number of modern drugs have beenisolated from natural sources, many based on their uses in traditional med-

design represents the natural evolution of this old tradition It has beenextensively documented that the traditional medicine systems of many

products have been regarded as important sources that could producepotential chemotherapeutic agents A comprehensive review of the history

of medicine may be consulted, in this regard, on the homepage of theNational Library of Medicine (NLM), History of Medicine atwww.nlm.nih.gov/hmd/hmd.html

Large numbers of promising lead molecules have come out of

Ayurvedic experimental base including Rauwolfia alkaloids for

hyperten-sion, psoralens in vitiligo, guggulsterons as hypolipidemic agents,

Mucuna pruriens for Parkinson’s disease, bacosides in mental retention,

phyllanthus as antivirals, picrosides in hepatic protection, curcumines ininflammations, withanolides and many others steroidal lactones and gly-

source of natural product leads — a few more examples are: morphine,cocaine, digitalis, quinine, tubocurarine, nicotine, muscarine, paclitaxel(Taxol™) and artemisinin There are growing evidences where the oldmolecules are finding new applications through better understanding oftraditional knowledge and clinical observations For instance, the alka-loid, forskolin isolated by Hoechest and coleonol by Central DrugResearch Institute (CDRI), Lucknow, India a few decades ago from

Coleus forskohlii121 and phytochemicals from Stephania glabra, which

were shelved for a considerable time are now being rediscovered asadenylate cyclase and nitric oxide activators, which may help in prevent-

also provide a vast pool of pancreatic lipase inhibitors as potential dates, which can be developed into new drugs for the treatment of

development of newer anti-inflammatory drugs are also available in

The blossoming of natural product discovery efforts occurred after thelarge scale production of penicillin during World War II, when the phar-maceutical companies that contributed to the war-time efforts to build stocks

of penicillin refocused their programs on the search for new antibiotics

identifica-tion of crucial targets followed by study of new bacterial or fungal strainshave resulted in the discovery of significant antibacterial agents such ascephalosporins, streptomycin, gentamicin, tetracycline, chloramphenicol,

aminoglycosides, rifamycins and many others that spurred the industry todevelop large research and development programs around natural product

All of the major pharmaceutical companies had programs on natural uct discovery, and these programs focused not only on anti-bacterial andanti-fungal targets, but also on targets other than infectious diseases In the1970s for example, the discovery of cholesterol biosynthesis-inhibiting

successful statin therapeutics, which even today represent successes in

Since the past five decades, marine sources (viz coral, sponges, fish andmarine microorganisms) have attracted scientists from different disci-plines leading to the discovery of several marine natural products withpromising biological activities; a few of them include curacin A, eleuther-

Venoms and toxins (peptides and non-peptides) found in snakes, spiders,scorpions, insects, and other microorganisms are also significant in drugdiscovery due to their specific interactions with macromolecular targets inthe body, and have been proven crucial while studying receptors, ion

tetrodotoxin (from puffer fish and many other widely varying animals

etc are in clinical trials for drug development Similarly, neurotoxins

obtained from Clostridium botulinum (responsible for botulism, a serious

food poisoning), were been found to be significant in preventing muscle

The impact of natural products on drug discovery has, thus, been mous; natural products originating from microorganism, plant and animalsources have been the single most productive source of leads for the devel-

substances involved in drug discovery programs in “olden times” (i.e.before the advent of high-throughput screening (HTS) and the post-genomicera) were reported to be natural products or inspired by natural product

presented on sources of new drugs from 1981 to 200751,72 indicate thatalmost half of the drugs approved since 1994 are based on natural products.

In the areas of cancer and infectious diseases, 60% and 75% of new drugs,

Between 2001 and 2005, 23 new drugs derived from natural products wereintroduced for the treatment of disorders such as bacterial and fungal infec-tions, cancer, diabetes, dyslipidemia, atopic dermatitis, Alzheimer’s diseaseand genetic diseases such as tyrosinaemia and Gaucher disease; two drugshave been approved as immunosuppressive agents and one for pain man-agement Thirteen natural product-related drugs were approved from 2005

to 2007 and, as pointed out by Butler, five of these represented the first

90 antibacterial drugs that became commercially available in the US or wereapproved worldwide from 1982 to 2002, ~79% can be traced to a natural

