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1 NATURAL PRODUCTS: A RICH SOURCE OF DRUG DISCOVERY LEADS

1 NATURAL PRODUCTS: A RICH SOURCE OF DRUG DISCOVERY LEADS

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9340_C001.fm Page 2 Monday, April 3, 2006 1:19 PM



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Combinatorial Synthesis of Natural Product-Based Libraries



TABLE 1.1

Dictionary of Natural Products Classification of Natural Products

Classification



Representative Natural Product



Aliphatics



Name

Prostaglandin D3



HO

CO2H



O



HO



Polyketides



Spongistatin 1



OH



HO



HO

H



O



H



H



O



H



O

HO



O

OH



O



O



H



H

OH

Cl



O



OMe



O



H



O



AcO



OAc

OH



Carbohydrates



O



HO



α-D-Glucose



OH



OH



HO

OH

Oxygen heterocycles



Kojic acid



O



HO



OH

O

Simple aromatics



OMe



Griseofulvin



O OMe

O

O



MeO

Cl



Copyright © 2006 Taylor & Francis Group, LLC



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Chemistry on the Interface of Natural Products and Combinatorial Chemistry



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TABLE 1.1 (CONTINUED)

Dictionary of Natural Products Classification of Natural Products

Classification



Representative Natural Product



Benzofuranoids



OMe



Name

Angeolide



O OMe

O

O



MeO

Cl

Benzopyranoids



HO2C



Myrsinoic acid C



OH



O



Flavonoids



Crotafuran B

HO



O



O

O

O



Tannins



Thonningianin B



OH

OH



HO



HO



COO



O



CH2

O



OH



O



Ph



OH

COO



HO



OH

HO

OH

Lignans



Gomisin A



O

O



MeO

OH



MeO



MeO

OMe



Copyright © 2006 Taylor & Francis Group, LLC



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Combinatorial Synthesis of Natural Product-Based Libraries



TABLE 1.1 (CONTINUED)

Dictionary of Natural Products Classification of Natural Products

Classification



Representative Natural Product



Polycyclic aromatics



Name

β-Rubromycin



O



MeO



O

MeO

OH



COOMe



O

O



HO



O



O



Terpenoids



O

H



Dysidiolide



O



OH



Steroids



O



OH



O



Digitoxigenin



OH

HO

Alkaloids



O



Mappicine



N



N

HO

Amino acids



L-4-Hydroxyproline



O

HO



OH

HN



Copyright © 2006 Taylor & Francis Group, LLC



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Chemistry on the Interface of Natural Products and Combinatorial Chemistry



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TABLE 1.1 (CONTINUED)

Dictionary of Natural Products Classification of Natural Products

Classification



Representative Natural Product



Name



Polypyrroles



Chlorophyll A



N



N

Mg



N



N



O



O

O



O



O



are just a few natural compounds that have made a significant impact on the treatment of human disease.

Not only are many drugs natural products, but many drugs are inspired by or derived from natural

compounds.8 A number of semisynthetic derivatives have made it to market. Compounds such as

simvastatin (derived from lovastatin and an analog of mevastatin), topotecan and irinotecan (semisynthetic derivatives of camptothecin), and miglitol (an analog of 1-deoxynojirimycin) are some of the

natural product-like drugs that have been recently approved (Figure 1.1). In the top 35 drugs sold

worldwide, natural product-derived drugs are well-represented.9

Natural products

OH



O



O



O



O



O



N



O



HO



H



HO

O



N



OH



HO

OH

1-Deoxynojirimycin



Camptothecin



R



NH



Lovastatin (R = CH3)

Mevastatin (R = H)



Natural product analogs

O

OH



O



N



O



O



O



OH



N

O

H



HO

O



R1



R2O



Simvastatin



N



HO

Topotecan



OH



R1 = −NMe2, R2 = H

Irinotecan O

R1 = CH3, R2 =



N

O



FIGURE 1.1 Marketed drugs derived from natural products.

