Bioactive natural products opportunities and challenges in medicinal chemistry

BIOACTIVE
NATUR AL PRODUCTS
Opportunities and Challenges in Medicinal Chemistry

8033hc.9789814335379-tp.indd 1

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BIOACTIVE
NATURAL PRODUCTS
Opportunities and Challenges in Medicinal Chemistry

editor

Goutam Brahmachari
Visva-Bharati University, India

World Scientific
NEW JERSEY

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BEIJING

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TA I P E I

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CHENNAI

8/29/11 10:32 AM


Published by
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BIOACTIVE NATURAL PRODUCTS
Opportunities and Challenges in Medicinal Chemistry
Copyright © 2012 by World Scientific Publishing Co. Pte. Ltd.
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ISBN-13 978-981-4335-37-9
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To
All those who are working globally with
bioactive natural products for the cause of human
welfare



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Foreword

Unlike other books with a similar title, this edited volume covers not only
secondary metabolites from natural product sources and their derivatives,
but also a significant amount of what might best be covered under the

rubric 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”. Thus
there are chapters by well-known experts on not only classical fermentation processes using microbes, but also on the methodologies involved in
plant tissue culture. This latter system is one that is not often referred to
for drug production, but over the last 5+ years, it has become a major
method for the production of the antitumor drug Taxol® by BristolMyers
Squibb.
A point that is often forgotten in westernized medicine is that of the
approximate 7 billion people in the world at this moment, more than 80%
of them do not have routine access to drugs as they are defined in Western
medicine, but rely upon predominately plant-based therapies as their
sources of medicinal agents. Even in areas of the world where single agent
drugs are available, traditional therapeutic regimens such as Ayurveda in
India, Traditional Chinese Medicine, and Japanese and Korean herbals are
still the major source of medicinals.
Thus in this volume, as a result of a careful juxtaposition of what
might be called “classical natural product-based drug discovery” where
pure single compounds or their close chemical relatives, are used as ethical pharmaceutical agents, with commentaries on the history and use of
agents found in “functional foods and alternative therapies”, the reader
will have a more nuanced understanding of the role that natural

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Foreword

products, in the widest sense of the term, has had upon the discovery and
development of agents — be they single agents, or validated mixtures,
that can be utilized to maintain the health of people from all areas of
the world.
David J. Newman
Wayne, Pennsylvania, USA
June, 2011


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Preface

This single volume entitled Bioactive Natural Products: Opportunities &
Challenges in Medicinal Chemistry is an endeavor to underline how natural product research continues to make significant contributions in the

domain of discovery and development of new medicinal entities; the present book brings together a total of fourteen articles contributed by eminent
natural product chemists from several countries in response to my personal invitation. I am most grateful to the authors for their generous and
timely response in spite of their busy and tight schedules with academics,
research, and other responsibilities.
Nature stands as an inexhaustible source of novel chemotypes and
pharmacophores; natural products present in the plant and animal kingdom offer a large diversity of chemical structures which are the result
of biosynthetic processes that have been modulated over the millennia
through genetic effects. Interest in obtaining biologically active compounds from natural sources has recently spiked due to their low
toxicity, availability from renewable sources, complete biodegradability, and in most cases, low cost as well. Bioactive natural products are
proving to be a rich source of novel therapeutics. The search for bioactive molecules from nature (plants, animals, microflora) continues to
play an important role in fashioning new medicinal agents. With the
advent of modern techniques, particularly the rapid improvements in
spectroscopic as well as accompanying advances in high-throughput
screening techniques, it has become possible to have an enormous
repository of bioactive natural compounds, thus opening up exciting
new opportunities in the field of new drug development to the pharmaceutical industry.
Medicinal chemistry of bioactive natural products spans a wide range
of fields, including isolation and characterization of bioactive compounds
from natural sources, structure modification for optimization of their
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Preface