representative 150 prescription drugs (prescribed mainly as anti-allergy/pulmonary/respiratory agents, analgesics, cardiovascular drugs, and forinfectious diseases) in the US were natural products and related drugs.Another study found that natural products or related substances accountedfor 40%, 24%, and 26% of the top 35 worldwide ethical drug sales in 2000,

pacli-taxel (ranked at 25 in 2000), a plant-derived anticancer drug, had sales of

can-cer chemotherapeutic agents were responsible for approximately one third

of the total anticancer drug sales worldwide, or just under $3 billion dollars

in 2002; namely, the taxanes, paclitaxel and docetaxel, and the camptothecin

suc-cess in drug discovery, natural products are likely to continue to be sources

of new commercially viable drug leads Combined with pharmacologicalscreening, the chemistry of natural products has always provided highlyuseful leads for drug discovery The search for new biologically active com-pounds are most often based on hints from ethnobotany but there are still alarge number of unstudied plants, mushrooms, marine organisms, insects,and microorganisms There is a wealth of molecular diversity out there,waiting to be discovered and utilized

4.2 Lacunae/Constrains

After very successful drug discovery and development programs based onnatural products, the pharmaceutical industry, in particular the large phar-maceutical companies, de-emphasized natural product discovery research in

alternative drug discovery methods such as rational drug design involvingautomated high-throughput screening (HTS) technology in combination

developed technologies would result in the development of drugs within ashort and affordable time scale of the so-called “blitz” screen (start to finish

in 3 months) Thus, the promise of a ready supply of large synthetic pound libraries led many companies to eliminate or considerably scale

that directed the downfall of natural products in the pharmaceutical try in the 1990s include difficulties in access and supply, complexities ofnatural product chemistry, the inherent slowness of working with naturalproducts, and concerns about intellectual property rights Rediscovery ofknown compounds is a major problem when screening natural productlibraries This is caused by a lack of efficient dereplication methodologiesfor both natural product sourcing and compounds in the natural productlibraries The time-consuming processes of dereplication and purificationare not compatible with the present regime of “blitz” screening campaigns

indus-in which assay support is only available for a limited duration (3 months).Besides, natural products are often structurally complex; modification ofcomplex natural products using organic chemistry is frequently challenging.Medicinal and combinatorial chemists prefer not to work with natural prod-ucts because of the large size and complexity of the compounds, which havetoo many functional groups to protect It is difficult to prepare as many nat-

However, despite the promise of these alternative drug discovery methods,there is still a shortage of lead compounds progressing into clinical trials.This is especially the case in therapeutic areas such as oncology, immuno-suppression and metabolic diseases where natural products have played acentral role in lead discovery Marketed drugs derived from natural productsstill account for significant revenues in many of the major pharmaceutical

therapeutic agents derived from the natural product statin class of pounds, continue to generate multi-billion dollar revenues Antibiotics, likezithromax and the generic penicillins, continue to be essential in medicalcare, however they contribute less to pharmaceutical revenues than non-antibiotics due to their relatively limited dosing intervals.

com-4.3 New Approaches for Possible Remedies

Recent technological advances and the development of new methods haverevolutionized the screening of natural products and offer a unique oppor-tunity to re-establish natural products as major source of drug leads Thenew methods and technologies can address the aforementioned limitations

of the screening of natural products Examples of recent advances in theapplication of these technologies that have immediate impact on the dis-covery of novel drugs are: (i) development of a streamlined screeningprocess for natural products, (ii) improved natural product sourcing,(iii) advances in organic synthetic methodologies, (iv) combinatorialbiosynthesis, and (v) microbial genomics Each of these technologies wasdiscussed in details by Kin S Lam in his article “New aspects of natural

may also offer efficient platforms for herbal formulations; the impact ofsuch approaches has recently been elaborately reviewed by Patwardhan

on the development of natural product leads arising out of varying naturalsources inducing microbial and marine environments The biosynthesis ofnatural products themselves can also be manipulated with the understand-ing of the genetics and biosynthesis pathways to yield new derivatives with

new natural products, genome mining would certainly have an impact onthe understanding and manipulation of the production of natural products.Natural product compounds not only serve as drugs or templates fordrugs, but in many instances lead to the discovery and better understand-ing of targets and pathways involved in the disease process Elucidation ofthe anti-inflammatory mechanism of aspirin action led to the discovery ofthe cyclooxygenase isozymes COX-1 and -2, which are being used in the