Gordon M. Cragg

Anticancer agents from natural products

Introduction Gordon M. Cragg, David G. I. Kingston, and David J. Newman Camptothecin and Its Analogs Nicolas J. Rahier, Craig J. Thomas, and Sidney M. Hecht The Discovery and Development of the Combretastatins Kevin G. Pinney, George R. Pettit, Mary Lynn Trawick, Christopher Jelinek, and David J. Chaplin Homoharringtonine and Related Compounds Hideji Itokawa, Yukio Hitotsuyanagi, and Kuo-Hsiung Lee Podophyllotoxins and Analogs Kuo-Hsiung Lee and Zhiyan Xiao Taxol and its Analogs David G. I. Kingston The Vinca Alkaloids Fanny Roussi, Francoise Gueritte, and Jacques Fahy The Bryostatins David J. Newman The Isolation, Characterization, and Development of a Novel Class of Potent Antimitotic Macrocyclic Depsipeptides: The Cryptophycins Rima S. Al-awar and Chuan Shih Chemistry and Biology of the Discodermolides, Potent Mitotic Spindle Poisons Sarath P. Gunasekera and Amy E. Wright The Dolastatins: Novel Antitumor Agents from Dolabella auricularia Erik Flahive and Jayaram Srirangam Ecteinascidin-743 (Yondelis(R)), Aplidin(R), and Irvalec(R) Carmen Cuevas, Andres Francesch, Carlos M. Galmarini, Pablo Aviles, and Simon Munt Discovery of E7389, a Fully Synthetic Macrocyclic Ketone Analog of Halichondrin B Melvin J. Yu, Yoshito Kishi, and Bruce A. Littlefield HTI-286 (Taltobulin), A Synthetic Analog of the Antimitotic Natural Product Hemiasterlin Raymond J. Andersen, David E. Williams, Wendy K. Strangman, and Michel Roberge The Actinomycins Anthony B. Mauger and Helmut Lackner Anthracyclines Federico-Maria Arcamone Ansamitocins (Maytansinoids) Tin-Wein Yu, Heinz G. Floss, Gordon M. Cragg, and David J. Newman Benzoquinone Ansamycins Kenneth M. Snader Bleomycin Group Antitumor Agents Sidney M. Hecht Biochemical and Biological Evaluation of (+)-CC-1065 Analogs and Conjugates with Polyamides Rohtash Kumar and J. William Lown Epothilone, a Myxobacterial Metabolite With Promising Antitumor Activity Gerhard Hofle and Hans Reichenbach Enediynes Philip R. Hamann, Janis Upeslacis, and Donald B. Borders The Mitomycins William A. Remers Staurosporines and Structurally Related Indolocarbazoles as Antitumor Agents Michelle Prudhomme Combinatorial Biosynthesis of Anticancer Natural Products Steven G. Van Lanen and Ben Shen Developments and Future Trends in Anticancer Natural Products Drug Discovery Gordon M. Cragg and David J. Newman Index

Metabolism of plant-derived anticancer agents

Information on the metabolism of antitumor drugs of plant origin is not extensive for most compound types. This can be attributed to the fact that really only two groups of plant-derived drugs are broadly used clinically, the alkaloids of the vincristine-vinblastine family and the epipodophyllotoxin derivatives etoposide and teniposide. An important factor in fewer plant-derived drugs than microbial or synthetic ones being developed is the relatively small investment in plant research in the U.S. pharmaceutical industry. We have tried to cover, in addition to clinically useful drugs, those compounds which have been in trials recently (even if inactive) and those which are currently in development. Some compounds which might otherwise have been included were omitted because no metabolic studies have been reported. These include maytansine, camptothecin, tetrandrine, thalicarpine and acronycine. We have in some cases included data on metabolism of related compounds which do not have antitumor activity or which have not been developed to clinical study where we felt that this aided the perspective of metabolism of compounds as a group or class. The drug development program with which we are affiliated at the National Cancer Institute is heavily oriented towards seeking target-specific or at least highly target-selective compounds using a screen composed of batteries of human tumor cell lines organized by tissue type (Boyd et al., 1986). The screen looks for selective cytotoxicity towards target cells which could result from such possibilities as specific receptors being present, greater sensitivity of enzyme systems or isozymes, permeability differences or transport specificity, or tissue specific metabolic activation. This last situation, tissue-specific metabolic activation, is discussed in Section 6 and may become of increasing significance as the emphasis in cancer drug discovery turns away from the search for broad spectrum agents, which often have broad toxicity as well, towards more selective ones. We therefore anticipate that metabolic studies of antitumor agents will increasingly become a key component of decisions on development of new drugs towards clinical trials and decisions on clinical protocols.

Antineoplastic agents. 551. Isolation and structures of bauhiniastatins 1-4 from Bauhinia purpurea.

Bioassay-guided (P388 lymphocytic leukemia cell line) separation of extracts prepared from the leaves, stems, and pods of Bauhinia purpurea, and, in parallel, its roots, led to the isolation of four new dibenz[b,f]oxepins (2a, 3-5) named bauhiniastatins 1-4, as well as the known and related pacharin (1) as cancer cell growth inhibitors. The occurrence of oxepin derivatives in nature is quite rare. Bauhiniastatins 1-4 were found to exhibit significant growth inhibition against a minipanel of human cancer cell lines, and bauhiniastatin 1 (2a) was also found to inhibit the P388 cancer cell line. Structures for these new cancer cell growth inhibitors were established by spectroscopic techniques that included HRMS and 2D NMR.

