Natural products: A continuing source of novel drug leads

doi:10.1016/j.bbagen.2013.02.008

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1830, Issue 6, June 2013, Pages 3670-3695

https://doi.org/10.1016/j.bbagen.2013.02.008 Get rights and content

Abstract

Background

Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench.

Scope of Review

This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations.

Major Conclusions

The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases.

General Significance

The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (> 10 per species) the potential of microbial diversity remains essentially untapped.

Highlights

► We have given a history of natural products as drugs. ► We have discussed the reasons for the decreased interest in NPs in the Pharmaceutical industry. ► We have shown that the use of genomic techniques has allowed the recognition of new microbial sources of structures ► We demonstrate that the new frontier will be the interplay of genomics, chemistry and controlled biosynthesis. ► We demonstrate that biodiversity is in the microbial realm.

Introduction

Throughout the ages humans have relied on Nature to cater for their basic needs, not the least of which are medicines for the treatment of a wide spectrum of diseases. Plants, in particular, have formed the basis of sophisticated traditional medicine systems, with the earliest records, dating from around 2600 BCE, documenting the uses of approximately 1000 plant-derived substances in Mesopotamia. These include oils of Cedrus species (cedar) and Cupressus sempevirens (cypress), Glycyrrhiza glabra (licorice), Commiphora species (myrrh), and Papaver somniferum (poppy juice), all of which are still used today for the treatment of ailments ranging from coughs and colds to parasitic infections and inflammation. Egyptian medicine dates from about 2900 BCE, but the best known record is the "Ebers Papyrus" dating from 1500 BCE, documenting over 700 drugs, mostly of plant origin [1]. The Chinese Materia Medica has been extensively documented over the centuries [2], with the first record dating from about 1100 BCE (Wu Shi Er Bing Fang, containing 52 prescriptions), followed by works such as the Shennong Herbal (~ 100 BCE; 365 drugs) and the Tang Herbal (659 CE; 850 drugs). Likewise, documentation of the Indian Ayurvedic system dates from before 1000 BCE (Charaka; Sushruta and Samhitas with 341 and 516 drugs respectively) [3], [4].

The Greeks and Romans contributed substantially to the rational development of the use of herbal drugs in the ancient Western world. Dioscorides, a Greek physician (100 CE), accurately recorded the collection, storage, and use of medicinal herbs during his travels with Roman armies throughout the then "known world", whilst Galen (130–200 CE.), a practitioner and teacher of pharmacy and medicine in Rome, is well known for his complex prescriptions and formulae used in compounding drugs. The Arabs, however, preserved much of the Greco-Roman expertise during the Dark and Middle Ages (5th to 12th centuries), and expanded it to include the use of their own resources, together with Chinese and Indian herbs unknown to the Greco-Roman world. A comprehensive review of the history of medicine may be found on the website of the National Library of Medicine (NLM), United States National Institutes of Health (NIH), at www.nlm.nih.gov/hmd/medieval/arabic.html.

Section snippets

The Role of Traditional Medicine and Plants in Drug Discovery

Plant-based systems continue to play an essential role in healthcare, and their use by different cultures has been extensively documented [5], [6]. The World Health Organization (WHO) estimated in 1985 that approximately 65% of the population of the world predominately relied on plant-derived traditional medicines for their primary health care, while plant products also play an important, though more indirect role in the health care systems of the remaining population who mainly reside in

The Role of Marine Organisms in Drug Discovery

While marine organisms do not have a significant history of use in traditional medicine, the ancient Phoenicians employed a chemical secretion from marine molluscs to produce purple dyes for woolen cloth, and seaweeds have long been used to fertilize the soil. The world's oceans, covering more than 70% of the earth's surface, represent an enormous resource for the discovery of potential chemotherapeutic agents. Of the 33 animal phyla listed by Margulis and Schwartz [40] 32 are represented in

An Historical Perspective

The serendipitous discovery of penicillin from the filamentous fungus, Penicillium notatum, by Fleming in 1929, and the observation of the broad therapeutic use of this agent in the 1940s, ushered in a new era in medicine, "the Golden Age of Antibiotics", and promoted the intensive investigation of Nature as a source of novel bioactive agents [58]. Microorganisms are a prolific source of structurally diverse bioactive metabolites and have yielded some of the most important products of the

Other Sources

Teprotide, isolated from the venom of the pit viper, Bothrops jaracaca, led to the design and synthesis of the ACE inhibitors, captopril and enalapril (Fig. 10) [9], used in the treatment of cardiovascular disease, while epibatidine, isolated from the skin of the poisonous frog, Epipedobates tricolor, has led to the development of a novel class of potential painkillers (Fig. 10) [92]. A further notable discovery was the isolation of exendin-4 from the venom of the Gila monster, Heloderma

The Importance of Natural Products In Drug Discovery And Development

In 2 The Role of Traditional Medicine and Plants in Drug Discovery, 3 The Role of Marine Organisms in Drug Discovery, 4 The Role of Microorganisms in Drug Discovery., 5 Other Sources we have listed a relatively small number of selected examples of some of the useful drugs discovered from a variety of natural sources. In our paper published in 2012 [95], we analyzed the sources of new drugs over the period 01/1981-12/2010, and classified these compounds as N (an unmodified natural product), NB

Classical Natural Sources: Untapped Potential.

The exceptional complexity and molecular diversity of natural products has been highlighted in earlier sections, but even more remarkable is the fact that the surface of these unique natural resources has barely been scratched. Despite the intensive investigation of terrestrial flora, it is estimated that only 6% of the approximately 300,000 species (some estimates are as high as 500,000 species) of higher plants have been systematically investigated, pharmacologically, and only some 15%

The Unexplored Potential of Microbial Diversity.

Until recently, the inability to cultivate most naturally occurring microorganisms has severely limited the study of natural microbial ecosystems, and it has been estimated that much less than 1% of microorganisms seen microscopically have been cultivated. Yet, despite this limitation, the number of highly effective microbe-derived chemotherapeutic agents discovered and developed thus far has been impressive. Given the observation that “a handful of soil contain billions of microbial organisms”

Total Synthesis

The total synthesis of complex natural products has long posed challenges to the top synthetic chemistry groups worldwide, and has led to dramatic advances in the field of organic chemistry, particularly at the turn of the 21st Century and onwards [195]_. As eloquently stated by Nicolaou and his coauthors in 2000: “Today, natural product total synthesis is associated with prudent and tasteful selection of challenging and preferably biologically important target molecules; the discovery and

The Rio Convention

In May of 1992, the Nairobi Conference led directly to the opening of what has become known as the Convention on Biodiversity (CBD) which was opened for signature at the Earth Summit in Rio, and by the end of the first year, it had been signed by 168 nations. The history can be found at the following URL: http://www.cbd.int/history/

Although the CBD was signed by the US President, it has never been ratified by the US Senate, so the USA is one of the very few nations that are not a voting member

Summary

The preceding sections have provided a very brief impression of the importance of natural products, both as pharmaceutical agents and/or as leads to bioactive molecules. With the emergence of novel screening systems related to the explosion of genetic information accelerating, the need to rapidly identify effective, novel lead structures is a vital necessity. We believe that a very significant portion of these leads will continue to be natural product derived. It should be remembered that

References (254)

