Synthesis and cytotoxic evaluation of some cyclic arylidene ketones and related oximes, oxime esters, and analogs.

A number of arylidene derivatives of alicyclic ketones and some corresponding oximes, oxime esters, and related compounds were prepared as candidate cytotoxic agents. All of the compounds were evaluated against murine L1210 lymphoid leukemia cells. In general, cytotoxicity was greatest with the alpha,beta-unsaturated ketones and diminished with the oximes, and the oxime esters had little or no activity in this screen. When the same compounds were examined in both the in vitro L1210 and P388 leukemia screens, in the majority of cases the L1210 cells were more sensitive to these derivatives. Over half of the compounds prepared were evaluated against approximately 55 human tumors in vitro and showed selective toxicity toward one or more groups of neoplastic diseases, particularly leukemia. Some correlations between structure and bioactivity were discerned. The cytotoxicity screening and stability studies of representative compounds suggested that the ketones, oximes, and oxime esters were stable under the conditions of bioevaluation. X-ray crystallography of four representative compounds revealed structural features associated with cytotoxicity which may be considered in the design of future candidate cytotoxins.