Copyright © 2006 Taylor & Francis Group, LLC



HO



Miglitol

N



OH



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Combinatorial Synthesis of Natural Product-Based Libraries



In 2003 and 2004 alone, six additional natural product-based drugs were launched.10 In addition

to the several recently approved low-molecular-weight therapeutics shown in Table 1.2, a number

of derivatives are currently being evaluated as drug candidates, primarily in the oncology and

antiinfective therapeutic areas. Interestingly, marine natural products have seen the least commercial

development11; development of molecules such as discodermolide show promise for this emerging

source of drugs. Furthermore, a survey of drugs approved in the U.S. from 1981 to 2002 described

the place of natural products in nonsynthetic new chemical entities (NCE).12 Of the 877 smallmolecule NCEs from all diseases, countries, and sources during this time period, 49% came from

nonsynthetic origins. In the cancer area, 62% of the small-molecule NCEs were of natural origin.

Forty-eight out of the 74 antihypertensive drugs are derived from natural product structures or

mimics. In the area of antimigraine therapeutics, seven of the ten drugs are based upon serotonin,

a low-molecular-weight natural product. Furthermore, many infectious disease drugs are derived

from natural products.

Despite the prevalence of natural products as marketed drugs, the pharmaceutical industry

began to look elsewhere for drugs. Several factors drove this trend: (1) high-throughput screening

of molecular targets encouraged the use of chemical libraries instead of natural product extract

libraries, (2) combinatorial chemistry promised greater chemical diversity than natural product

libraries, and (3) the increase of molecular targets led to short timelines and made natural productdriven discovery impractical.13 Yet, advances in the utilization of natural product extract libraries,

the slow pace at which combinatorial chemistry has yielded new clinical candidates, and the appeal

of using natural products as probes of biological pathways has led to a renewed interest in natural

products as a strategic component of the drug discovery process. This has been driven in part by

the favorable properties, high chemical diversity, and biochemical specificity that natural products

have as lead compounds. Although synthetic small molecules continue to hold certain advantages

(i.e., physicochemical properties such as Lipinski’s “Rule of Five”),14 natural products are privileged

structures for modulating the activity of cellular pathways. Furthermore, advances in screening

technologies, and molecular biology have made it more practical to incorporate natural products

into the drug discovery process.

With the exception of several important low-molecular-weight natural products such as amine

neurotransmitters (i.e., noradrenaline, adrenaline, serotonin, and melatonin), most natural products

are different from synthetic drugs or drug candidates in several ways.15 They have more stereogenic

centers, are more architecturally complex with greater conformational biases and constraints, and

contain more oxygen and less nitrogen. Other differences include molecular weight; natural products

typically violate Lipinski’s Rule of Five14 by generally having molecular weights greater than 500.

Synthetic molecules designed by medicinal chemists, on the other hand, tend to have a higher

proportion of aromatic and heteroaromatic rings, fewer stereocenters, and lower molecular weights

(complying with Lipinski’s Rule of Five). Figure 1.2 illustrates these differences between natural

and synthetic drugs by comparing marketed anticancer (Taxol® and Gleevec®) and hypercholesterolaemia (Mevacor® and Lipitor®) drugs. These differences suggest the necessity of exploring both

natural products and synthetic molecules as therapeutic agents.



1.2 NATURAL PRODUCT-BASED COMBINATORIAL SYNTHESIS

FOR LEAD DISCOVERY

Combinatorial chemistry grew in the 1990s as a technology-based solution to the demand for

compounds in high-throughput screening campaigns against various therapeutic targets.16 Small

molecules generated via high-throughput synthesis began to dominate preclinical drug discovery

programs. Many approaches to combinatorial chemistry, ranging from the synthesis of mixtures

using chemical and radiofrequency tags48 to discrete compounds on solid support or in solution,

were successfully developed and utilized.17 Furthermore, various high-throughput methods were

Copyright © 2006 Taylor & Francis Group, LLC



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Chemistry on the Interface of Natural Products and Combinatorial Chemistry



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TABLE 1.2

Representative Examples of Recently Approved Natural Product, Natural Product-Derived,

or Semisynthetic Natural Product Small-Molecule Drugs

Generic Name

(Brand Name)



Structure



Miglitol (Glyset®)



HO

HO



Disease Area



Company



Diabetes



Bayer



Type 1

Gaucher’s

disease

(metabolic

disorder)



Pfizer, Actelion



Immunosuppression



Novartis



Antiviral



Hoffmann-La

Roche, Gilead



Dypslipidemia



Sankyo, Kowa,

Nissan



OH



N



HO

OH

Miglustat

(Zavescađ)



HO

HO



N



HO

OH

Mycophenolate

sodium

(Myforticđ)



OH



O



O Na+



O



O



OMe



Oseltamivir

(Tamifluđ)



O

O



O



HN

O

Pitavastatin

(Livalođ)



NH2



F



OH



OH



O

2+

O Ca



N



Copyright â 2006 Taylor & Francis Group, LLC



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Combinatorial Synthesis of Natural Product-Based Libraries



TABLE 1.2 (CONTINUED)

Representative Examples of Recently Approved Natural Product, Natural Product-Derived,

or Semisynthetic Natural Product Small-Molecule Drugs

Generic Name

(Brand Name)



Structure



Rosuvastatin

(Crestor®)



F



OH



OH



Disease Area



Company



Dypslipidemia



Astra-Zeneca,

Shionogi



Anticonvulsant,

antiepileptic



Ortho-McNeil,

Johnson &

Johnson



Diabetes



Takeda, Abbott



Antiviral



GlaxoSmithKline



O

2+

O− Ca



N

SO2

Topiramate

(Topamax®)



OSO2NH2

O



O



O

O



Voglibose (Basen,

Glustat®)



O



H



HO

H

N



HO



OH



OH

HO



OH

OH



Zanamivir

(Relenza®)



OH



O

O



HO



OH



OH

HN

O



HN



NH2

NH



developed for solution-phase array syntheses including polymer-supported reagents, polymer-supported scavengers, and fluorous chemistry (see Chapter 6).18 Methods for producing a range of

molecular structures have been extensively reviewed and described.19 Furthermore, engineered

biosynthesis and biotransformations to generate compounds, as indicated in the preceding text, are

yet other methods for compound synthesis (see Chapter 4 and Chapter 5).20

Copyright © 2006 Taylor & Francis Group, LLC



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Chemistry on the Interface of Natural Products and Combinatorial Chemistry



Natural product drugs



Synthetic drugs



O

N

AcO

O



O



NH



9



O OH

H



OH

S



O



N



O



O



HN



OH

HO



BzO



H



Taxol (anti-cancer agent)



HO



N



O



HN



OAc



N

Gleevec



(chronic myelogenous leukaemia)



N



O

F

O



O

O



O

N

O



NH



Mevacor (hypercholesterolaemia)



OH



OH



++

O− Ca

2



Lipitor (hypercholesterolaemia)



FIGURE 1.2 Differences between natural product drugs and synthetic drugs.



Combinatorial chemistry is equivalent to high-throughput synthesis of compound arrays in which

side-chain, core structure, and stereochemical diversity are varied. At the heart of combinatorial chemistry is the parallel synthesis of compounds that may be lead-like,21 drug-like,15 or natural product-like

(Figure 1.3). Two terms, recently introduced by Schreiber, define directionality of such libraries —

target-oriented synthesis (TOS) and diversity-oriented synthesis (DOS).22,23 In the strictest sense, these

two types of libraries fall within the scope of combinatorial chemistry yet possess unique characteristics.