C. Wongsrichanalai et al.
Epidemiology of drug-resistant malaria
Lancet Infect. Dis.
(2002)
L.H. Miller et al.
Atermisinin: Discovery from the Chinese herbal garden
Cell
(2011)
M.R. Green et al.
Abraxane, a novel cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer
Ann. Oncol.
(2006)
A. Kirschning et al.
The chemistry and biology of the maytansinoid antitumor agents
C. R. Chimie
(2008)
P.D. Senter
Potent antibody drug conjugates for cancer therapy
Curr. Opin. Chem. Biol.
(2009)
S.C. Alley et al.
Antibody-drug conjugates: Targeted drug delivery for cancer
Curr. Opin. Chem. Biol.
(2010)
J. Caravella et al.
Design of next-generation protein therapeutics
Curr. Opin. Chem. Biol.
(2010)
W.H. Gerwick et al.
Lessons from the past and charting the future of marine natural products drug discovery and chemical biology
Chem. Biol.
(2012)
R.J. Clark et al.
Cyclization of conotoxins to improve their biopharmaceutical properties
Toxicon
(2012)
M.J. Yu et al.
Case history: Discovery of eribulin (halaven™), a halichondrin b analogue that prolongs overall survival in patients with metastatic breast cancer

J. Cortes et al.

Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (embrace): A phase 3 open-label randomised study

Lancet

(2011)

K.N. Chi et al.

A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian urologic oncology group study p07a

Ann. Oncol.

(2012)

N.H. Georgopapadakou et al.

The fungal cell wall as a drug target

Trends Microbiol.

(1995)

M.B. Kurtz et al.

Glucan synthase inhibitors as antifungal agents

Adv. Protein Chem.

(2001)

T. Roemer et al.

Confronting the challenges of natural product-based antifungal discovery

Chem. Biol.

(2011)

J. Eng et al.

Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspecturn venom

J. Biol. Chem.

(1992)

J.K. Borchardt

The beginnings of drug therapy: Ancient mesopotamian medicine

Drug News Perspect.

(2002)

K.C. Huang

The pharmacology of chinese herbs

(1999)

L.D. Kapoor

CRC handbook of ayurvedic medicinal plants

(1990)

S. Dev

Ancient-modern concordance in ayurvedic plants: Some examples

Environ. Health Perspect.

(1999)

D.E. Moerman

Medicinal plants of native America

(1986)

T. Johnson

CRC ethnobotany desk reference

(1999)

N.R. Farnsworth et al.

Medicinal plants in therapy

Bull. World Health Organ.

(1985)

D.S. Fabricant et al.

The value of plants used in traditional medicine for drug discovery

Environ. Health Perspect.

(2001)

A.D. Buss et al.

Natural products as leads for new pharmaceuticals

D.L. Klayman et al.

Isolation of artemisinin (qinghaosu) from artemisia annua growing in the United States

J. Nat. Prod.

(1985)

D.L. Klayman

Qinghaosu (artemisinin): An antimalarial drug from China

Science

(1985)

P.M. O'Neill et al.

A medicinal chemistry perspective on artemisinin and related endoperoxides

J. Med. Chem.

(2004)

P.M. O'Neill et al.

The molecular mechanism of action of artemisinin - the debate continues

Molecules

(2010)

J. Wang et al.

Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation

PLoS One

(2010)

J.L. Vennerstrom et al.

Identification of an antimalarial synthetic trioxolane drug development candidate

Nature

(2004)

G.H. Posner et al.

Malaria-infected mice are cured by a single dose of novel artemisinin derivatives

J. Med. Chem.

(2007)

G.A. Cordell et al.

Natural products and traditional medicine: Turning on a paradigm

J. Nat. Prod.

(2012)

J.L. Hartwell

Plants used against cancer

(1982)

G.M. Cragg et al.

Ethnobotany and drug discovery: The experience of the US National Cancer Institute

F. Gueritte et al.

The vinca alkaloids

F. Roussi et al.

The vinca alkaloids

K.-H. Lee et al.

Podophyllotoxin and analogs

K.-H. Lee et al.

Podophyllotoxin and analogs

D.G.I. Kingston

Taxol and its analogs

D.G.I. Kingston

Taxol and its analogs

P.B. Schiff et al.

Taxol stabilizes microtubules in mouse fibroblast cells

Proc. Natl. Acad. Sci. U. S. A.

