Recent advances in the field of tubulin polymerization inhibitors.
In recent years, enormous progress has been made in the field of tubulin targeting agents. Several companies and academic laboratories have entered this field and competition has become very strong. Nevertheless, clinically promising compounds often face substantial limitations, such as high systemic toxicity, poor water solubility and bioavailability, as well as complex synthesis and isolation procedures. As a drawback of established drugs, like paclitaxel or the vinca alkaloids, the outcome of cancer chemotherapy is often affected by the emergence of the multidrug resistance phenotype. Among the recently disclosed tubulin polymerization inhibitors, there are several interesting low molecular weight compounds with improved oral bioavailability and demonstrated activity against multi-drug resistance positive phenotypes. As documented by the imidazole-based combretastatin analogs, to name just one example, chemical optimization of a lead structure resulted in compounds with potent in vitro and in vivo activity along with appropriate pharmacodynamic and pharmacokinetic requirements for a potential therapeutic candidate. Currently, several compounds are undergoing Phase I or Phase II clinical trials, among them orally bioavailable sulfonamides or dolastatin 10. Several other compounds are close to entering Phase I trials. The purpose of this review is to focus on the most recent advances in tubulin polymerization inhibitors from a survey of the published patent literature and related publications between late 1999 and April 2002. However, biological data, especially for the inhibition of tubulin polymerization, obtained from different laboratories cannot easily be compared.
Prinz
Helge
H
Institut für Pharmazeutische und Medizinische Chemie, Westfàlische Wilhelms Universität Münster, D-48149 Münster, Germany. prinzh@uni-muenster.de
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001632:Bibenzyls / Q000494:pharmacology; D001685:Biological Factors / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011485:Protein Binding; D013267:Stilbenes; D014404:Tubulin / Q000096:biosynthesis / Q000187:drug effects; D050257:Tubulin Modulators
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D001685:Biological Factors; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin