Jr. Dimmock et al., CYTOTOXIC EVALUATION OF SOME 3,5-DIARYLIDENE-4-PIPERIDONES AND VARIOUS RELATED QUATERNARY AMMONIUM-COMPOUNDS AND ANALOGS, Journal of pharmaceutical sciences, 83(8), 1994, pp. 1124-1130
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.