PODOPHYLLOTOXIN, STEGANACIN AND COMBRETASTATIN - NATURAL-PRODUCTS THAT BIND AT THE COLCHICINE SITE OF TUBULIN

A large number of antimicrotubule agents are known that bind to tubulin in vitro and disrupt microtubule assembly in vitro and in vivo. Many of these agents bind to the same site on the tubulin molecule, as does colchicine. Of these, the natural products podophyllotoxin, steganacin and combretastatin are the subjects of this review. For each of these, the chemistry and biochemistry are described. Particular attention is given to stereochemical considerations. Biosynthetic pathways for podophyllotoxin and congeners are surveyed. The binding to tubulin and the effects on microtubule assembly and disassembly are described and compared. In addition, structural features important to binding are examined using available analogs. Several features significant for tubulin interaction are common to these compounds and to colchicine. These are described and the implications for tubulin structure are discussed. The manifold results of applying these agents to biological systems are reviewed. These actions include effects that are clearly microtubule mediated and others in which the microtubule role is less obvious. Activity of some of these compounds due to inhibition of DNA topoisomerase is discussed. The range of species in which these compounds occur is examined and in the case of podophyllotoxin is found to be quite broad. In addition, the range of species that are sensitive to the effects of these compounds is discussed.