Synthesis and cytotoxic activity of tetrahydropyridylidene-2- and -4-sulfonamides.

1,2,3,4-Tetrahydropyridylidene-4-sulfonamides, 1,2,3,4-tetrahydropyridylidene-2-sulfonamides, and 1,2,3,6-tetrahydropyridylidene-2-sulfonamides, of structures 10, 12 and 14, respectively (given in Table I), were synthesized in order to investigate the effect of nuclear substituents and the position of the sulfonamido group on cytotoxicity. The relative potency order was 12 greater than 10 greater than 14. Compounds possessing an R1 CONEt2 substituent were more potent than those possessing a R1 CN substituent. The nature of the aryl(alkyl)-sulfonamido substituent was a determinant of activity, the relative potency order being 4-chlorophenyl greater than phenyl, 4-methoxy- or 4-nitrophenyl greater than methyl. 1-Methyl-4-tert-butyl-5-diethylaminocarbonyl-1,2,3,4-tetrahydro pyridylidene- 2-(4-chlorophenyl)sulfonamide (12c) was the most active cytotoxic agent, exhibiting an ED50 of 5.4 micrograms/ml in the L1210 in vitro screen.