activity and other physical properties, and also total and semi-synthesis
for a thorough scrutiny of structure–activity relationship (SAR). It has
been well documented that natural products played crucial roles in modern drug development, especially for antibacterial and antitumor agents;
however, their uses in the treatment of other epidemics such as AIDS, cardiovascular, cancerous, neurodegradative, infective, and metabolic
diseases have also been extensively explored. The need for leads to solve
such health problems threatening the world population makes all natural
sources important for the search of novel molecules, diversified and
unique structural architectures of which inspired scientists to pursue new
chemical entities with completely different structures from known drugs.
This book, which comprises a variety of fourteen chapters written by
active researchers and leading experts in natural products chemistry on
biologically active natural products, brings together an overview of current discoveries and trends in this remarkable field. The introductory book
editorial (Chapter 1) attempts to assess the impacts and opportunities of
bioactive natural products in ongoing drug discovery programmes; new
drugs launched during the last decade, originating from terrestrial plants,
terrestrial microorganisms, marine organisms, and terrestrial vertebrates
and invertebrates are summarized categorically (as per disease area) in
this article. In addition, this overview incorporates natural products, semisynthetic natural products and natural product-derived compounds that
are being presently evaluated in clinical trials or are in registration highlighting their mechanism of action. Chapter 2 (Matsui et al.) offers an
overview of a new functionality of small peptides in preventing hypertension and vessel dysfunctions including atherosclerosis. Chapter 3 (by
Fotie) focuses on naturally occurring secondary metabolites that played a
key role in the malaria chemotherapy; besides, advances in the total synthesis of these compounds and their derivatives along with their
implications in new strategies for the development of new generation of
antimalarial drugs are also discussed. Chapter 4 (Scott et al.) provides an
update on naturally occurring bioactive compounds that can inhibit, activate, or modulate the activity of histone deacetylases (HDACs). Chapter

5 (da Silva et al.) summarizes the recent advances on the analytical methods for extraction and quantification of artemisinin from Artemisia annua
plants, and also the biological properties of this natural product highlighting


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anti-proliferative structure–activity relationships of a large number (96) of
artemisinin derivatives. Chapter 6 (Brahmachari) describes multidirectional biological activities exhibited by another promising natural
bioactive compound — andrographolide — the principal bioactive chemical 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 prevention 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 of
natural remedies for various types of skin ailments. Chapter 12
(Brahmachari) provides an overview of a wide range of promising antidiabetic chemical entities of varying structural skeletons isolated from

different natural sources. Chapter 13 (Demain and Sanchez) highlights
several aspects of process improvement to yield natural products for
industry at the laboratory, pilot plant and factory scales; improvement of
microbial strains for overproduction of natural metabolites has been the
hallmark 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 also
provides examples of promoters for specific gene expression; besides, a
discussion on the advances in the use of cell suspension cultures and
transgenic plants for the cost-effective production of therapeutic drugs
and proteins is presented as well.
This book encourages interdisciplinary work among chemists, pharmacologists, biologists, botanists, and agronomists with an interest in
bioactive natural products. This definite volume is also an outstanding
source of information with regard to the industrial application of natural
products for medicinal purposes. The broad interdisciplinary approach
dealt in this book would surely make the work interesting to scientists
deeply engaged in the research and/or use of bioactive natural products. It
will serve not only as a valuable resource for researchers in their own


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fields to predict promising leads for developing pharmaceuticals to treat
various ailments and disease manifestations, but also motivates young
scientists to the dynamic field of bioactive natural products research.
Representation of facts and their discussions in each chapter are
exhaustive, authoritative and deeply informative; hence the book would
serve as a key reference for recent developments in the frontier research
on bioactive natural products, and also would find much utility to the scientists working in this area. I would like to express my sincere thanks
once again to all the contributors in this volume for the excellent reviews
of bioactive natural products that they have produced. It is their participation that makes my effort to organize such a book possible. Their masterly
accounts will surely provide its readers with a strong awareness of current
cutting-edge research approaches being followed in some of the promising fields of biologically active natural products.
I would like to express my sincere thanks and deep sense of gratitude
to Dr. David J. Newman, Chief, Natural Products Branch, National
Cancer Institute, USA for his keen interest in the manuscript.
I would also like to express my deep sense of appreciation to all of the
editorial 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 are
maintained in bringing out the book.
Goutam Brahmachari
Santiniketan, June 2011


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Contents

Foreword
Preface
List of Contributors

vii
ix
xvii

1.

Natural Products in Drug Discovery: Impacts and
Opportunities — An Assessment
Goutam Brahmachari

2.

Vascular Regulation by Small Peptides
Toshiro Matsui, Zhengquan Wang and Mitsuru Tanaka

201

3.

Key Natural Products in Malaria Chemotherapy:
From Quinine to Artemisinin and Beyond
Jean Fotie

223

4.

Natural Product Inhibitors and Activators
of Histone Deacetylases
Michael D. Scott, Manas K. Haldar and Sanku Mallik

273

5.

Artemisinin: A Promise for the Development
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

311

6.

