Design and QSAR study of analogs of alpha-tocopherol with enhanced antiproliferative activity against human breast adenocarcinoma cells

Abstract

Quantitative structure-activity relationships (QSAR) have been established for two sets of the antitumor drugs, a-tocopherol derivatives. Constitutional, geometrical, physico-chemical and electronic descriptors (using the B3LYP/6-31G (d, p) basis set) were computed and analyzed. The most relevant of these descriptors were grouped and multiple linear regressions have been carried out. QSAR model with four variables, R-2 = 0.98 and cross-validation parameter q(pre)(2) = 0.91, was selected. Analogs of alpha-tocopherol (compounds D-1 and D-2) have been designed and their antiproliferative activities were evaluated using the proposed regression model. Calculated antiproliferative activities of the designed lysine/alpha-tocopherol/cholesterol conjugates, IC50 (D-1) = 2.25 mu M and IC50 (D-2) = 3.42 mu M, were significantly stronger than activities of the other analyzed compounds IC50 > 4 mu M.