Natural Products as Pharmaceuticals and newman2008

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159
Copyright © 2008, Elsevier Ltd
All rights reserved.Wermuth’s The Practice of Medicinal Chemistry
 Chapter 8 
 I . 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 myriad of diseases. Plants, in par-
ticular, have formed the basis of sophisticated traditional 
medicine systems, with the earliest records documenting 
the uses of approximately 1,000 plant-derived substances 
in Mesopotamia, and the “ Ebers Papyrus ” dating from 
1500 BCE, documenting over 700 drugs, mostly of plant 
origin. 1 The fi rst record of the Chinese Materia Medica 
documenting 52 prescriptions dates from about 1100 BCE, 
and was followed by works such as the Shennong Herbal 
( ~ 100 BCE; 365 drugs) and the Tang Herbal (659 CE; 850 
drugs). 2 Documentation of the Indian Ayurvedic system 
also 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 
 I. INTRODUCTION 
 II. THE IMPORTANCE OF 
NATURAL PRODUCTS IN 
DRUG DISCOVERY AND 
DEVELOPMENT 
 A. The origin of natural products 
 B. The uniqueness of the natural 
products approach 
 C. The impact of new screening 
methods 
 III. THE DESIGN OF AN 
EFFECTIVE NATURAL-
PRODUCTS-BASED 
APPROACH TO DRUG 
DISCOVERY 
 A. Acquisition of biomass
 B. The unexplored potential of 
microbial diversity
 C. Extraction 
 D. Screening methods 
 E. Isolation of active compounds 
 F. Structure elucidation 
 G. Further biological assessment 
 H. Procurement of large-scale 
supplies 
 I. Determination of structure–
activity relationships 
 IV. EXAMPLES OF NATURAL 
PRODUCTS OR ANALOGS AS 
DRUGS 
 A. Antihypertensives
 B. Anticholesterolemics
 C. Immunosuppressives 
 D. Antibiotics 
 E. Microbial anticancer agents 
 F. Anticancer agents from plants
 G. Anticancer agents from 
marine organisms 
 H. Antimalarial agents 
 I. Other natural products 
 V. FUTURE DIRECTIONS IN 
NATURAL PRODUCTS AS 
DRUGS AND DRUG DESIGN 
TEMPLATES 
 A. Introduction 
 B. Combinatorial chemistry 
 C. Natural products as design 
templates 
 D. Interactions of microbial 
sources, genomics, and 
synthetic chemistry 
 VI. SUMMARY 
 REFERENCES 
 Natural Products as Pharmaceuticals and 
Sources for Lead Structures 
 David J. Newman , Gordon M. Cragg and David G. I. Kingston 1 
 1 Note: This chapter refl ects the opinions of the authors, not necessarily those of the US Government. 
 Accuse not Nature, she hath done her part; do thou but thine 
 Milton, Paradise Lost 
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CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures160
(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 prescrip-
tions and formulae used in compounding drugs. However, 
it was the Arabs who preserved much of the Greco-Roman 
expertise during the Dark and Middle Ages (5th–12th cen-
turies), and who 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 web site of 
the National Library of Medicine (NLM), US National 
Institutes of Health (NIH), at www.nlm.nih.gov/hmd/
medieval/arabic.html. 
 Plant-based systems continue to play an essential role in 
healthcare, and their use by different cultures has been exten-
sively documented. 5 , 6 It has been estimated by the World 
Health Organization that approximately 80% of the world’s 
inhabitants rely mainly on traditional medicines for their pri-
mary healthcare, while plant products also play an important 
role in the healthcare systems of the remaining 20% of the 
population, mainly residing in developed countries. 7 
 II . THE IMPORTANCE OF NATURAL 
PRODUCTS IN DRUG DISCOVERY 
AND DEVELOPMENT 
 The continuing value of natural products as sources of 
potential chemotherapeutic agents has been reviewed by 
Newman and Cragg. 8 An analysis of the sources of new 
drugs over the period January 1981–June 2006 classifi ed 
these compounds as N (an unmodifi ed natural product), ND 
(a modifi ed natural product), S (a synthetic compound with 
no natural product conception), S*, S*/NM (a synthetic 
compound with a natural product pharmacophore; /NM 
indicating competitive inhibition), and S/NM (a synthetic 
compound showing competitive inhibition of the natural 
product substrate). This analysis indicated that 66% of the 
974 small molecule, new chemical entities (NCEs) are for-
mally synthetic, but 17% correspond to synthetic molecules 
containing pharmacophores derived directly from natural 
products classifi ed as S* and S*/NM. Furthermore, 12% 
are actually modeled on a natural product inhibitor of the 
molecular target of interest, or mimic (i.e. competitively 
inhibit) the endogenous substrate of the active site, such 
as adenosine triphosphate (ATP) (S/NM). Thus, only 37% 
of the 974 NCEs can be classifi ed as truly synthetic (i.e. 
devoid of natural inspiration) in origin (S) ( Figure 8.1 ). In 
the area of anti-infectives (anti-bacterial, -fungal, -parasitic, 
and -viral), close to 70% are naturally derived or inspired 
(N; ND; S*; S*/NM; S/NM), while in the cancer treatment 
area 77.8% are in this category, with the fi gure being 63% 
if the S/NM category is excluded. 
 In recent years, a steady decline in the output of the 
R & D programs of the pharmaceutical industry has been 
reported, with the number of new active substances, also 
known as NCEs, hitting a 20-year low of 37 in 2001. 9 
Furthermore, this drop in productivity was refl ected by 
the report that only 16 New Drug Applications had been 
received by the US Food and Drug Administration (FDA) 
in 2001, down from 24 the previous year. While various 
factors have been held to blame for this downturn, it is sig-
nifi cant that the past 10–15 years has seen a decline in inter-
est in natural products on the part of major pharmaceutical 
companies in favor of reliance on new chemical techniques, 
such as combinatorial chemistry, for generating molecu-
lar libraries. The realization that the number of NCEs in 
drug development pipelines is declining may have led to 
the rekindling of interest in “ rediscovering natural prod-
ucts, ” 10 as well as the heightened appreciation of the value 
of natural product-like models in “ improving effi ciency ” 
in so-called diversity-oriented synthesis. 11 The urgent need 
for the discovery and development of new pharmaceuti-
cals for the treatment of cancer, AIDS and infectious dis-
eases, as well as a host of other diseases, demands that all 
approaches to drug discovery be exploited aggressively, 
and it is clear that nature has played, and will continue to 
play, a vital role in the drug discovery process. As stated by 
Berkowitz in 2003 commenting on natural products, 10 “ We 
would not have the top-selling drug class today, the statins; 
the whole fi eld of angiotensin antagonists and angiotensin-
converting enzyme inhibitors; the whole area of immuno-
suppressives; nor most of the anticancer and antibacterial 
drugs. Imagine all of those drugs not being available to 
physicians or patients today. ” Or, as was eloquently stated 
byDanishefsky in 2002, “ a small collection of smart com-
pounds may be more valuable than a much larger hodgep-
odge collection mindlessly assembled. ” 12 Recently, he and 
a coauthor restated this theme in their review on the appli-
cations of total synthesis to problems in neurodegeneration: 
 “ We close with the hope and expectation that enterprising 
and hearty organic chemists will not pass up the unique 
head start that natural products provide in the quest for new 
agents and new directions in medicinal discovery. We would 
chance to predict that even as the currently fashionable 
 FIGURE 8.1 Sources of drugs. 
N
6%
ND
28%
S
37%
S/NM
12%
S*
5%
S*/NM
12%
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II. The Importance of Natural Products in Drug Discovery and Development 161
 “ telephone directory ” mode of research is subjected to 
much overdue scrutiny and performance-based assessment, 
organic chemists in concert with biologists and even clini-
cians will be enjoying as well as exploiting the rich troves 
provided by nature’s small molecules. ” 13 
 A . The origin of natural products 
 While the contributions of natural secondary metabolites 
(all non-proteinaceous natural products would fall under 
this term) to modern medicine are abundantly clear, the 
question of their origins has long intrigued chemists and 
biochemists. Six major hypotheses have been proposed, and 
these have been well summarized by Haslam. 14 (1) They 
are simply waste products with no particular physiological 
role. (2) They are compounds that at one time had a func-
tional metabolic role, which has now been lost. (3) They 
are products of random mutations, and have no real func-
tion in the organism. (4) They are an example of “ evolution 
in progress, ” and provide a pool of compounds out of which 
new biochemical processes can emerge. (5) Production pro-
vides a way of enabling the enzymes of primary metabo-
lism to function when they are not needed for their primary 
purpose. “ It is the processes of secondary metabolism, 
rather than the products (secondary metabolites) which are 
important. ” (6) They play a key role in the organism’s sur-
vival, providing defensive substances or other physiologi-
cally important compounds. 
 Although each of the above has (or has had) its support-
ers, Williams et al. 15 and Harborne 16 amongst others, argue 
convincingly that the weight of the evidence is behind the 
sixth hypothesis. Indeed, it seems reasonable to assume 
that, in many instances, the production of these com-
plex and often toxic chemicals has evolved over eons as a 
means of chemical defense by essentially stationary organ-
isms, such as plants and many marine invertebrates, against 
predation and consumption (e.g. herbivory). For instance, 
pupae of the coccinellid beetle, Epilachna borealis , appear 
to exert a chemical defensive mechanism against preda-
tors through the secretion of droplets from their glandular 
hairs containing a library of hundreds of large-ring (up to 
98 members) macrocyclic polyamines. 17 These libraries are 
built up from three simple (2-hydroxyethylamino)-alkanoic 
acid precursors, and are clear evidence that combinatorial 
chemistry has been pioneered and widely used in nature 
for the synthesis of biologically active compound libraries. 
