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

Quantitative structure–activity relationships (QSAR) have been established for two sets of the antitumor drugs, α-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, R2 = 0.98 and cross-validation parameter qpre2=0.91, was selected. Analogs of α-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/α-tocopherol/cholesterol conjugates, IC50 (D-1) = 2.25 μM and IC50 (D-2) = 3.42 μM, were significantly stronger than activities of the other analyzed compounds IC50 > 4 μM.