A number of 3,5-diarylidene-4-piperidones (1) and some related quaternary ammonium salts (5) as well as closely related analogs were prepared principally as candidate cytotoxic agents in two screens. The first test system used an average of 54 human tumor cell lines from eight neoplastic diseases, namely leukemia, melanoma, colon, non-small-cell lung, small-cell lung, central nervous system, ovarian, and renal cancers. Selective toxicity was demonstrated by some of the compounds, especially toward leukemia. The second screen used L1210 lymphoid leukemia cells. In general, the compounds were less cytotoxic than the reference drug melphalan in both screens. Linear plots were made between the Hammett (sigma), fragment (f), and molar refractivity (MR) constants of the nuclear substituents in series 1 and 5 with the IC50 figures of both the human tumor cell lines and L1210 cells. Evaluation against the human tumor cell lines revealed that increases in the f values were correlated with elevation of cytotoxicity in both series 1 and 5; MR constants were also important in series 5. In the L1210 screen, sigma and MR constants were positively correlated with cytotoxicity. X-ray crystallography was undertaken on 3,5-bis[[4'-(methylthio)phenyl]methylene]-1-methyl-4-piperidone methiodide (5d), which had significant cytotoxicity, and 3,5-bis(4-pyridylmethylene)-1-methyl-4-piperidone methiodide (6), which was virtually inactive in both screens. A number of structural features were noted, and in particular a smaller interplanar angle made by one of the arylidene groups with the central piperidine ring in the case of 5d than either of the 4-pyridylmethylene moieties in 6 may contribute to the variation in cytotoxicity between these two compounds. Eleven compounds which were Examined for activity against a panel of 12 viruses were shown to display only marginal potencies or to be inactive at the highest concentrations utilized. Two compounds with slight activity both had the hydrophilic carboxylate ion in the aryl rings. From this study, various conclusions pertaining to future molecular modification with a view to increasing cytotoxic potency were made.