A further example is that of the venom composed of com-
binatorial libraries of several hundred peptides and injected 
by species of the cone snail genus, Conus , to stun their prey 
prior to capture. 18 One component of this mixture has been 
developed as Ziconotide, a non-narcotic analgesic that is 
currently marketed as Prialt ® . 19 
 Microorganisms are reported to kill sensitive strains 
of the same or related microbial species through excretion 
of antimicrobial toxins, 20 which resembles the process of 
allelopathy whereby plants release toxic compounds in 
order to suppress the growth of neighboring plants. 21 , 22 
Bacteria also use a cell to cell “ chemical language ” as a 
signaling mechanism known as quorum sensing, involv-
ing the excretion of quorum-sensing compounds, to control 
their density of population growth and so-called biofi lm 
formation. The best studied of these compounds, the acyl-
homoserine lactones (AHLs) exemplifi ed by compounds 
such as N -3-oxohexanoyl- l -homoserine lactone ( Figure 8.2 ) 
from Vibrio fi sheri, and a furanone boronate diester that 
appears to be a universal signal ( Figure 8.2 ) promoting the 
activation of genes promoting virulence, spore formation, 
biofi lm formation, and other phenomena. 23 , 24 A solid-phase 
synthetic route, adaptable to the synthesis of combinato-
rial libraries of AHL analogs, has been developed, and two 
such analogs have been identifi ed which inhibit the forma-
tion of biofi lms of Pseudomonas aeruginosa , the organism 
responsible for lung infections in cystic fi brosis patients 
which can often prove fatal. 25 
 B . The uniqueness of the natural products 
approach 
 Natural products are generally complex chemical structures, 
whether they are cyclic peptides like cyclosporin A, or com-
plex diterpenes like paclitaxel. Inspection of the structures 
that are discussed in Section IV is usually enough to con-
vince any skeptic that few of them would have been dis-
covered without application of natural products chemistry. 
Recognition and appreciation of the value of natural prod-
uct-like models in “ improving effi ciency ” in so-called diver-
sity-oriented synthesis has already been mentioned. 11 
 Structural diversity is not the only reason why natural 
products are of interest to drug development, since they often 
provide highly selective and specifi c biological activities 
based on mechanisms of action. Two very good examples 
of this are the β -hydroxy- β -methylglutary-CoA reductase 
(HMG-CoA reductase) inhibition exhibited by lovastatin, 
and the tubulin-assembly promotion activity of paclitaxel. 
These activities would not have been discovered without the 
natural product leads and investigation of their mechanisms 
of action. A striking illustration of the infl uence of natural 
products on many of the enzymatic processes operative in 
OO
O
H
N
O O
Acylhomoserine lactone
OO
O
B
O OO
HO
HOO
HOO OHO
Furanone boronate diester
�
 FIGURE 8.2 Quorum-sensing compounds. 
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CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures162
cell cycle progression may be found at the web site of the 
Roscoff Biological Station ( http://www.sb-roscoff.fr/CyCell/
Frames80.htm ) which covers diagrams originally published 
by Meijer 26 on natural products and the cell cycle, with a 
modifi ed version shown in Figure 8.3 . The bioactivity of 
natural products stems from the previously discussed hypoth-
esis that essentially all natural products have some receptor-
binding activity; the problem is to fi nd which receptor a 
given natural product is binding to. Viewed another way, 
a given organism provides the investigator with a complex 
library of unique bioactive constituents, analogous to the 
library of crude synthetic products initially produced by 
combinatorial chemistry techniques. The natural products 
approach can thus be seen as complementary to the syn-
thetic approach, each providing access to (initially) different 
lead structures. In addition, development of an active natu-
ral product structure by combinatorially directed synthesis is 
an extremely powerful tool. The task of the natural products 
researcher is thus to select those compounds of pharmaco-
logical interest from the “ natural combinatorial libraries ” 
produced by extraction of organisms. Fortunately, the means 
to do this effi ciently are now at hand. 
 C . The impact of new screening methods 
 Inthe early days of natural products research, new com-
pounds were simply isolated at random, or at best by the 
use of simple broad-based bioactivity screens based on anti-
microbial or cytotoxic activities. Although these screens did 
result in the isolation of many bioactive compounds, 27 they 
were considered to be too non-specifi c for the next gen-
eration of drugs. Fortunately, a large number of robust and 
specifi c biochemical and genetics-based screens using trans-
formed cells, a key regulatory intermediate in a biochemical 
or genetic pathway, or a receptor–ligand interaction (often 
derived from the explosion in genomic information since 
the middle 1990s), are now in routine use. These screens 
will permit the detection of bioactive compounds in the 
complex matrices that are natural product extracts with 
greater precision. 
 One interesting feature of such screens has increased 
the attractiveness of natural products to the pharmaceutical 
industry. The screens themselves are all highly automated 
and high throughput (upwards of 50,000 assay points per 
day in a number of cases). Because of this, the screening 
Chk1
Chk2
G2
M
S
Tyrosine kinases
DNA synthesis
Topoisomerase I
CDK2
Cdc7
Tubulin
Polymerisation/
depolymerisation
Taxol/taxotere
Halichondrin
Spongistatin
Rhizoxin
Cryptophycin
Sarcodictyin
Eleutherobin
Epothilones
Discodermolide
Indibulin
Dolastatin
Combretastatin
Eribulin
Camptothecin
CDK4
Flavopiridol
(R)-Roscovitine (CYC202)
Paullones, indirubins
Gleevec
Iressa
Erlotinib
Hydroxyurea
Cytarabine
Antifolates
5-Fluorouracil
6-Mercaptopurine
Nitrogen mustards
Nitrosoureas
Mitomycin C
CDK1
UCN-01, SB-218078
Debromohymenialdisine
Isogranulatimide
AhR
Actin
Kinesin Eg5
Monastrol
Trabectedin
Podophyllotoxin, Doxorubicin
etoposide, mitoxantrone
Topoisomerase II
ATM/ATR
Tipifarnib
Lonafarnib
ROCK
Y-27632
CDC25
DF203
FK317 HMGA
Plk1
Aurora
Wortmannin
caffeine
ODC/SAMDC
Pin1
GSK-3
Nucleotide excision
repair
Raf Cytochalasins
Latrunculin A
Scytophycins
Dolastatin 11
Jaspamide
Paullones, indirubins
(R)-Roscovitine (CYC202)
Paullones, indirubins
Sorafenib*
Fumagillin, TNP-470
PRIMA-1, pifithrin α
MEK1/Erk-1/2
PD98059, U0126
Menadione (K3)
Farnesyl transferase
Wee1
PD0166285
Vinca alkaloids
Polyamine analogues
Pin1
p53/MDM2
Sorafenib is the first de novo combinatorial chemistry drug
PS-341 proteasome
CT-2584 choline kinase
Rapamycin mTOR/FRAP
Bryostatin, PKC412 PKC
HSP90Geldanamycin, 17-AAG
ATK, MAFP cytosolic phospholipase A2
histone deacetylaseTrichostatin, FK228
Hexadecylphosphocholine phospholipase D
phosphatasesOkadaic acid, fostreicin, calyculin A
G1
G0
 FIGURE 8.3 Natural products and the cell cycle. Source : Modifi ed from Meijer 26 (original used by permission from Springer-Verlag). 
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III. The Design of an Effective Natural-Products-Based Approach to Drug Discovery 163
capacity at many companies is signifi cantly larger than 
the potential input from in-house chemical libraries. Since 
screening capacity is no longer the rate-limiting-step, many 
major pharmaceutical companies are becoming very inter-
ested in screening natural products (either as crude extracts 
or as prefractionated “ peak libraries ” ) as a low-cost means 
of discovering novel lead compounds. This is well illus-
trated by the discovery of a new antibiotic, platensimycin, 
by a team of scientists from Merck Research Laboratories. 
It has in vitro activity against several drug-resistant bacteria, 
is a selective FabF inhibitor, and was discovered through 
the testing of a library of 250,000 natural product extracts 
in a custom-designed assay involving an engineered strain 
of Staphylococcus aureus incorporating the fatty acid syn-
thase pathway enzyme, FabF. 28 Such promise has also 
spawned small companies such as Merlion Pharmaceuticals 
in Singapore which has a library of many thousands of 
natural products derived from a variety of sources which it 
exposes to validated drug targets provided by pharmaceuti-
cal companies, with the goal of generating drug leads. 29 
 III . THE DESIGN OF AN EFFECTIVE 
NATURAL-PRODUCTS-BASED 
APPROACH TO DRUG DISCOVERY 
 There are four major elements in the design of any suc-
cessful natural-products-based drug discovery program: 
acquisition of biomass, effective screening, bioactivity-
driven fractionation, and rapid and effective structure elu-
cidation (which includes dereplication). Although some of 
these have been mentioned earlier, it is instructive to bring 
them together here. 
