David G. I. Kingston

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

The chemistry of taxol

Abstract The chemistry of the potent anticancer diterpenoid taxol is reviewed, with an emphasis on isolation and analysis, structural modifications, partial synthesis, and structure-activity relationships.

Tubulin-Interactive Natural Products as Anticancer Agents

This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly of tubulin to microtubules. The emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials. The vinca alkaloids, the combretastatins, NPI-2358, the halichondrin B analogue eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhibitors, while the taxanes and the epothilones are the major classes of tubulin polymerization promoters presented, with brief treatments of discodermolide, eleutherobin, and laulimalide. The challenges and future directions of tubulin-interactive natural products-based drug discovery programs are also discussed briefly.

Modern Natural Products Drug Discovery and its Relevance to Biodiversity Conservation

Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery, but maintaining their continued eminence as source compounds is challenging in the face of the changing face of the pharmaceutical industry and the changing nature of biodiversity prospecting brought about by the Convention on Biological Diversity. This review provides an overview of some of these challenges and suggests ways in which they can be addressed so that natural products research can remain a viable and productive route to drug discovery. Results from International Cooperative Biodiversity Groups (ICBGs) working in Madagascar, Panama, and Suriname are used as examples of what can be achieved when biodiversity conservation is linked to drug discovery.

Taxol : the chemistry and structure-activity relationships of a novel anticancer agent

Taxol is an exciting new anticancer drug, showing clinical activity against ovarian and breast cancer. Its development as a clinically useful drug has involved major efforts to overcome the supply problem; this has now been done, and the focus of interest has moved to the development of improved analogs of the drug. Recent notable achievements include the first total synthesis of taxol, and the first indications of its binding site on tubulin.

Structure-activity study of cytotoxicity and microtubule assembly in vitro by taxol and related taxanes.

Abstract Structure-activity relationships of natural and semisynthetic taxanes are reported. Activity is measured in vivo by cytotoxicity toward the macrophage-like cell line J774.2, and in vitro by promotion of microtubule assembly in the absence of exogenous GTP and by inhibition of [3H]taxol binding to microtubule protein. Cytotoxicity and in vitro activity require both an intact taxane ring and ester side chain at position C-13. Addition of acetyl moieties at positions 2′ and 7 results in loss of in vitro activity but not cytotoxicity.

Mass spectrometry of organic compounds—VI : Electron-impact spectra of flavonoid compounds

Abstract The mass spectra of some simple flavones, flavonols, and their permethyl ethers have been examined. A new fragmentation pathway of 6-methoxyflavones is discussed, and the formation of (M—H)+ and (M—H3O)+ ions is discussed. It is shown that significant structural information can be obtained from the mass spectra of polyhydroxyflavones and their ethers.

Taxol, a molecule for all seasons

The diterpenoid natural product taxol, first discovered in the 1960’s has proved to be the most important new anticancer drug introduced in the last ten years. A brief history of taxol’s development from laboratory curiosity to blockbuster drug is followed by a summary of its chemistry, including an overview of the six completed syntheses of taxol. The review concludes with a discussion of its bioactivity as a promoter of tubulin polymerization and as a drug.

A fluorescence-based high-throughput assay for antimicrotubule drugs.

With the advent of combinatorial chemistry and the extensive libraries of potential drugs produced from it, there is a growing need for rapid sensitive, high-throughput screening for drug potency. Microtubules are important targets for anticancer agents, and new antimicrotubule compounds are of continued interest in drug development. The in vitro potency of antimicrotubule drugs may be evaluated by measuring the extent of tubulin assembly. The extent of polymerization is proportional to the turbidity of the solution, which usually has been measured as apparent absorption. The turbidity method has inherent problems that hinder its adaptation to a high-throughput format, such as a requirement for high protein concentrations and a high coefficient of variation. We present here a high-throughput assay for antimicrotubule activity in which fluorescence is used to monitor microtubule assembly. Both assembly-inhibiting and assembly-promoting compounds can be evaluated. The assay is rapid and easy to perform, and the data are reliable, with good accuracy and reproducibility.

Conversion of IQ, a dietary pyrolysis carcinogen to a direct-acting mutagen by normal intestinal bacteria of humans.

The dietary carcinogen, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) is mutagenic in the Salmonella/microsomal mutagenicity assay when activated by microsomal enzymes. IQ is found in many cooked foods, notably fried beef and pork. In laboratory rodents IQ is carcinogenic. We showed that mixed and pure cultures of human intestinal anaerobes, notably Eubacterium spp., metabolized IQ to 2-amino-3,6-dihydro-3-methyl-7H-imidazo[4,5-f]quinoline-7-one (HOIQ). Unlike IQ, both the synthetic and bacterially produced HOIQ were direct-acting mutagens, i.e. active without microsomal activation. This new direct-acting mutagen, from the bacterial metabolism of a dietary pyrolysis carcinogen, raises new concerns about the possible role of this class of genotoxins in the etiology of human cancer.