Natural Product Drug Discovery and Development

Over the ages, humans have relied on nature for their basic needs for the production of foodstuffs, shelters, clothing, means of transportation, fertilizers, flavors and fragrances, and not least, medicines. Plants have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years in countries such as China1 and India.2 These plant-basedsystems continue to play an essential role in health care, and it has been estimated by the World Health Organization that approximately 80% of the world’s inhabitants rely mainly on traditional medicines for their primary health care.3 Plant products also play an important role in the health care systems of the remaining 20% of the population mainly residing in developed countries. Analysis of data on prescriptions dispensed from community pharmacies in the United States from 1959 to 1980 indicates that about 25% contained plant extracts or active principles derived from higher plants, and at least 119 chemical substances, derived from 90 plant species, can be considered as important drugs currently in use in one or more countries.3 Of these 119 drugs, 74% were discovered as a result of chemical studies directed at the isolation of the active substances from plants used in traditional medicine. Well-known examples of plant-derived medicinal agents include: the antimalarial drug quinine, obtained from the bark of Cinchona officinalis; the analgesics, codeine and morphine from Papaver somniferum; the antihypertensive reserpine from Rauwolfia serpentina; and the cardiac glycoside, digoxin, from Digitalis purpurea.4

Antineoplastic agents. 536. New sources of naturally occurring cancer cell growth inhibitors from marine organisms, terrestrial plants, and microorganisms(1a,).

Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.

Antineoplastic agents. 489. Isolation and structures of meliastatins 1-5 and related euphane triterpenes from the tree Melia dubia

The bark of the giant neem tree Melia dubia was found to contain 11 euphane-type triterpenes. Five new compounds, meliastatins 1-5 (1-5), proved to inhibit growth of the P388 lymphocytic leukemia cell line (ED(50) 1.7-5.6 microg/mL). Four of the others, the previously known methyl kulonate (8), kulinone (9), 16-hydroxybutyrospermol (10), and kulactone (11), were also found to inhibit (ED(50) 2.5-6.2 microg/mL) the P388 cancer cell line. In addition, two new euphane triterpenes were isolated and named dubione A (6) and dubione B (7). Structures for each of the 11 euphane triterpenes were established by spectral techniques that included HRMS and 2D NMR.

Antitumor agents. Part 212: Bucidarasins A–C, three new cytotoxic clerodane diterpenes from Bucida buceras

As part of a study on antitumor agents from rainforest plants, four new clerodane diterpenes, bucidarasins A--D (1-4), were isolated from Bucida buceras. Their structures were elucidated from detailed 2D NMR analyses. Compounds 1-3 showed potent cytotoxicity against human tumor cell lines with IC(50) values of 0.5-1.9 microM. The potency was retained in drug resistant lines.

Antineoplastic agents. 558. Ampelocissus sp. cancer cell growth inhibitory constituents

An investigation of the Phillippine Ampelocissus sp. roots for cancer cell growth inhibitory components led to the isolation of a new acetogenin characterized as 22-epicalamistrin (1) employing primarily 2D NMR and high-resolution mass spectral analysis. Two other antineoplastic constituents proved to be the known acetogenin uvaribonin (2) and chalcone 3. Constituents 1-3 were all found to show significant cancer cell growth inhibitory activity against a panel of human cancer cell lines.

Drugs from nature: past achievements, future prospects.

Abstract Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. The past century, however, has seen an increasing role played by micro-organisms in the production of the antibiotics and other drugs for the treatment of diseases, ranging from bacterial infections to cardiovascular problems and cancer. Much of the worlds biodiversity remains unexplored as a source of novel drug leads, and the search for new bioactive agents from natural sources, including extreme environments, will continue. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, and from symbiotic and endophytic microbes associated with terrestrial and marine macro-organisms, will provide access to a vast untapped reservoir of genetic and metabolic diversity. These resources will provide a host of novel chemical scaffolds, which can be further developed by combinatorial chemical and biosynthetic approaches to yield chemotherapeutic and other bioactive agents, which have been optimized on the basis of their biological activities. The investigation of these resources requires multi-disciplinary, international collaboration in the discovery and development process.

Natural Products as Pharmaceuticals and Sources for Lead Structures

Publisher Summary Plant-based systems continue to play an essential role in health care, and their use by different cultures is extensively documented. This chapter reviews the continuing value of natural products as sources of potential chemotherapeutic agents. While the contributions of natural secondary metabolites to modern medicine are abundantly clear, the question of their origins has long intrigued chemists and biochemists. Six major hypotheses are summarized here. Structural diversity is not the only reason why natural products are of interest to drug developers, since they often provide highly selective and specific biological activities based on mechanisms of action. The natural products approach can thus be seen as complementary to the synthetic approach, each providing access to (initially) different lead structures. The task of the natural products researcher is thus to select these compounds of pharmacological interest from the “natural combinatorial libraries” produced by extraction of organisms. There are four major elements in the design of any successful natural-products–based drug discovery program: acquisition of biomass, effective screening, bioactivity- driven fractionation, and rapid and effective structure elucidation. The selection of plant samples often raises the question of the ethnobotanical/ethnopharmacological approach versus a random approach. Structure elucidation of the bioactive constituent depends almost exclusively on the application of modern instrumental methods, particularly high-field NMR and MS. Novel methods of chemical syntheses that have the potential to produce base “natural product” molecules that can be optimized for specific medicinal chemistry purposes are also reported.