 A . Acquisition of biomass 
 The acquisition of biomass has undergone a very signifi -
cant transition from the days when drug companies and 
others routinely collected organisms without any thought 
of ownership by, or reimbursement to, the country of ori-
gin. Today, thanks to the Convention on Biodiversity (or 
CBD) and similar documents and agreements such as the 
US National Cancer Institute’s Letter of Collection (NCI’s 
LOC: http://ttc.nci.nih.gov/forms/loc.doc ), all ethical bio-
mass acquisitions now include provisions for the country 
of origin to be recompensed in some way for the use of 
its biomass. It should be noted that the LOC predated the 
CBD by 3 years; its tenets, as a minimum, must be adhered 
to by any investigator who has his or her collections funded 
by the NCI/NIH. Such recompense to the country of origin 
is best provided through formal agreements with govern-
ment organizations and collectors in the host country, with 
such agreements providing not only for reimbursement 
of collecting expenses, but also for further benefi ts (often 
in the form of milestone and/or royalty payments) in the 
event that a drug is developed from a collected sample. 
Agreements often include terms related to the training of 
host country scientists and transfer of technologies involved 
in the early drug discovery process. Recognition of the role 
played by indigenous peoples through the stewardship of 
resources in their region and/or the sharing of their ethno-
pharmacological information in guiding the selection of 
materials for collection is important in determining the 
distribution of such benefi ts. There have been sample legal 
agreements, 30 and discussions as to methods used by vari-
ous groups published in the last few years. 31–33 
 It is axiomatic that all samples collected, irrespective 
of type of source, must if at all possible be fully identifi ed 
to genus and species. Such identifi cation is usually possi-
ble for all plant species, but it is not always possible for 
microbes and marine organisms. Voucher specimens should 
be provided to an appropriate depository in the host coun-
try as well as to a similar operation in the home country of 
the collector. 
 The selection of plant samples often raises the ques-
tion of the ethnobotanical/ethnopharmacological approach 
versus a random approach. The former method, which usu-
ally involves the selection of plants that have a documented 
(written or oral) use by native healers, is attractive in that it 
can tap into the empirical knowledge developed over cen-
turies of use by large numbers of people. In addition, the 
bioactive constituents may be considered as having had 
a form of continuing clinical trial in man. The benefi ts of 
this approach have been extolled in several relatively recent 
articles, 34–36 and one author provides personal experience 
of the effectiveness of some jungle medicines. 37 The weak-
ness of the ethnobotanical approach has always been that 
it is slow, requiring careful interviewing of native healers 
by skilled scientists, including ethnobotanists, anthropolo-
gists, trained physicians, and pharmacologists. In addition, 
the quoted folkloric activity in the collected plant(s) may 
not be detectable, given the particular screens in use by the 
screening laboratory. Whereethnobotanical approaches 
have the highest possibility of success is in studies related 
to overt diseases/conditions such as parasitic infections, 
fungal sores, and contraception/conception to name a few. 
In such cases, there are adequate controls, even on the same 
patient. Where there does not yet appear to be any success-
ful relationship is in diseases such as cancer and AIDS-
related conditions, where extensive testing of the patient is 
required for an accurate diagnosis. 
 1 . Classical natural sources: untapped potential 
 Despite the intensive investigation of terrestrial fl ora, it is 
estimated that only 5–15% of the approximately 300,000 
species of higher plants have been systematically investi-
gated, chemically and pharmacologically, 38 , 39 while the 
potential of the marine environment as a source of novel 
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CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures164
drugs remains virtually unexplored. 40 , 41 Until recently, the 
investigation of the marine environment has largely been 
restricted to tropical and subtropical regions, but colder 
climes are now being explored, and the isolation of the 
cytotoxic macrolide palmerolide A ( Figure 8.4 ) from an 
Antarctic tunicate has recently been reported. 42 Its structure 
has recently been revised and it has been synthesized. 43 The 
novel pyrido-pyrrolo-pyrimidine derivatives, the variolins 
( Figure 8.4 ) were isolated a few years earlier, 44 , 45 and this 
work was followed by total synthesis of these compounds 
and derivatives by chemists at PharmaMar a decade later. 46 
 Exposure of the roots of hydroponically grown plants to 
chemical elicitors has been reported to selectively and repro-
ducibly induce the production of bioactive compounds, 47 
while feeding of seedlings with derivatives of selected 
biosynthetic precursors can lead to the production of non-
natural analogs of the natural metabolites. This has been 
demonstrated in the production of non-natural terpene indole 
alkaloids related to the vinca alkaloids through the feeding 
of seedlings of Catharanthus roseus with various tryptamine 
analogs. 48 
 B . The unexplored potential of microbial 
diversity 
 Until recently, the study of natural microbial ecosystems 
has been severely limited due to an inability to cultivate 
most naturally occurring microorganisms, and it has been 
estimated that much less than 1% of microorganisms seen 
microscopically have been cultivated. Given that “ a handful 
of soil contain billions of microbial organisms, ” 49 and the 
assertion that “ the workings of the biosphere depend abso-
lutely on the activities of the microbial world, ” 50 it seems 
clear that the microbial universe presents a vast untapped 
resource for drug discovery. In addition, greatly enhanced 
understanding of the gene clusters that encode the multi-
modular enzymes, such as polyketide synthases (PKSs) 
and/or nonribosomal peptide synthetases (NRPSs), both 
of which are involved in the biosynthesis of a multitude of 
microbial secondary metabolites, has enabled the sequenc-
ing and detailed analysis of the genomes of long-studied 
microbes such as Streptomyces avermitilis . Through such 
studies, the presence of additional PKS and NRPS clusters 
has been revealed, leading to the discovery of novel sec-
ondary metabolites not detected in standard fermentation 
isolation processes. 51 Genome mining has been used in the 
discovery of a novel peptide, coelichelin, from the soil bac-
terium, Streptomyces coelicolor 52 and this concept is fur-
ther expanded on in the discussion in Section V.D. 
 1 . Improved culturing procedures 
 Recent developments of procedures for cultivating and iden-
tifying microorganisms are aiding microbiologists in their 
assessment of the earth’s full range of microbial diversity. 
For example, in an application of a technique pioneered by 
a small, now defunct biotechnology company known as 
 “ One-Cell Systems ” in the late 1980s, “ nutrient-sparse ” 
media simulating the original natural environment have been 
used for the massive parallel cultivation of gel-encapsulated 
single cells (gel micro-droplets (GMDs)) derived from 
microbes separated from environmental samples (sea water 
and soil). 53 This has permitted “ the simultaneous and 
relatively non-competitive growth of both slow- and fast-
growing microorganisms. ” This process prevents the over-
growth by fast-growing “ microbial weeds, ” and has led to 
the identifi cation of previously undetected species (using 
16S rRNA gene sequencing), and the culturing and scale-
up cultivation of previously uncultivated microbes. To add 
to this, recently Moore’s group at the Scripps Institute of 
Oceanography has reported 54 the initial results of sequenc-
ing Salinispora tropica where they found that approxi-
mately 10% of the genome coded for potential secondary 
metabolites. If one couples this work to the recent paper on 
cultivation of Gram-positive marine microbes by Gontang 
 et al. 55 then the potential for novel agents is immense. 
 2 . Extremophiles 
 Extremophilic microbes (extremophiles) abound in extreme 
habitats, such as acidophiles (acidic sulfurous hot springs), 
alkalophiles (alkaline lakes), halophiles (salt lakes), piezo 
(baro)- and (hyper)thermophiles (deep-sea vents), 56–60 and 
O
O
O
NH2
H
N
O
O
OH
HO
Palmerolide A
N N
N
N
N
H2N
OH
NH2
Variolin B
 FIGURE 8.4 Natural products from novel sources. 
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III. The Design of an Effective Natural-Products-Based Approach to Drug Discovery 165
psychrophiles (arctic and antarctic waters, alpine lakes). 61 
While investigations thus far have focused on the isolation 
of thermophilic and hyperthermophilic enzymes (extrem-
ozymes), 62–66 these extreme environments will also indubi-
tably yield novel bioactive chemotypes. 
 An unusual group of acidophiles which thrive in acidic, 
metal-rich waters has been found in abandoned mine waste 
disposal sites, polluted environments which are gener-
ally toxic to most prokaryotic and eukaryotic organisms. 67 
In this work, the novel sesquiterpenoid and polyketide–
terpenoid metabolites berkeleydione and berkeleytrione 
( Figure 8.5 ) showing activity against metalloproteinase-3 
and caspase-1, activities relevant to cancer, Huntington’s 
disease and other diseases, have been discovered from 
 Penicillium species found in the surface waters of Berkeley 
Pit Lake in Montana. 67–69 
 3 . Endophytes 
 While plants have received extensive study as sources of 
bioactive metabolites, the endophytic microbes which 
reside in the tissues between living plant cells have received 
little attention. Endophytes and their host plants may have 
relationships varying from symbiotic to pathogenic, and 
limited studies have revealed an interesting realm of novel 
chemistry. 70–72 Amongst the new bioactive molecules dis-
covered are novel wide-spectrum antibiotics, kakadumy-
cins, isolated from an endophytic Streptomycete associated 
with the fern leafed grevillea ( Grevillea pteridifolia ) from 
the Northern Territory of Australia, 73 ambuic acid ( Figure 
8.5 ), an antifungal agent, which has been recently described 
from several isolates of Pestalotiopsis microspora found in 
many of the world’s rainforests, 74 peptide antibiotics, the 
coronamycins, from a Streptomyces species associated with 
an epiphytic vine ( Monastera species) found in the Peruvian 
Amazon 75 and aspochalasins I, J, and K ( Figure 8.5 ), 76 from 
endophytes of plants from the southwestern desert regions 
of the United States. 
