CYTOTOXIC EVALUATION OF SOME 3,5-DIARYLIDENE-4-PIPERIDONES AND VARIOUS RELATED QUATERNARY AMMONIUM-COMPOUNDS AND ANALOGS

A number of 3,5-diarylidene-4-piperidones (1) and some related quatern ary ammonium salts (5) as well as closely related analogs were prepare d principally as candidate cytotoxic agents in two screens. The first test system used an average of 54 human tumor cell lines from eight ne oplastic diseases, namely leukemia, melanoma, colon, non-small-cell lu ng, small-cell lung, central nervous system, ovarian, and renal cancer s. Selective toxicity was demonstrated by some of the compounds, espec ially toward leukemia. The second screen used L1210 lymphoid leukemia cells. In general, the compounds were less cytotoxic than the referenc e drug melphalan in both screens. Linear plots were made between the H ammett (sigma), fragment (f), and molar refractivity (MR) constants of the nuclear substituents in series 1 and 5 with the IC50 figures of b oth the human tumor cell lines and L1210 cells. Evaluation against the human tumor cell lines revealed that increases in the f values were c orrelated with elevation of cytotoxicity in both series 1 and 5; MR co nstants were also important in series 5. In the L1210 screen, sigma an d MR constants were positively correlated with cytotoxicity. X-ray cry stallography was undertaken on 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 featur es were noted, and in particular a smaller interplanar angle made by o ne of the arylidene groups with the central piperidine ring in the cas e of 5d than either of the 4-pyridylmethylene moieties in 6 may contri bute to the variation in cytotoxicity between these two compounds. Ele ven compounds which were Examined for activity against a panel of 12 v iruses were shown to display only marginal potencies or to be inactive at the highest concentrations utilized. Two compounds with slight act ivity both had the hydrophilic carboxylate ion in the aryl rings. From this study, various conclusions pertaining to future molecular modifi cation with a view to increasing cytotoxic potency were made.