Abstract

A quantitative structure-activity relationship (QSAR) based upon molecular shape analysis has been developed for a set of 18 1-(X-phenyl)-3,3-dialkyltriazenes for which mutagenic potency is reported. An "active" molecular shape is proposed which suggests, in turn, a self-consistent mechanism for the microsomal hydroxylation of the nitrogen methyl group. A second QSAR has been constructed for an alternate set of 24 1-(X-phenyl)-3,3-dialkyltriazenes for which antitumor potency is reported. The QSAR suggests that the "active shape for antitumor potency is the same as that hypothesized for Ames mutagenic potency. A QSAR for a therapeutic index (TI) has been constructed to allow optimization of the difference between antitumor and mutagenic potencies. Large TIs require substituents on position 3 of the phenyl ring which are hydrophilic. The antitumor QSAR has been applied to three known compounds to test its reliability. A compound is predicted that is expected to have high antitumor activity and low mutagenicity. An overview of the methodology of molecular shape analysis, and its limitations, is included as part of this report on the development of QSARs.