 In the case of endophytic fungi, recent reports (see 
below) of the isolation of important plant-derived antican-
cer drugs have served to focusattention on these sources. 
A recent genomic analysis of the fungus Aspergillus nid-
ulans reported that “ Sequence alignments suggest that 
 A. nidulans has the potential to generate up to 27 polyketides, 
14 nonribosomal peptides (NRPs), one terpene, and two 
indole alkaloids; similar predictions can be made from the 
 A. fumigatus and A. oryzae ” as a result of the analysis of the 
potential number of secondary metabolite clusters in these 
fungi. 77 This analysis demonstrated not only the presence 
of “ clustered ” secondary metabolite genes in this fungus, 
but also identifi ed the potential “ controller ” of expression of 
these clusters and demonstrated it by expressing terrequi-
none A ( Figure 8.5 ), a compound not previously reported 
from this species. 77 A recent review expands the discussion 
on control of secondary metabolites in fungi. 78 
 As mentioned above, in the last few years fungi have 
been isolated from plants that have produced small quanti-
ties of various important anticancer agents. Examples are 
Taxol ® from Taxomyces 79 and many Pestalotiopsis spe-
cies, 80 camptothecin, 81 , 82 podophyllotoxin, 83 , 84 vinblastine, 85 
and vincristine 86 , 87 from endophytic fungi isolated from the 
producing plants. It has been demonstrated that these com-
pounds are not artifacts, and so the identifi cation of the 
gene/gene product controlling metabolite production by 
O
OH
H
OCH3
O
OH
O
O
Berkeleytrione
N
H
O
O
HO
NH
Terrequinone A
O
Berkeleydione
CH3OO O
H OH
O
O
OO
O
O
OHOH
Ambuic acid
COOH
CH3
H3CH
O
O RHOO
HN
H3C
H
Aspochalasin I R � OH
Aspochalasin J R � H
HN O
O
CH3
H3CH
H3C
H
H3CO OH
Aspochalasin K
OH
O
 FIGURE 8.5 Natural products from extremophiles and endophytes. 
Ch08-P374194.indd Sec2:165Ch08-P374194.indd Sec2:165 5/30/2008 5:07:57 PM5/30/2008 5:07:57 PM
CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures166
these microbes could provide an entry into greatly increased 
production of key bioactive natural products. 
 4 . Marine microbes 
 Deep ocean sediments are proving to be a valuable source 
of new actinomycete bacteria that are unique to the marine 
environment, 88 and based on a combination of culture and 
phylogenetic approaches, the fi rst truly marine actino-
mycete genus named Salinospora has been described. 55 , 89 
Members of the genus are ubiquitous, and are found in 
sediments on tropical ocean bottoms and in more shallow 
waters, often reaching concentrations up to 10 4 per cc of 
sediment, as well as appearing on the surfaces of numerous 
marine plants and animals. Culturing using the appropriate 
selective isolation techniques has led to the observation of 
signifi cant antibiotic and cytotoxic activity, leading to the 
isolation of a potent cytotoxin, salinosporamide A ( Figure 
8.6 ), a very potent proteasome inhibitor (IC 50 � 1.3 nM), 
90 
currently in Phase I clinical trials. More recent studies have 
led to the isolation and cultivation of another new actino-
mycete genus, named Marinispora , which is also yielding 
rich new chemistry. Novel macrolides called marinomycins 
have been isolated, and marinomycins A–D ( Figure 8.6 ) 
show potent activity against drug-resistant bacterial patho-
gens and some melanomas. 91 Publications by the Fenical 
group on the novel and diverse chemistry of these new 
microbial genera continue to appear regularly. 
N
H
N
Cl O O
O
CH3O
O
OCH3
H
HO
N
O
O
O
H
N
OCH3O
OH
OCH3
H
H3CO
OCH3
OH
OH OH OH O
OH
HO
OO OHOHOHOO
HO
OH
OO
O
O
O
O
HO
O
OCH3
N
O
O
O
OO
OOH
N
S
HO
H
N
O
O
OO
H
OH
H
H
Cl
Maytansine Pederin
Rhizoxin
Marinomycin A
Epothilone D
Salinosporamide A
 FIGURE 8.6 Examples of novel microbial natural products. 
Ch08-P374194.indd Sec2:166Ch08-P374194.indd Sec2:166 5/30/2008 5:07:57 PM5/30/2008 5:07:57 PM
III. The Design of an Effective Natural-Products-Based Approach to Drug Discovery 167
 5 . Microbial symbionts 
 There is mounting evidence that many bioactive compounds 
isolated from various macroorganisms are actually metabo-
lites synthesized by symbiotic bacteria. 92 These include the 
anticancer maytansanoids ( Figure 8.6 ), originally isolated 
from several plant genera of the Celastraceae family, 93 the 
pederin class of antitumor compounds ( Figure 8.6 ) isolated 
from beetles of genera Paederus and Paederidus which have 
also been isolated from several marine sponges, 94–96 and a 
range of antitumor agents isolated from marine organisms 
which closely resemble bacterial metabolites. 40 
 An interesting example of endo-symbiosis between 
a fungus and a bacterium has been discovered in the case 
of rice seedling blight where the toxic metabolite, rhizoxin 
( Figure 8.6 ), originally isolated from the contaminating 
 Rhizopus fungus, has actually been found to be produced 
by a symbiotic Burkholderia bacterial species. 97 This unex-
pected fi nding reveals a complex symbiotic–pathogenic rela-
tionship, extending the fungal–plant interaction to a third, 
key bacterial player, thereby offering potentially new ave-
nues for pest control. In addition, rhizoxin exhibits potent 
antitumor activity, but toxicity problems have precluded its 
further development as an anticancer drug. The cultivation 
of the bacterium independently of the fungal host has ena-
bled the isolation of rhizoxin as well as rhizoxin analogs 
which may have signifi cant implications in development of 
agents with improved pharmacological properties. 
 6 . Combinatorial biosynthesis 
 Great advances have been made in the understanding of the 
role of multifunctional polyketide synthase enzymes (PKSs) 
in bacterial aromatic polyketide biosynthesis, and many such 
enzymes have been identifi ed, together with their encoding 
genes. 98–101 The same applies to NRPSs responsible for the 
biosynthesis of NRPs. 100 Through the rapidly increasing 
analysis of microbial genomes, a multitude of gene clusters 
encoding for polyketides, NRPs, and hybrid polyketide-
NRP metabolites have been identifi ed, thereby providing the 
tools for engineering the biosynthesis of novel “ non-natural ” 
natural products through gene shuffl ing, domain deletions, 
and mutations. 100 , 102 Examples of novel analogs of anthra-
cyclines, ansamitocins, epothilones, enediynes, and amino-
coumarins produced by combinatorial biosynthesis of the 
relevant biosynthetic pathways have recently been reviewed 
by Shen et al . 103 
 A recent example of the power of this technique when 
applied to natural products is the development of an effi cient 
method for scale-up production of epothilone D ( Figure 
8.6 ), which entered clinical trials as a potential anticancer 
agent but has now been discontinued in favor of a congener, 
9,10-didehydroepothilone D. Epothilone D was the most 
active of the epothilone series isolated from the myxobacte-
rium, Sorangium cellulosum , and is the des-epoxy precursor 
of epothilone B. The isolation and sequencing of the poly-
ketide gene cluster producing epothilone B from two S. cel-
lulosum strains has been reported, 104 , 105 and the role of the 
last gene in the cluster, epo K, encoding a cytochrome P 450 , 
in the epoxidation of epothilone D to epothilone B has been 
demonstrated. Heterologous expression of the gene cluster 
minus the epo K in Myxococcus xanthus resulted in large-
scale production of crystalline epothilone D. 106 Further 
discussion on the integration of this technology into investi-
gations of natural products is given in Section V. 
 C . Extraction 
 In the case of microbes and marine organisms, extraction 
is normally carried out on the whole organism (though 
now some groups are isolating the commensal/associated 
microbes from marine invertebrates before a formal extrac-
tion). With plants however, which may be large and have 
well-differentiatedparts, it is common to take multiple sam-
ples from one organism and to extract them separately. The 
methods used by the NCI are summarized at http://npsg.
ncifcrf.gov/ . The procedures used for extraction vary with 
the nature of the sample, and in some cases are dependent on 
the nature of the ultimate assay. Thus, a number of screens 
are sensitive to the tannins and complex carbohydrates 
that are extractable from a variety of organisms, and sys-
tems have been developed that permit easy removal of such 
 “ nuisance ” compounds before assay. 107 , 108 In the simplest 
cases, however, extraction with a lower alcohol (methanol 
to isopropanol) will bring out compounds of interest, though 
in most cases a sequential extraction system is utilized with 
compounds being extracted with solvents of ever-increasing 
polarity. 
