Sequential cytotoxicity: A theory evaluated using novel 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanones and related compounds

Five series of novel compounds were synthesized in order to evaluate the th eory of sequential cytotoxicity which seeks to exploit the view that variou s cancer cells are particularly susceptible to successive attacks by cytoto xic agents. The compounds prepared were various 2-[4-(3-aryl-2-propenoyloxy )phenylmethylene]cyclohexanones 1 and the related Mannich bases 2. In addit ion the analogues 3-5 lacking an olefinic bond in the ester group were also synthesized, which were predicted to be less cytotoxic than the compounds of series 1 and 2. The atomic charges at the potential sites for interactio n with cellular constituents were determined by molecular modeling calculat ions. The biodata obtained from murine and human neoplastic cells revealed that the predictions made regarding the viability of the theory were fulfil led in approximately two-thirds of the cases indicating that further invest igation of this hypothesis is warranted. In addition, the significant poten cies of some of the Mannich bases toward human tumor cell lines, in particu lar coupled to their selective toxicity toward human leukemic and colon can cer cells, confirms their usefulness in serving as lead molecules for furth er development. A preliminary investigation into the mode of action of repr esentative compounds revealed their ability to induce apoptosis and inhibit the biosyntheses of ribonucleic acid and proteins.