title: Understanding tubulin/microtubule-taxane interactions: a quantitative structure-activity relationship study.
abstract: For years, the microtubule-stabilizing agents paclitaxel and docetaxel (progenitors of the family of taxanes) have been the most successful anticancer drugs currently used in clinics. However, both drugs are associated with notorious side effects, drug resistance, and cross resistance with other chemotherapeutic agents. These limitations have led to the search for new drugs with improved biological activity. In the present paper, we discuss the interaction of taxanes with the tubulin/microtubule system by the formulation of 6 QSARs. Hydrophobicity of the substituents (pi) is found to be one of the most important determinants of the activity followed by steric parameters. Parabolic correlations (eqs 3 and 7) with B5 and pi are the most encouraging examples, where the optimum values of these parameters are well defined. We believe that these two QSARs may prove to be adequate predictive models that can help to provide guidance in design/synthesis and subsequently yield very specific compounds (IV and VIII) that may have high biological activities. On the basis of these two QSARs 3 and 7, 18 compounds (IV-12- IV-22 and VIII-16- VIII-22) are suggested as potential synthetic targets. Cross-validation, quality factor (Q), Fischer statistics (F), and Y-randomization tests have validated all the QSAR models.
authors.affiliation: Department of Chemistry, Pomona College, 645 North College Avenue, Claremont, California 91711, USA.
authors.forename: Corwin
authors.initials: C
authors.lastname: Hansch
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Verma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002417:Cattle; D000077143:Docetaxel; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011897:Random Allocation; D043823:Taxoids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; D000077143:Docetaxel; C080625:taxane; D017239:Paclitaxel