 D . Screening methods 
 As mentioned earlier, the advent of new and robust high-
throughput screens has had and continues to have a major 
impact on natural products research in the pharmaceutical 
industry. Most of the screens used are proprietary and pub-
lished information is rare, although general summaries of 
this approach have been published. 109 One screen that has 
been described in detail is the NCI’s 60-cell line cytotox-
icity screen for anticancer agents. 110 Although this is not a 
true receptor-based screen, it has now been developed into a 
system whereby a large number of molecular targets within 
the cell lines may be identifi ed by informatics techniques, 
and refi nements are continuing. Information can be obtained 
from the following URL; http://dtp.nci.nih.gov as to the cur-
rent status of the screens involved. An assay based on dif-
ferential susceptibility to genetically modifi ed yeast strains 
has been described, 111 and has led to many screens based on 
genetically modifi ed yeasts, but at times, the low permeabil-
ity of the unmodifi ed yeast cell wall to chemical compounds 
Ch08-P374194.indd Sec2:167Ch08-P374194.indd Sec2:167 5/30/2008 5:07:57 PM5/30/2008 5:07:57 PM
CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures168
has been overlooked. Thus, data from such screens, particu-
larly those designed with gene deletions, must be carefully 
scrutinized since a large number are based on hosts without 
a modifi ed cell wall. In addition there are simple but robust 
assays that can be utilized by workers in academia that do 
not have access to or may not need high-throughput screens. 
Examples are the brine shrimp and potato disc assays 112 , 113 
or the still useful disc-based antimicrobial assays. 
 High-throughput assays, where large numbers of sam-
ples can be screened in a short period of time, are becoming 
less expensive, and such assays are moving from the indus-
trial or industrial/academic consortium-based groups to 
academia in general, with specifi c expression systems being 
employed as targets for natural product lead discovery. 114 
The application of new techniques, including new fl uo-
rescent assays, NMR, affi nity chromatography and DNA 
microarrays, has led to signifi cant advances in the effective-
ness of high-throughput screening. 115 , 116 
 E . Isolation of active compounds 
 The isolation of the bioactive constituent(s) from a given 
biomass can be a challenging task, particularly if the active 
constituent of interest is present in very low amounts. 
The actual procedure will depend to a large extent on the 
nature of the sample extract: a marine sample, 117 for exam-
ple, may well require a somewhat different extraction and 
purifi cation process from that derived from a plant sam-
ple. 118 Nevertheless, the essential feature in all of these 
methods is the use of an appropriate and reproducible bio-
assay to guide the isolation of the active compound. It is 
also extremely important that compounds that are known 
to inhibit a particular assay, or those that are nuisance com-
pounds be dereplicated (identifi ed and eliminated) as early 
in the process as possible. Procedures for doing this have 
been discussed, 119–124 and various new approaches to isola-
tion and structure elucidation have been reviewed. 125–127 
 F . Structure elucidation 
 Structure elucidation of the bioactive constituent depends 
almost exclusively on the application of modern instrumen-
tal methods, particularly high-fi eld NMR and MS. These 
powerful techniques, coupled in some cases with selective 
chemical manipulations, are usually adequate to solve the 
structures of most secondary metabolites up to 2 kD molec-
ular weight. X-ray crystallography is also a valuable tool if 
crystallization of the material can be induced, and in some 
cases, it is the only method to unambiguously assign abso-
lute confi gurations. Nowadays, the determination of the 
amino acid sequences of polypeptides or peptide-containing 
natural products up to 10–12 kD is a relatively straight-
forward task, requiring less than 5 mg of a polypeptide. 
In addition, MS techniques have developed to the stage 
where polypeptides containing unusual amino acids not 
recognized by conventional sequence techniques can be 
sequenced entirely by MS. 
 G . Further biological assessment 
 Once the bioactive component has been obtained in pure 
form and shown to be either novel in structure or to exhibit 
a previously unknown function (if it is a compound that 
is in the literature), then it must be assessed in a series of 
biological assays to determine its effi cacy, potency, toxic-
ity, and pharmacokinetics. These will help to position the 
new compound’s spectrum of activity within the portfolio 
of compounds that a group may be judging for their util-
ity as either drug candidates or leads thereto. If an idea can 
be gained as to its putative mechanism of action (MOA) 
(assuming that the screening techniques used to discover it 
were not MOA-driven) at this stage, then it too can help as 
a discriminator in the prioritizing process. 
 H . Procurement of large-scale supplies 
 Once a compound successfully completes evaluation in 
the initial biological assays then larger amounts of mate-
rial will be required for the studies necessary if activity and 
utility are maintained as the compound proceeds along the 
path from “ Hit ” to a “ Drug Lead ” and then to a “ Clinical 
Candidate. ” The supplies could be made available by 
cultivation of the plant or marine starting material, or by 
large-scale fermentation in the case of a microbial product. 
Chemical synthesis or partial synthesis may also be possi-
ble if the structure of the active compound is amenable to 
large-scale synthesis. The example of paclitaxel is instruc-
tive here: after initial large-scale production by direct 
extraction from Taxus brevifolia bark, it is now generally 
produced by a semi-synthetic procedure starting from the 
more readily available precursor 10-deacetylbaccatin III. 128 
 Another method of obtaining adequate supplies of 
a natural plant product is by utilizing plant tissue culture 
methods. Although there are a few examples of the com-
mercial production of secondary metabolites by plant cell 
culture (shikonin being perhaps the best known one 129 ), the 
application of this technique to commercial production of 
pharmaceuticals had not found general acceptance, prima-
rily for economic reasons. 130 However, the development of 
viable methods for the large-scale production of paclitaxel 
(Taxol ® ), has illustrated that this technology can now be 
successfully applied to the production of a major drug for 
commercial purposes. 131 
 The discovery that several major anticancer drugs, 
originally isolated from plants, are produced by associ-
ated endophytic fungi (Section III.B.3.) opens up further 
avenues for exploring the large-scale production of plant-
derived pharmaceuticals. Likewise, the probable role of 
microbial symbionts in the production of bioactive agents 
frommarine macroorganisms (Section III.B.4.) offers 
Ch08-P374194.indd Sec2:168Ch08-P374194.indd Sec2:168 5/30/2008 5:07:58 PM5/30/2008 5:07:58 PM
IV. Examples of Natural Products or Analogs as Drugs 169
similar opportunities for scaling up the production of marine-
derived pharmaceuticals. It is interesting to note that the 
anticancer agent, Yondelis ® (ecteinascidin 743), originally 
isolated from the tunicate, Ecteinascidia turbinata , is now 
produced on a large scale by semi-synthesis from the anti-
biotic, cyanosafracin B, produced through fermentation of 
the bacterium, Pseudomonas fl uorescens (Section IV.G.1.). 
As noted in Section III.B.6. an effi cient method for scale-up 
production of epothilone D ( Figure 8.6 ), isolated from the 
myxobacterium, S. cellulosum was developed through 
the manipulation of the polyketide gene cluster producing 
the epoxy analog, epothilone B, and heterologous expres-
sion of the modifi ed gene cluster in M. xanthus . 
 In a relatively few cases, total synthesis has provided a 
viable route to large-scale production of important bioac-
tive agents. A good example was the marine-derived anti-
cancer agent, discodermolide 132 which entered Phase I 
clinical trials but currently is not progressing to later phases 
due to toxicity. However, in contrast, the modifi cation of 
the halichondrin B skeleton to produce E7389 (eribulin; 
Section IV.G.2.) by total synthesis is an excellent example 
of modifi cation of a very complex molecule to a slightly 
less complex agent that is now in Phase III trials for breast 
cancer. 133 
 I . Determination of structure–activity 
relationships 
 The initial hit isolated from the biomass, irrespective of 
source, is not necessarily the lead required for further devel-
opment into a drug. It may be too insoluble, not potent 
enough, or be broadly rather than specifi cally active. Once 
the structure has been determined, then synthetic chemistry, 
involving both conventional and combinatorial methods, 
may be used in order to generate derivatives/analogs that 
have the more desirable characteristics of a potential drug. 
Several examples of these types of processes are shown in 
Section IV. 
 The use of natural product-like compounds as scaffolds 
is leading to the generation of smaller, more meaningful 
combinatorial libraries. This is exemplifi ed by the work of 
the Schreiber group who have combined the simultaneous 
reaction of maximal combinations of sets of natural-product-
like core structures ( “ latent intermediates ” ) with peripheral 
groups ( “ skeletal information elements ” ) in the synthesis of 
libraries of over 1,000 compounds bearing signifi cant struc-
tural and chiral diversity. 134 , 135 As stated in an article by 
Borman, 136 “ an initial emphasis on creating mixtures of very 
large numbers of compounds has largely given way in indus-
try to a more measured approach based on arrays of fewer, 
well-characterized compounds ” with “ a particularly strong 
move toward the synthesis of complex natural-product-like 
compounds – molecules that bear a close structural resem-
blance to approved natural-product-based drugs. ” Borman 
further emphasized this point in a second article, 137 in which 
he stated that “ the natural product-like compounds produced 
in diversity oriented synthesis (DOS) have a much better 
shot at interacting with the desired molecular targets and 
exhibiting interesting biological activity. ” 
 Detailed analyses of active natural product skeletons 
have led to the identifi cation of relatively simple key pre-
cursor molecules which form the building blocks for use 
in combinatorial synthetic schemes that have produced 
numbers of potent molecules, thereby enabling structure 
activity relationships to be probed. Thus, in the study of 
the structure–activity relationships of the epothilones, 
solid-phase synthesis of combinatorial libraries was used 
to probe regions of the molecule important to retention or 
improvement of activity. 138 
 The use of an active natural product as the central scaf-
fold in the combinatorial approach can also be applied to 
the generation of large numbers of analogs for structure–
activity studies, the so-called parallel synthetic approach. 
