Overcoming tumor drug resistance with C2-modified 10-deacetyl-7-propionyl cephalomannines: a QSAR study.

The microtubule-stabilizing taxanes such as paclitaxel and docetaxel are the two most important anticancer drugs currently used in clinics for the treatment of various types of cancers. However, the major common drawbacks of these two drugs are drug resistance, neurotoxicity, substrate for drug transporter P-gp, cross-resistance with other chemotherapeutic agents, low oral bioavailability, and no penetration in the blood-brain barrier (BBB). These limitations have led to the search for new taxane derivatives with improved biological activity. In the present paper, we discuss the quantitative structure-activity relationship (QSAR) studies on a series of C2-modified 10-deacetyl-7-propionyl cephalomannines (IV) with respect to their binding affinities toward beta-tubulin and cytotoxic activities against both drug-sensitive and drug-resistant tumor cells, in which resistance is mediated through either P-gp overexpression or beta-tubulin mutation mechanisms, by the formulation of five QSARs. Hydrophobicity and molar refractivity of the substituents (pi(X) and MR(X)) are found to be the most important determinants for the activity. Parabolic correlations in terms of MR(X) (eqs 2 and 4 ) are encouraging examples in which the optimum values of MR(X) are well-defined. We believe that these two QSAR models may prove to be adequate predictive models that can help to provide guidance in design and synthesis, and subsequently yield very specific cephalomannine derivatives (IV) that may have high biological activities. On the basis of these two QSAR models, 10 cephalomannine analogues (IV-21 to IV-30) are suggested as potential synthetic targets. Internal (cross-validation (q(2)), quality factor (Q), Fischer statistics (F), and Y-randomization) and external validation tests have validated all the QSAR models.