Targeted libraries generated by TOS aim to elicit a specific biological response based on a gene family

or a therapeutic area. DOS libraries, on the other hand, seek to generate more diversity than what has

historically been the case for combinatorial libraries, by varying the skeletal and stereochemical elements of the core library structures.24 Tan has described several categories of such DOS libraries: (1)

core scaffolds of individual natural products, (2) specific substructures from classes of natural products,

and (3) general structural characteristics of natural products.25

Although a significant number of biologically active compounds have been generated by combinatorial chemistry, the field continues to be criticized for its inability to generate leads and drugs.26

This could not be farther from the truth. For example, Golebiowski and coworkers at Procter & Gamble

described leads, with “sufficient potential (as measured by potency, selectivity, pharmacokinetics,

physicochemical properties, novelty, and absence of toxicity) to progress to a full drug development

program,” discovered from libraries.27 These leads originated from diversity libraries, thematic libraries

(natural products, privileged scaffolds, and protein surface motifs), or focused libraries. Breitenbucher

and Lee, emphasizing the impact of combinatorial chemistry on target-focused libraries, also illustrated

the usefulness of libraries for analyzing structure–activity relationships (SARs).28

In the last 5 to 10 years, there has been a renaissance in natural products research29 and a

movement to combine combinatorial chemistry with natural products.30–34 A cursory examination

of the literature reveals many articles and reviews written in the area.35,36 In 2001, Hall provided

one of the earlier surveys of solution- and solid-phase strategies for libraries based on natural

Copyright © 2006 Taylor & Francis Group, LLC



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Combinatorial Synthesis of Natural Product-Based Libraries



Combinatorial chemistry

(high-throughput synthesis)



Parallel synthesis

Distinctives:

• Varying diversity

Designs:

• Lead-like

• Drug-like

• Natural product-like



Synthetic approaches

Solid-phase

Spatially separated

Split-mix pool synthesis

(chemical or radiofrequency tags)

Solution-phase

Fluorous chemistry

Solid-supported reagents

Biotransformations

Combinatorial biosynthesis

Gene shuffling



Diversity-oriented synthesis

Distinctives:

• Skeletal, stereochemical diversity

Designs:

• Core scaffolds of individual natural products

• Specific substructures from classes of natural products

• General structural characteristics of natural products

Target-oriented synthesis

Distinctives:

• Diversity based upon biological activity

Designs:

• Therapeutic area

• Gene family



FIGURE 1.3 Combinatorial chemistry approaches.



product templates.35c Because natural products already possess known biological activity, they are

good starting points for the design and synthesis of combinatorial libraries (see Chapter 2, Section

2.3).37 A number of computational design studies validated the premise that natural product-like

arrays improve biological relevance of combinatorial libraries.38 For example, Feher and Schmidt,

upon examining natural products, combinatorial compounds, and drug molecules, found that integration of natural product distribution properties make arrays more valuable in exploring cellular

pathways.39 Comparison of natural products, synthetic compounds, and marketed drugs have also

been made by Henkel,40 Schneider,41 and Bajorath (see Chapter 3).42 In the protein structure and

bioinformatics design approach of Waldmann and coworkers described later in this chapter (Section

1.6), a powerful new approach to designing natural product-like libraries has been validated.

The molecular complexity present in nature is, in fact, diversity generated by combinatorial

processes.43 The immune system is a classic example of shuffling gene segments in order to assemble

different antibodies for recognizing foreign antigens. Following carefully choreographed combinatorial synthetic steps, biological macromolecules, such as polypeptides, oligonucleotides, and

polysaccharides, are assembled biosynthetically. Researchers have harnessed this biosynthetic

machinery with techniques such as phage display44 and gene shuffling.45 Furthermore, combinatorial

biosynthesis of natural products such as macrolide antibiotics is achieved by the assembly and

shuffling of polyketide synthases (see Chapter 4).46

Although the biological machinery in living organisms generates natural products (see Chapter