This is embodied in the concept of “ privileged structures, ” 
originally proposed by Evans et al. 139 and then advanced 
further by Nicolaou et al. 140–142 and the Waldmann 
et al. 143,144 
 IV . EXAMPLES OF NATURAL PRODUCTS 
OR ANALOGS AS DRUGS 
 A . Antihypertensives 
 1 . Angiotensin-converting enzyme inhibitors 
(captopril and derivatives) 
 The synthetic Angiotensin-Converting Enzyme (ACE) 
inhibitors were derived from studies of principles in the 
venom of the pit viper, Bothrops jararaca , that inhibited 
the degradation of the nonapeptide, bradykinin. 145 This 
active principle was shown to be the simple nonapeptide, 
teprotide with specifi c activity as an ACE inhibitor and 
with hypotensive activity in clinical trials. 146 , 147 . The pro-
totypical ACE drug, Captopril ® 146 , 147 ( Figure 8.7 ) was then 
developed based on the C-terminal proline structure of all 
known peptidic ACE inhibitors. 146 , 147 In the last 20-plus 
years, 13 more compounds based on this original discov-
ery have become approved drugs acting on this target, with 
the latest compounds being Benazepril ® ( Figure 8.7 ) and 
Cilazepril ® ( Figure 8.7 ). 148 
 B . Anticholesterolemics 
 1. Lovastatin 
 An elevated serum cholesterol level is an important risk fac-
tor in cardiac disease (and in hypertension), and thus a drug 
which could lower this level would be an important prophy-
lactic against cardiovascular diseases in general. Humans 
synthesize about 50% of their cholesterol requirement with 
Ch08-P374194.indd Sec6:169Ch08-P374194.indd Sec6:169 5/30/2008 5:07:58 PM5/30/2008 5:07:58 PM
CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures170
the rest coming from diet, thus if an inhibitor of choles-
terol uptake/absorption is available, then a two-pronged 
approach might be feasible. 
 A potential site for inhibition of cholesterol biosyn-
thesis is at the rate-limiting-step in the system, the reduc-
tion of hydroxymethylglutaryl coenzyme A by HMG-CoA 
reductase to produce mevalonic acid. Following the origi-
nal identifi cation in 1975 of compactin ( Figure 8.8 ) from a 
fermentation beer of Penicillium citrinum as an inhibitor of 
HMG-CoA reductase by Sankyo, 149 , 150 it was also reported 
as an antifungal agent the next year by Brown et al. 151 from 
 Penicillium brevicompactum . Using the HMG-CoA reduct-
ase inhibitor assay, Endo isolated the 7-methyl derivative of 
compactin, mevinolin ( Figure 8.8 ), from Monascus ruber 
and submitted a patent for its biological activity to the 
Japanese Patent Offi ce but without a structure under the 
name Monacolin K. 152 , 153 Concomitantly, Merck discovered 
the same material using a similar assay from an extract of 
 Aspergillus terreus . It was reported in 1980 154 with an US 
Patent issued in the same year. 155 
 Following a signifi cant amount of development work, 
mevinolin (Lovastatin ® ) became the fi rst commercial-
ized HMG-CoA-reductase inhibitor in 1987. 156 , 157 Further 
work using either chemical modifi cation of the basic struc-
ture or by use of biotransformation techniques led to two 
slightly modifi ed compounds; one from converting the 
2-methylbutanoate side-chain into 2,2-dimethylbutanoate 
(Simvastatin ® ) ( Figure 8.8 ) and the second, by open-
ing of the exocyclic lactone to give the free hydroxy acid 
(Pravastatin ® ) ( Figure 8.8 ). Further development start-
ing with compounds such as these has led to a number of 
totally synthetic “ statins, ” with atorvastin (Lipitor ® ) ( Figure 
8.8 ) shown above. What is signifi cant about these synthetic 
compounds, irrespective of which company has synthesized 
and/ordeveloped them as commercial drugs, is that in every 
case, their “ operative ends ” are the dihydroxy-heptenoic 
N
O
HS
H
OHO
Captopril
N
N
O
OH
N
H
OHO
CilazaprilBenazepril
N
N
H
OCH3CH2O
O
COOH
 FIGURE 8.7 Natural product-based 
ACE inhibitors. 
O
O
O
R
H H
H
OHO
Compactin R � H
Mevinolin R � CH3
O
H
OHO
HH
O
O
Simvastatin
HO
HOOC
O
O
HO
H H
H
OH
Pravastatin
N
OH
CO2H
HO
FF
HN
OO
Atorvastin (lipitor)
N
O
F
F
OH
OH
Ezetimibe
 FIGURE 8.8 Natural and natural-
product-based anticholesterolemics. 
Ch08-P374194.indd Sec6:170Ch08-P374194.indd Sec6:170 5/30/2008 5:07:58 PM5/30/2008 5:07:58 PM
IV. Examples of Natural Products or Analogs as Drugs 171
acid side-chain (or its reduced form) from the fungal prod-
ucts linked to a lipophilic ring structure. All of these com-
pounds demonstrate the intrinsic value of natural products 
as the source of the pharmacophore, with Lipitor ® grossing 
over US $13B in sales in 2006. 
 Although the early compounds are now out of patent, in 
an excellent example of what can be best described as both 
pharmacologic and corporate synergies, recently Merck 
and Schering-Plough were able to obtain FDA approval for 
a combination drug where Schering-Plough’s cholesterol 
uptake inhibitor ezetimibe ( Figure 8.8 ) was combined with 
simvastatin under the trade name of Vytorin ® . Aside from 
the unusual situation of two major competing pharma-
ceutical houses cooperating in production of a new drug, 
the base structure of ezetimibe is derived from the mono-
bactam nucleus, fi rst described as an antibiotic agent in 
the early 1980s. The derivation of this cholesterol uptake 
inhibitor was described by the Schering-Plough chemistry 
group in 1998. 158 They were designed as acyl coenzyme 
A:cholesterol acyl transferase(ACAT) inhibitors but were 
then discovered to inhibit cholesterol uptake not by ACAT 
inhibition, but rather by inhibition of NPC1L1 (Niemann-
Pick C1-like 1 protein). 159 The review by Burnett and 
Huff 160 should be consulted for more information on the 
pharmacology background. 
 C . Immunosuppressives 
 1 . Rapamycin and derivatives 
 The most important immunosuppressive agent is the fun-
gal secondary metabolite, rapamycin ( Figure 8.9 ), a natural 
product that has both been highly successful as a drug in its 
own right and as the basis for a series of potentially impor-
tant drugs in a variety of disease conditions. This com-
pound was approved as an immunosuppressive drug under 
the trade name Rapamune ® in 1999 though it was fi rst 
identifi ed as an antifungal drug years earlier. Modifi cation 
at one site, the C 43 alcoholic hydroxyl group, has led to 
three further clinical drugs (everolimus; Figure 8.9 , zotar-
olimus; Figure 8.9 , and temsirolimus (CCI-779; Figure 8.9 ) 
and one in Phase II clinical trials (AP23573; Figure 8.9 ). 
In all cases, modifi cations were made in one area that 
avoids both the FKBP-12 and the target of rapamycin 
(TOR) binding sites, as modifi cations in other areas would 
negate the basic biological activity of this molecule. 161 . 
The recent review by Koehn should be consulted for fur-
ther details of these and related compounds. 162 
 D. Antibiotics 
 1. General comments 
 Although the pundits will claim that the “ Golden Age of 
Antibiotics ” is long past, the necessity for new agents to 
combat infectious disease of all types is still with us, and 
with the massive misuse of potent antibiotics, the microbes 
that are now major causes of diseases of man (and animals) 
are rapidly exhibiting multiresistant phenotypes. Perhaps 
nowhere is the effect of multiple resistance phenotype seen 
more than in the problems that arise in the treatment of 
tuberculosis. Most if not all clinical strains are resistant to at 
least two if not more of the commonly used antibiotics, and 
currently, increasing numbers of patients present with strains 
OO
HOO
CH3OO
OO
OO
O
HO
HO
CH3OO
N
NN
NN
OO
PP
OO
O
TOR
FKBP
N
OOO
O
OOO OO
O
OO
HO
OO
O
R
OH
OOOOOOO
CH3OO
HOO
 FIGURE 8.9 Immunosuppressives. 
Ch08-P374194.indd Sec3:171Ch08-P374194.indd Sec3:171 5/30/2008 5:07:58 PM5/30/2008 5:07:58 PM
CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures172
that are resistant to six or more of the antibiotics commonly 
used for treatment. A recent review by Janin gives an exten-
sive coverage of the drugs in use or in clinical trials for TB 
and should be consulted for further information. 163 
 M. tuberculosis is not the only “ problem microbe ” 
with high-level resistance, as shown by the listing from 
the Infectious Disease Society of America of the following 
 “ problem ” microbes; methicillin-resistant S. aureus (MRSA), 
vancomycin-resistant E. faecium (and early reports of the 
similar S. aureus ), extended-spectrum β-lactamase-producing 
members of the Enterobacteriaceae, and the multiply drug-
resistant (MDR) strains of A. baumannii , P. aeruginosa , 
and C. diffi cile , with others “ waiting in the wings. ” A fuller 
discussion of the problem is given in the review by Wright 
and Sutherland 164 which should be consulted for further 
information. 
