QSAR Study and Design of Novel Organoselenium and alpha-Tocopherol Derivatives with Enhanced Chemotherapeutic Activity

Abstract

Organic selenides, such as Se-alkyl-selenocysteine and derivatives, are active in suppressing chemically induced mammary carcinogenesis in rats. Here the quantitative structure-activity relationship (QSAR) study of ten related alkyl-chalcogens was performed to correlate their structural properties with the measured chemotherapeutic activities (ED(50)). The CS Gaussian 98 program with Hartree-Fock/3-21G (d) basis set was applied for molecular properties computations of the optimized models. Electron Density on chalcogen (ED(X)) expressed the strongest influence on anticancer activity of the examined molecules. Linear regression model of the alkyl-chalcogens, log(ED(50)) = f (ED(X)), was obtained with R(2) = 0.964 and cross-validation parameter q(pre)(2) = 0.950. Synergy between organo-selenides and vitamin E in chemotherapeutic activity led to propose novel organoselenium-alpha-tocopheryl esters as potent anticancer agents. Anticancer activities (log(ED(50))) of the designed alkyl-seleno/tocopheryl esters (S-1 to S-4) were evaluated using the developed QSAR/alkyl-chalcogens model and the most potent chemotherapeutic agents (ED(50)(S-1): 2.60 ppm and ED(50)(S-4): 2.55 ppm). On the other side, previously created QSAR model for in vitro anticancer activity (IC(50)) for tocopherol derivatives, log(IC(50))= f (NCH(3), logDpH 5.0, O-charge) with R(2)= 0.940 and q(pre)(2)= 0.879, was employed with IC(50) evaluation of the proposed alkyl-seleno/tocopheryl esters (S-1 to S-4). Calculated antiproliferative activities of the designed compounds, IC(50)(S-1): 25.65 mu M and IC(50)(S-4): 31.36 mu M, were significantly stronger than activities of other related anticancer agents, IC(50): 4-1461 mu M.