4 and Chapter 5), synthetic chemistry is the primary method used by the pharmaceutical industry

for generating natural product-based molecules. Several synthetic organic approaches have been

used to increase the diversity of compounds related to natural products; all chemical approaches

either start from a natural product or a synthetic starting material (Figure 1.4).47 Using natural

Copyright © 2006 Taylor & Francis Group, LLC



O



H

N



HO2C



Natural product-like libraries

Approach: Natural product hybrids

Example: Bridged piperidine-fused pyrrolidine hybrids



R1



H



O

O

O



NH



AcO



O



O

H



O



R2



HO



NH



R3



R1



N



O



O



R2



R2



O



HO

O



BzO



Approach: Multicomponent reactions

Example: Aromatic polycyclic cores



O



H

AcO



R2



R1

N



Natural product-derived libraries

Approach: Partial degradation and core functionalization

Example: Meroquinene-derived piperidines

H



H



N



R3



N

H

N



O



R2



R4



Approach: Solid-phase and solution-phase synthesis

Example: Non-aromatic polycyclic cores



R3

N



OH



H



R3∗



MeO2C



R1



O



N



O



Quinine



Copyright © 2006 Taylor & Francis Group, LLC



R1



R2



11



FIGURE 1.4 Natural product-based library synthetic approaches.



R4



HN



N

O



O



O



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Natural product analog libraries

Approach: Derivatize or decorate

Example: Taxol analogs



Chemistry on the Interface of Natural Products and Combinatorial Chemistry



Synthetic starting material (total synthesis)



Natural product starting material (semi-synthesis)



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Combinatorial Synthesis of Natural Product-Based Libraries



I



SiO

N



H



HO2C



OH



O



O

O



NH



R3



6

H R



N



Ph



R1



O



R2 1

20 compounds



2

24 compounds



R4



NH

R5 O



Ph



SiO



3



16 compounds



I

O

O

H

O

HO

N

R2



R3



R1



O



O

NH



6

H R



N



Ph

Ph



O

4



NH

R5



O



O

O



R4

HO



H

R3



480 compounds

5



384 compounds



O

NH



O

R4



SCHEME 1.1 Natural product hybrid libraries.



products as starting materials, libraries of natural-product analogs are prepared by derivatization

or decoration of natural products with diversity. A library of Taxol® analogs, prepared by Nicoloau

and coworkers, exemplifies this traditional approach in natural products drug discovery programs.48

Alternatively, natural products can be partially degraded and the core functionalized.49 Meroquinene-derived piperidines, synthesized from quinine by Johnson and Zhang, illustrate this

approach.50,51

A number of different approaches to natural product-like libraries have also been developed

(Figure 1.4). One interesting new approach recently reviewed by Tietze and coworkers is the concept

of natural product hybrids.52 The idea is to combine portions of two different natural products into

one molecule with the goal of discovering new or attenuated biological activity. A recent example

described by Schreiber and coworkers illustrates this approach by using three natural product

subunits, bridged piperidines 1, fused pyrrolidines 2, and spirocyclic oxindoles 3, to prepare two

natural product hybrid libraries 4 and 5 (Scheme 1.1).53 Libraries of the three subunits were prepared

and assembled by the formation of ester linkages.

Another approach is the use of multicomponent reactions (MCRs) to rapidly and efficiently

construct structurally complex and varied polycyclic natural product-like compounds (Figure 1.5).54

A number of synthetic transformations played a key role in the rapid assembly of such molecules

including isocyanide-based reactions, aza- and non-aza [4+2] cycloadditions, [3+2] cycloadditions,

and transition-metal-catalyzed reactions. Using isocyanide-based MCRs, pyrrolopyridines exemplified by mappicine represent an attractive library target for their biological activity.55 Furthermore,

the furoquinoline alkaloid tecleabine represents a common quinoline alkaloid core similar to

structures found in a polycyclic library.56

Copyright © 2006 Taylor & Francis Group, LLC



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