 Fortunately natural products continue to provide new 
antibiotics. The review by Lam 165 on natural products in 
drug discovery, lists seven natural products or derivatives 
that were approved as antibacterial or antifungal agents in 
the United States in the time frame 2001–2005. The review 
by Newman and Cragg, 8 lists 11 antibacterial compounds 
and three antifungal compounds that are either natural 
products or derivatives that have been approved by all regu-
latory authorities in the time frame 1997–2006. A thorough 
recent review of antibacterial natural products has just been 
published by von Nussbaum et al. and should be consulted 
for information on such agents. 166 
 2. Avermectin, ivermectin, and doramectin 
 The avermectins are a family of broad-spectrum antipara-
sitic compounds with avermectin A ( Figure 8.10 ) being an 
example. These compounds were originally sold by Merck 
(with a slight chemical modifi cation) as veterinary agents 
(ivermectins) under the name Mectizan ® ( Figure 8.10 ). 
Subsequently, it was discovered that the molecules had 
excellent activity against some of the West African para-
site strains that caused river blindness, and they moved into 
human medicine and recently (2006) this agent was regis-
tered in Japan for the treatment of human scabies infections. 
 Since these molecules are polyketides, in recent years 
groups at Pfi zer and elsewhere have been working on 
ways to modify the keto-synthases that would permit 
novel agents to be expressed by suitable microbial hosts. 
These efforts have led to the modifi ed agents known col-
lectively as the doramectins which have improved activities 
( Figure 8.10 ). 167 
 E . Microbial anticancer agents 
 1 . Epothilones 
 Over the last ten or so years, some of the most interesting 
natural product base structures being considered as agents 
for clinical trials in cancer chemotherapy, have been the 
myxobacterial products known collectively as the epothi-
lones. These macrolides, with a mechanism of action simi-
lar to that of Taxol ® , have been extensively studied, initially 
by the discoverers in Germany 168 and then by Merck and 
Kosan in the United States, and also from a chemical per-
spective, by three major groups, those of Danishefsky 
at Memorial Sloan-Kettering 169 , Nicolaou at the Scripps 
Institute 138 and Altmann, originally at Schering AG and 
now at the Eidgenössische Technische Hochschule (ETH) 
Zurich. 170 , 171 
 Enough material was amassed to begin the evaluation 
of this class of agents as antitumor drugs, initially by the 
production of epothilones A and B ( Figure 8.11 ) through 
a combination of classical fermentation and isolation ofO
O
O O
R2H
H
H
OR1
O
H
O
O
OCH3
H
O
O
OCH3
HO
H
Avermectin A1a R1 � CH3, R2 � A
Ivermectin B1a R1 � H, 22,23-dihydro, R2 � A
Doramectin R1 � CH3, R2 � B
23
22
H
A
O
B
 FIGURE 8.10 Natural antiparasitic compounds. 
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IV. Examples of Natural Products or Analogs as Drugs 173
the natural products, and then subsequent work on the 
biosynthetic gene cluster involving the deletion of the ter-
minal P 450 gene leading to production on a signifi cant 
scale of epothilones C and D ( Figure 8.11 ) ( cf. comments 
in Section III.B.6. above). In addition, total syntheses were 
performed by a number of groups, including variations 
on the macrolide ring giving the azaepothilone (ixabepi-
lone or 16-azaepothilone B; Figure 8.11 ). This compound 
was approved in late 2007 by the FDA for monotherapy 
against breast cancer. It is the fi rst non-taxane with tubulin-
stabilizing activity to be granted marketing authority. A 
recent review concludes. “There is a clear need for new 
agents active against resistant metastatic breast cancer and 
ixabepilone might be a welcome new compound in this 
situation.”172 
 However, other molecules are still in the race, includ-
ing some natural products and others that are products of 
semi-synthesis and in two particular cases, total synthe-
ses. Currently (July 2007) there are at least 16 molecular 
entities in varying stages of testing from biological test-
ing through to Phase III clinical trials. Of these, four are 
in clinical trials in addition to ixabepilone. These are 
composed of epothilone B (patupilone, or EPO-906) in Phase 
III with Novartis, a slight modifi cation of epothilone B 
where the thiazole sidechain of epothilone B has an amino 
group in the 21 position, known as BMS-310705 ( Figure 
8.11 ) in Phase I; and a second generation version of epothi-
lone D known as 9,10-didehydroepothilone D or KOS-1584 
( Figure 8.11 ). The latter compound was licenced by Kosan 
from the Danishefsky group together with epothilone D, but 
was later selected to replace epothilone D in clinical devel-
opment; it is currently in Phase I with a projected Phase II 
trial to commence late in 2007 (Prous Integrity ® listing). 
 From a totally synthetic aspect, another group has intro-
duced a very interesting molecule that is now in Phase II 
clinical trials with Schering AG. This is the molecule known 
as ZK-EPO ( Figure 8.11 ), which for a number of years did 
not have a published structure. In 2006, the full ration-
ale for and synthetic methods employed were published 
for this molecule, which is a modifi cation of epothilone B 
with a benzothiazole in place of the thiazole on the Western 
side (effectively a ring-closure of the pendant thiazole in 
epothilone B), and the substitution of an allyl group for the 
methyl on the Eastern side of epothilone B. Although these 
O
O
O
O
OH
N
S
HO
Epothilone C R � H
Epothilone D R � CH3
RR
O
O
O
O
OH
N
S
HO
O
Epothilone A R � H
Epothilone B R � CH3
CH3
O
NH
OOH
N
S
HO
O
Ixabepilone
CH3
O
O
O
O
OH
N
S
HO
O
BMS-310705
NH2
O
O
OOH
N
S
HO
9,10-Didehydroepothilone D
(KOS-1584)
CH3
O
O
O
O
OH
N
S
HO
O
ZK-EPO
 FIGURE 8.11 Epothilone antican-
cer agents. 
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CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures174
are relatively modest changes, the molecule is no longer 
an MDR substrate, has no effect on confl uent normal cells 
and is as active on resistant phenotypes as on their wild type 
precursors. 173 
 In addition to these molecules in trials there are 
others that have some interesting substituents from a 
medicinal chemistry perspective. One is the trifl uoromethyl-
substituted molecule fl udelone 169 ( Figure 8.12 ) and the 
others have sulfur substituents in the macrolide ring, 
one being 5-thiaepothilone B ( Figure 8.12 ) and the other 
3-thiaepothilone D ( Figure 8.12 ). The sulfur substituted 
compounds have only been referenced in patents but appear 
to have activities in vitro in the nanomolar to subnanomolar 
range against selected cell lines. Then last year, in an exten-
sion of the concept expressed in the work leading to ixabe-
pilone, where the 16 position was substituted by nitrogen 
thus giving rise to a formal lactam ring, the Altmann group 
reported a novel form of “ Azathilones ” where the epoxide 
was removed from epothilone B and a ring nitrogen sub-
stituted. This ring system is now being further explored 
by this group utilizing substitution patterns reminiscent 
of the ZK-EPO molecule, with the most active reported 
molecule 174 being the N - tert -butyloxycarbonyl derivative 
( Figure 8.12 ). 
 Thus just as with the taxanes, which are still actively 
being worked on close to 15 years after approval (see below) , 
the epothilones, are still exercising the minds of medicinal 
chemists and will continue to do so, particularly as there 
are other molecules with similar activity against tubu-
lin such as peloruside, that has structural features similar 
to the epothilones but comes, at least formally, from a marine 
invertebrate. 
 What is potentially exciting is that recently, Khosla’s 
group 175 demonstrated that the biosynthetic pathways that 
encode the C 1 –C 8 portion of the epothilone molecule lead-
ing to the formal production of epothilone C, will accept 
non-natural substrates. This has the potential to lead to 
 “ manufacturing ” by a combination of precursor-directed 
biosynthesis coupled to chemical bond formation by stand-
ard techniques, of unnatural epothilones whose properties 
may well be quite different from those previously reported. 
The C 1 –C 8 chain is apparently signifi cant for tubulin bind-
ing but changes to the rest of the molecule may “ tune ” these 
interactions. However, only time and experimentation will 
tell if such unnatural molecules will have antitumor activi-
ties or other, previously unknown biological interactions. 
 2 . Other examples 
 Rather than discuss other anticancer examples in this chap-
ter, interested readers are referred to a book with data on 
recent advances in the medicinal chemistry of such agents, 
including the anthracyclines, 176 the bleomycins, 177 the 
mitomycins, 178 the endiynes, 179 and the staurosporines. 180 
 F . Anticancer agents from plants 
 The initial studies of natural products as potential anticancer 
agents were made in the 1950s based on compounds from 
CH3
S
O
OOH
N
S
HO
O
5-Thiaepothilone B
O
OOO
OH
N
S
HO
Fludelone
CF3
S
O
O
O
O
N
S
HO
3-Thiaepothilone D
CH3
O
O
OOH
N
S
HO
N
An azathilone
COOBut
 FIGURE 8.12 Additional epothilone 
anticancer agents. 