Andrographolide: A Plant-Derived Natural
Molecule of Pharmaceutical Promise
Goutam Brahmachari

335

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Contents

7.

Natural Products in Alzheimer’s Disease:
Impacts and Prospects
Shri Kant Mishra, Mark C. Stahl and Parampreet Singh

369

8.

Use of Multi-nutrient Functional Peptide Complex
«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 Shestakov
and Anatoliy Pechinka

401

9.

Anti-Infective Flavonoids: An Overview
María José Abad, Luis Miguel Bedoya,
Luis Apaza and Paulina Bermejo

443

10.

Anti-Helicobacter Pylori Activities of
Compounds of Natural Origin
Temitope O. Lawal, Kapil K. Soni, R. C. Saxena,
Bolanle A. Adeniyi and Gail B. Mahady

475

11.

Natural Bioactive Principles in the Treatment
of Skin Diseases
Emmanuel C. Ibezim

499

12.

Anti-Diabetic Agents of Natural Origin:
A Retrospective Account of Some Promising
Chemotypes
Goutam Brahmachari

519

13.

Fermentation Improvement of Processes
Yielding Natural Products for Industry
Arnold L. Demain and Sergio Sanchez

601


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14.

Index

Plant Cell Culture and Transgenic Plants:
The Goldmines for the Production of
Compounds of Pharmacological Interest
Ana Paula de Faria, Ângelo de Fátima,
Vagner A. Benedito and Luzia V. Modolo

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631

655



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List of Contributors

*María José Abad
Department of Pharmacology, Faculty of Pharmacy, University Complutense,
Ciudad Universitaria s/n, 28040, Madrid, Spain.
Bolanle A. Adeniyi
Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan,
Nigeria.
Galyna Anokhina
Chair of Gastroenterology, Dietology and Endoscopy, P.L. Shoupik National
Academy of Postgraduate Education, Ministry of Health of Ukraine,
9 Dorogozhytska str., 04112, Kyiv, Ukraine.
Luis Apaza
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 Sciences
Division, West Virginia University, 2090 Agricultural Sciences Building,
Morgantown, WV USA.

* Corresponding author

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Paulina Bermejo
Department of Pharmacology, Faculty of Pharmacy, University Complutense,
Ciudad Universitaria s/n, 28040, Madrid, Spain.
*Goutam Brahmachari
Laboratory of Organic Synthesis and Natural Products, Department of
Chemistry, Visva-Bharati University, Santiniketan-731 235, West Bengal,
India.
Anatoliy Bulavka
Department of Clinical Studies, Institute of Health of Nation, 3 Chapaev
str., 01030, Kyiv, Ukraine.
Ivan Chekman
Chair of Clinical Pharmacology, O.O. Bogomolets National Medical
University, Ministry of Health of Ukraine, 34 Victory Ave., 03055, Kyiv,
Ukraine.
*Arnold L. Demain

Charles A. Dana Research Institute for Scientists Emeriti (R.I.S.E), Drew
University, Madison NJ 07940, USA.
Georgiy Donchenko
Department biochemistry of vitamins and co-enzymes, A.V. Palladin
Institute of Biochemistry, National Academy of Sciences of Ukraine,
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


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*Alla Fedchuk
Laboratory of immune-biological and chemotherapeutical preparations,
I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of
Health 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.
*Jean Fotie
Southeastern Louisiana University, Department of Chemistry and
Physics, SLU 10878, Hammond, LA 70402-0878, USA.
Olga Golubovska
Chair of infectious diseases, O.O. Bogomolets National Medical
University, Ministry of Health of Ukraine, 34 Victory Ave., 03055, Kyiv,
Ukraine.
Irina Gomolyako
Laboratory of pathomorphology and cytology, O.O. Shalimov National
Institute of Surgery and Transplantology, Academy of Medical Sciences
of Ukraine, 30 Heroes of Sevastopol str., 03680, Kyiv, Ukraine.
Tetyana Grydina
Laboratory of immune-biological and chemotherapeutical preparations,
I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of
Health of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine.
Manas K. Haldar
Department of Pharmaceutical Sciences, North Dakota State University,
Fargo, North Dakota 58108, USA.
*Emmanuel C. Ibezim
Laboratory of Pharmaceutics and Pharmaceutical Microbiology,
Department of Pharmaceutics, University of Nigeria, Nsukka, Nigeria.