(1980)

A.C. Burman, R. Mukherjee, D. Khattar, M. Kumar, H. Bala, R.K. Shrivastava, Formulations of paclitaxel entrapped into...

D.G.I. Kingston et al.

Taxoids: Cancer-fighting compounds from nature

Curr. Opin. Drug Discov. Dev.

(2007)

N.J. Rahier et al.

Camptothecin and its analogs

J.-W. Yu et al.

Ansamitocins (maytansenoids)

J.M. Lambert

Antibody-maytansinoid conjugates: A new strategy for the trreatment of cancer

Drugs Future

(2010)

I. Kümler et al.

Trastuzumab emtansine: Tumor-activated prodrug (tap) immunoconjugate oncolytic

Drugs Future

(2011)

L. Margulis et al.

Five kingdoms, an illustrated guide to the phyla of life on earth

(1988)

D.J. Faulkner

Marine natural products

Nat. Prod. Rep.

(2000)

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Published by Elsevier B.V.

ReviewNatural products: A continuing source of novel drug leads☆

Abstract

Background

Scope of Review

Major Conclusions

General Significance

Highlights

Introduction

Section snippets

The Role of Traditional Medicine and Plants in Drug Discovery

The Role of Marine Organisms in Drug Discovery

An Historical Perspective

Other Sources

The Importance of Natural Products In Drug Discovery And Development

Classical Natural Sources: Untapped Potential.

The Unexplored Potential of Microbial Diversity.

Total Synthesis

The Rio Convention

Summary

Lancet Infect. Dis.

Cell

Ann. Oncol.

C. R. Chimie

Curr. Opin. Chem. Biol.

Curr. Opin. Chem. Biol.

Curr. Opin. Chem. Biol.

Chem. Biol.

Toxicon

Lancet

Ann. Oncol.

Trends Microbiol.

Adv. Protein Chem.

Chem. Biol.

J. Biol. Chem.

The beginnings of drug therapy: Ancient mesopotamian medicine

Drug News Perspect.

The pharmacology of chinese herbs

CRC handbook of ayurvedic medicinal plants

Ancient-modern concordance in ayurvedic plants: Some examples

Environ. Health Perspect.

Medicinal plants of native America

CRC ethnobotany desk reference

Medicinal plants in therapy

Bull. World Health Organ.

The value of plants used in traditional medicine for drug discovery

Environ. Health Perspect.

Natural products as leads for new pharmaceuticals

Isolation of artemisinin (qinghaosu) from artemisia annua growing in the United States

J. Nat. Prod.

Qinghaosu (artemisinin): An antimalarial drug from China

Science

A medicinal chemistry perspective on artemisinin and related endoperoxides

J. Med. Chem.

The molecular mechanism of action of artemisinin - the debate continues

Molecules

Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation

PLoS One

Identification of an antimalarial synthetic trioxolane drug development candidate

Nature

Malaria-infected mice are cured by a single dose of novel artemisinin derivatives

J. Med. Chem.

Natural products and traditional medicine: Turning on a paradigm

J. Nat. Prod.

Plants used against cancer

Ethnobotany and drug discovery: The experience of the US National Cancer Institute

The vinca alkaloids

The vinca alkaloids

Podophyllotoxin and analogs

Podophyllotoxin and analogs

Taxol and its analogs

Taxol and its analogs

Taxol stabilizes microtubules in mouse fibroblast cells

Proc. Natl. Acad. Sci. U. S. A.

Taxoids: Cancer-fighting compounds from nature

Curr. Opin. Drug Discov. Dev.

Camptothecin and its analogs

Ansamitocins (maytansenoids)

Antibody-maytansinoid conjugates: A new strategy for the trreatment of cancer

Drugs Future

Trastuzumab emtansine: Tumor-activated prodrug (tap) immunoconjugate oncolytic

Review
Natural products: A continuing source of novel drug leads☆