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IV. Examples of Natural Products or Analogs as Drugs 175
R2O
O
CH3
CH3
3
O
H3CO
OH
CH3
OR3
33
OR4
OOH
O
OH
Paclitaxel (TaxolTM) R1 � Ph, R2 � COCH3, R3 � H, R4 � Ac
Docetaxel R1 � OC(CH3)3, R2 � H, R3 � H, R4 � Ac
BMS-184776 R1 � Ph, R2 � COCH3, R3 � OCH2SCH3, R4 � Ac
BMS-188797 R1 � Ph, R2 � COCH3, R3 � H, R4 � COOCH3
TXD258 R1 � OC(CH3)3, R2 � Me, R3 � Me, R4 � Ac
NHR1
O
CH3COO
O
CH3
CH3
3
O
H3CO
OH OAc
OOH
O
OH
NHO
O
Larotaxel
 FIGURE 8.13 Taxane anticancer 
agents. 
plants, and the vinca alkaloids and the podophyllotoxin 
analogs etoposide and teniposide were the fi rst fruits of 
these investigations. Later work led to the very important 
taxane drugs and the camptothecin analogs. 
 1 . Paclitaxel 
 Paclitaxel (Taxol ® ; Figure 8.13 ) is the most exciting plant-
derived anticancer drug discovered in recent years. It 
occurs, along with several key precursors (the baccatins), 
in the leaves of various Taxusspecies .181 It was found to 
act by promoting the assembly of tubulin into microtu-
bules, and the discovery of this activity in 1979 by Schiff 
and Horwitz 182 was an important milestone in the develop-
ment of paclitaxel as a drug. After an extended period of 
development it was fi nally approved for clinical use against 
ovarian cancer in 1992 and against breast cancer in 1994. 
Since then it has become a blockbuster drug, with annual 
sales of over $1 billion. 
 The success of paclitaxel spurred an enormous amount 
of work on the synthesis of analogs, and this work has been 
summarized in several reviews. 131 , 183–188 The fi rst analog 
to be developed is the close chemical relative, docetaxel 
(Taxotere ® ; Figure 8.13 ). 189 The new albumin-bound for-
mulation of paclitaxel known as Abraxane ® has also been 
approved for clinical use and launched in 2005; this for-
mulation offers some important clinical advantages com-
pared with the original Cremophor formulation. 190 The 
reviews cited above should be consulted for information on 
new agents in development, such as BMS-184776, BMS-
188797, and larotaxel ( Figure 8.13 ). 
 2 . Other examples 
 As in the case of microbially derived anticancer agents 
(Section IV.E.2.), interested readers can consult the informa-
tion on podophyllotoxin and derivatives, 191 the vinca alka-
loids and derivatives, 192 and camptothecin and derivatives 193 
in the recent volume edited by the authors of this chapter. 
 G . Anticancer agents from marine 
organisms 
 The study of marine organisms as sources of anticancer 
agents only began in the late 1960s, and Yondelis ® , the 
fi rst marine-derived clinical agent has recently been recom-
mended for approval for treatment of soft tissue sarcoma 
by the EMEA. 194 This section will cover this compound 
and two additional marine-derived agents which are in 
advanced clinical trials. 
 1 . Yondelis ® 
 The complex alkaloid ecteinascidin 743 ( Figure 8.14 ) was 
discovered by the late Kenneth Rinehart 195 concomitantly 
with the Harbor Branch Oceanographic Institution group 
led by Amy Wright 196 from the colonial tunicate E. turbi-
nata . It was found to have a unique mechanism of action, 
binding to the minor groove of DNA and interfering with 
cell division, the genetic transcription processes, and DNA 
repair machinery. The issue of compound supply, always a 
problem with marine-sourced materials, was solved by the 
development of a nice semi-synthetic route from the micro-
bial product cyanosafracin B ( Figure 8.14 ). 197 Under the 
name Yondelis ® ecteinascidin 743 has been granted Orphan 
Drug designation in Europe and the United States, and 
was recommended for approval by the European Medicine 
Evaluation Agency (EMEA) in late July, 2007 for the treat-
ment of soft tissue sarcomas (STS). 194 It is also in a Phase 
III trial in ovarian cancer and in phase II trials for breast, 
prostate, and pediatric sarcomas. 
 2 . Other marine agents 
 The complex marine polyether halichondrin B ( Figure 
8.15 ) was fi rst isolated from a Japanese sponge by Uemura 
 et al. , 198 and was subsequently reisolated by Pettit from 
an Axinella species collected in Palau. 199 The compound 
had excellent bioactivity and showed a pattern of activity 
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CHAPTER 8 Natural Products as Pharmaceuticals and Sources for Lead Structures176
in the NCI 60-cell line screen comparable to the vinca 
alkaloids and paclitaxel. 199 The compound was only iso-
lated in miniscule yield, however, and its complex structure 
appeared to make total synthesis impractical as a source for 
drug development. Fortunately, in the course of synthetic 
studies on the synthesis of halichondrin B, 200 the group 
at Eisai Research Institute in the United States, working 
closely with Kishi’s group, discovered that certain macro-
cyclic ketone analogs of the right hand half of halichondrin 
B retained all or most of the potency of the parent com-
pound. 201 This key observation was then used as the impe-
tus for the heroic large-scale synthesis of the analog E7389 
(Eribulin; Figure 8.15 ), which is currently in Phase III clin-
ical trials with an NDA fi ling scheduled for late 2007. The 
discovery and development of E7389 (Eribulin) has been 
described in a recent book chapter. 133 
 Bryostatin 1 ( Figure 8.15 ) is a complex macrolide 
natural product originally discovered by Pettit and his col-
laborators under an early NCI program. 202 It has excel-
lent anticancer activity which is due, at least in part, to its 
ability to interact with protein kinase C (PKC) isozymes. 
Compound supply as usual proved to be a major problem, 
but enough cGMP-grade material could be isolated from 
wild collections to supply material for clinical trials. 203 
O
O
O O
O
OO
O
O
H
H
O
CH3OO
H2N
OH
E7389 (eribulin)
H
O
O
O O
O
O
O
O
H
H
O
H
O
O
O
OO
O
O
O
HO
HO
HO
H
H
H
H
H
Halichondrin B
O O
O
CH3O
O
O
OH
H
H HO
OAc
H
O
OHH
O
OCH3
O
OH
O
Bryostatin 1
 FIGURE 8.15 Other marine anticancer agents. 
NH
O
N
O
SAcO
CH3
O
O H
N
HO
OCH3
CH3
CH3
H
H
H
OH
HO
CH3O
Ecteinascidin 743 (Yondelis ®)
N
N
HO
OCH3
CH3
CH3
H
H
H
CN
O
O
CH3
CH3O
NH
OO
CH3
NH2
Cyanosafracin B
 FIGURE 8.14 Ecteinascidin 743 (Yondelis ® ) 
and its semi-synthetic precursor. 
Ch08-P374194.indd Sec3:176Ch08-P374194.indd Sec3:176 5/30/2008 5:08:01 PM5/30/2008 5:08:01 PM
V. Future Directions in Natural Products as Drugs and Drug Design Templates 177
Initial clinical results indicated that the drug would be most 
effective in combination therapy, and several Phase II trials 
of this nature are in progress. 204 
 H . Antimalarial agents 
 Malaria is a major scourge of mankind, and the discovery 
of new antimalarial drugs is a worldwide health impera-
tive. The alkaloid quinine was the fi rst effective antimalar-
ial agent to be discovered, and it served mankind well for 
about 300 years, although resistance to the drug was fi rst 
noted in 1910. It was largely replaced in the mid 20th cen-
tury by the synthetic analog chloroquine, but resistance to 
this drug emerged in 1957, and it is no longer of value in 
many areas of the world. 205 
 The discovery of artemisinin ( Figure 8.16 ) by Chinese 
scientists in 1971 provided an exciting new natural product 
lead compound, 206 and artemisinin is now used for the treat-
ment of malaria in many countries. Its unusual endoper-
oxide bridge is a key to its mechanism of action, which 
involves complexation with haemin by coordination of the 
peroxide bridge with iron. This in turn interrupts the detoxi-
fi cation process used by the parasite and generates free radi-
cal species which can attack proteins in the parasite. 
 Many analogs of artemisinin have been prepared in 
attempts to improve its activity and utility. 207 Two of the 
most promising of these are the totally synthetic ana-
log OZ277 ( Figure 8.16 ), 208 and the dimeric analog 
( Figure 8.16 ). Single doses of the latter compound were 
shown to cure malaria-infected mice, while corresponding 
treatments with artemisinin were much less effective. 209 
 I . Other natural products 
 The examples given above are simply a selection of the 
natural product and natural product analogs that have 
entered clinical use. There are several recent reviews 
that cover natural products as drugs and sources of struc-
tures. 8 , 166 , 169 , 170 , 210–215 These references should be con-
sulted for further examples of how natural products have 
led to novel drugs for a multiplicity of diseases, and for 
insights into the future potential of natural products in drug 
discovery. 
 V . FUTURE DIRECTIONS IN NATURAL 
PRODUCTS AS DRUGS AND DRUG 
DESIGN TEMPLATES 
 A . Introduction 
 The probability that a directly