* Corresponding author

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Xeniya Igrunova
Bacteriological laboratory, I.I. Mechnikov Ukrainian Anti-Plague
Research Institute, Ministry of Health of Ukraine, 2/4 Tserkovna str.,
65003, Odesa, Ukraine.
Nataliya Klochkova
Laboratory of pathomorphology and cytology, O.O. Shalimov National
Institute of Surgery and Transplantology, Academy of Medical Sciences
of Ukraine, 30 Heroes of Sevastopol str., 03680, Kyiv, Ukraine.
Temitope O. Lawal
Department of Pharmaceutical Microbiology, University of Ibadan,
Ibadan, Nigeria.
*Viktor Lozitsky
Laboratory of immune-biological and chemotherapeutical preparations,
I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of Health
of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine; and Bacteriological

laboratory, I.I. Mechnikov Ukrainian Anti-Plague Research Institute,
Ministry of Health of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine.
*Gail B. Mahady
Department of Pharmacy Practice, UIC PAHO/WHO Collaborating
Centre for Traditional Medicine, University of Illinois at Chicago,
College of Pharmacy, 833 South Wood st., Chicago, IL 60612, USA.
*Sanku Mallik
Department of Pharmaceutical Sciences, North Dakota State University,
Fargo, North Dakota 58108, USA.
*Toshiro Matsui
Faculty of Agriculture, Kyushu University, 6-10-1, Hakozaki, Higashi-ku,
Fukuoka, 812-8581, Japan.

* Corresponding author


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*Shri Kant Mishra

Professor of Neurology at the Keck School of Medicine, USC.; Clinical
Professor of Neurology, David Geffen School of Medicine, UCLA.;
Director of Neuromuscular Disease, VA Greater Los Angeles & Olive
View 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 of
Health of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine.
Anatoliy Pechinka
Chair of infectious diseases, O.O. Bogomolets National Medical University,
Ministry of Health of Ukraine, 34 Victory Ave., 03055, Kyiv, Ukraine.
Sergiy Pozdnyakov
Laboratory of immune-biological and chemotherapeutical preparations,
I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of
Health of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine.
Valentina Pushkina
Bacteriological laboratory, I.I. Mechnikov Ukrainian Anti-Plague
Research Institute, Ministry of Health of Ukraine, 2/4 Tserkovna str.,
65003, Odesa, Ukraine.
Rodney A. F. Rodrigues
Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas,
Universidade Estadual de Campinas, Paulínia, SP Brazil.

* Corresponding author

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Sergio Sanchez
Departamento de Biología Molecular y Biotecnología, Instituto de
Investigaciones Biomédicas, Universidad Nacional Autónoma de México,
México D.F. 04510.
R. C. Saxena
Department of Zoology, S.S.L. Jain P.G. College, Affiliated with
Barkatullah University Bhopal, Vidisha (M.P.), India.
Michael D. Scott
Department of Pharmaceutical Sciences, North Dakota State University,
Fargo, North Dakota 58108, USA.
Vladimir Shestakov
Department of Clinical Studies, Institute of Health of Nation, 3 Chapaev
str., 01030, Kyiv, Ukraine.
Larysa Shytikova
Laboratory of immune-biological and chemotherapeutical preparations,
I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of

Health of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine.
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.
Parampreet Singh
ERI, Olive View UCLA Medical Center, 16111 Plummer Street,
Sepulveda, California 91343, USA.
Lidiya Socheslo
Laboratory of immune-biological and chemotherapeutical preparations,
I.I. Mechnikov Ukrainian Anti-Plague Research Institute, Ministry of
Health of Ukraine, 2/4 Tserkovna str., 65003, Odesa, Ukraine.


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Kapil K. Soni
Department of Pharmacy Practice, UIC PAHO/WHO Collaborating
Centre for Traditional Medicine, University of Illinois at Chicago,

College of Pharmacy, 833 South Wood st., Chicago, IL 60612, USA.
Ilza M. O. Sousa
Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas,
Universidade Estadual de Campinas, Paulínia, SP Brazil.
Mark C. Stahl
Dept. of Neurology, David Geffen School of Medicine,Westwood, California.
Mitsuru Tanaka
Faculty of Agriculture, Kyushu University, 6-10-1, Hakozaki, Higashi-ku,
Fukuoka, 812-8581, Japan.
Zhengquan Wang
Faculty of Agriculture, Kyushu University, 6-10-1, Hakozaki, Higashi-ku,
Fukuoka, 812-8581, Japan.