Taxoids: A New Class of Antimitotic Compounds

Abstract

Paclitaxel (Taxol®) and docetaxel (Taxotere®) are the first representatives of taxoids , a new class of antitumor compounds. These two taxoids are clinically active against breast, ovarian and lung cancers. Taxoids are highly complex diterpenoids from natural origin. Preclinical and clinical develop-ments have been made possible after a long and sustained chemical effort : paclitaxel is extracted from the barks of the Pacific yew tree Taxus brevifolia whereas docetaxel is prepared by hemisynthesis starting from 10-deacetyl-baccatin ill, a non cytotoxic precursor found in the needles of the European yew tree Taxus baccata . These two drugs are active in various in vitro and in vivo preclinical models (cell lines, cloning of human tumor stem cells, murine grafted tumors , human xenografts). Taxoids constitute anew class of antimitotic agents different from vinca-alkaloids: on the one hand, paclitaxel and docetaxel can be considered as inhibitors of the reaction of depolymerization of microtubules into tubulin ; on the other hand, vinca-a!kaloids inhibit the reaction of polymerization of tubulin into microtubules. An active program of medicinal chemistry is done in various pharmaceutical and academic Institutions with two objectives: knowledge of structure-activity relationships and selection of new candidates for clinical trials. With the taxoid series, a variety of analogs have been prepared for their antitubulin and biological properties . Concerning the tubulin binding, some important structure activity relationships have been proposed. In this review the contribution of each functional group of docetaxel will be discussed following the evolution of antitubulin activity, going from docetaxel to taxoids possessing the minimum requirement of recognition by tubulin . The conformation of docetaxel and analogs will be compared taking into account the contribution and relevance of X-rays, NMR and molecular modelling studies in determining the molecular shape of active and inactive compounds.