Chemistry and chemical biology of taxane anticancer agents.
Taxol (paclitaxel) and Taxotere (docetaxel) are currently considered to be among the most important anticancer drugs in cancer chemotherapy. The anticancer activity of these drugs is ascribed to their unique mechanism of action, i.e., causing mitotic arrest in cancer cells, leading to apoptosis through inhibition of the depolymerization of microtubules. Although both paclitaxel and docetaxel possess potent antitumor activity, treatment with these drugs often results in a number of undesirable side effects, as well as multidrug resistance (MDR). Therefore, it has become essential to develop new anticancer agents with superior pharmacological properties, improved activity against various classes of tumors, and fewer side effects. This paper describes an account of our research on the chemistry of paclitaxel and taxoid anticancer agents at the biomedical interface, including: 1. The structure-activity relationship (SAR) study of taxoids leading to the development of the "second-generation" taxoids, which possess exceptional activity against drug-resistant cancer cells expressing the MDR phenotype. 2. Development of fluorinated taxoids to study the bioactive conformation of paclitaxel and photoaffinity labeling taxoids for mapping of the drug-binding domain on both microtubules and P-glycoprotein. 3. The synthesis of novel macrocyclic taxoids for the investigation into the common pharmacophore for microtubule stabilizing anticancer agents.
Miller
M L
ML
Department of Chemistry, State University of New York at Stony Brook, 11794-3400, USA.
Ojima
I
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008958:Models, Molecular; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D043823:Taxoids
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel