Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones

Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2-arylideneben zosuberones 3 were synthesized with the aim of determining the relative ori entations of the two aryl rings which favored cytotoxicity. Molecular model ing of the unsubstituted compound in each series revealed differences in th e spatial arrangements of the two aryl rings, and evaluation of these compo unds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of hu man tumor cell lines indicated that in general the order of cytotoxicity wa s 3 > 2 > 1. In particular 2-(4-methoxyphenylmethylene)-1-benzosuberone (3k ) had the greatest cytotoxicity, possessing 11 times the potency of the ref erence drug melphalan when all five screens were considered. Series 3 was c onsidered in further detail. First, excision of the aryl ring fused to the cycloheptanone moiety in series 3 led to some 2-arylidene-1-cycloheptanones 4 which had approximately one-third of the bioactivity of the analogues 3. Second, in some screens cytotoxicity was correlated negatively with the a values and positively with the MR constants of the substituents in the aryl idene aryl ring of 3. Third, X-ray crystallography of five representative c ompounds (3i,k-n) revealed differences in the locations of the aryl rings w hich may have contributed to the variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptos is in human Jurkat T cells. This study has revealed that 2-arylidene-1-benz osuberones are a group of useful cytotoxic agents, and in particular 3k ser ves as a prototypic molecule for subsequent structural modifications.