Taxane analogues against breast cancer: a quantitative structure-activity relationship study.

Breast cancer is the second leading cause of cancer death among women in the United States. Two taxane analogues, taxol and taxotere, are the most important antimitotic drugs currently in clinical use for the treatment of breast cancers. However, recent reports have indicated that the use of these drugs often results in various undesired side effects as well as multi-drug resistance. These limitations have led to the development of new taxane derivatives with fewer side effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for breast cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitory activities against breast cancer cells with their hydrophobic and steric properties in order to understand their chemical-biological interactions. The resulting QSARs show that the inhibitory activities of taxane analogues against breast cancers are mainly dependent either on their hydrophobicity or the hydrophobic/molar refractivity descriptor of their substituents. A parabolic correlation with MR(Y) is the most encouraging example, in which the optimum value of this parameter is well defined. We believe this correlation may prove to be an adequate predictive model that can help provide guidance in design and synthesis and subsequently yield highly specific compounds that may have high anti-breast-cancer activity with fewer side effects and superior pharmacological properties. On the basis of this QSAR model, five compounds are suggested as potential synthetic targets. Internal (cross-validation (LOO-q(2) and LMO-q(2)), quality factor (Q), Fischer statistics (F), and Y-randomization) and external validation tests have validated all the QSAR models.