Conformational and Quantitative Structure−Activity Relationship Study of Cytotoxic 2-Arylidenebenzocycloalkanones

Abstract

Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2-arylidenebenzosuberones 3 were synthesized with the aim of determining the relative orientations of the two aryl rings which favored cytotoxicity. Molecular modeling of the unsubstituted compound in each series revealed differences in the spatial arrangements of the two aryl rings, and evaluation of these compounds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of human tumor cell lines indicated that in general the order of cytotoxicity was 3 > 2 > 1. In particular 2-(4-methoxyphenylmethylene)-1-benzosuberone (3k) had the greatest cytotoxicity, possessing 11 times the potency of the reference drug melphalan when all five screens were considered. Series 3 was considered 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 sigma values and positively with the MR constants of the substituents in the arylidene aryl ring of 3. Third, X-ray crystallography of five representative compounds (3i,k-n) revealed differences in the locations of the aryl rings which may have contributed to the variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptosis in human Jurkat T cells. This study has revealed that 2-arylidene-1-benzosuberones are a group of useful cytotoxic agents, and in particular 3k serves as a prototypic molecule for subsequent structural modifications.

3-Benzylidene-4-chromanones: a novel cluster of anti-tubercular agents

“…The compounds in series 1-5 were prepared by condensation between various aryl aldehydes and the appropriate ketones 13,14 . These molecules were shown by 1 H-NMR spectroscopy and in several cases by X-ray crystallography to adopt the E stereochemistry 13,14,16 .…”

“…These molecules were shown by 1 H-NMR spectroscopy and in several cases by X-ray crystallography to adopt the E stereochemistry 13,14,16 . The choice of aryl substituents was made on the basis of their differing electronic, hydrophobic and steric properties.…”

“…The compounds in series 1 were prepared by a literature procedure 13 reported previously from our laboratory and the purity of the compounds was established by 1 H-NMR spectroscopy, melting points and elemental analyses while the synthesis of the analogs in series 2-5 has been described previously 14 .…”

(E)-2-Benzylidenecycloalkanones XII.* Kinetic Measurement of Bovine and Human Serum Albumine Interaction with Selected Chalcones and Their Cyclic Chalcone Analogues by UV Spectrophotometry

“…Among the naturally occurring chalcones and their synthetic analogues, several compounds displayed antineoplastic activity [2] [3]. Recently we have investigated in vitro antineoplastic activity of several synthetic chalcones and chalcone analogues [4]- [6]. (E)-2-(4'-methoxybenzylidene)-1-benzosuberone (4a) and (E)-2-(4'-dimethylaminobenzylidene)-1-benzosuberone (4c) (Figure 1) had the greatest tumor cytotoxicity of all studied molecules.…”

Asymmetric microbial conversion of (E)-2-benzylideneindan-1-one by the filamentous fungi Botrytis cinerea, Trichoderma viride, and Eutypa lata

“…1 Specifically, (E)-2-benzylideneindan-1-one 1 has been shown to exhibit cytotoxic activity against murine P388 and L1210 leukaemic cells as well as human Molt 4/C8 and CEM Tlymphocytes. 2 Several methods for their preparation have been reported, the most classic involving as the first step the synthesis of indan-1-one moiety followed by an aldol reaction with the appropriate aldehydes. 3 Problems may be encountered with chemical methods such as incomplete transformation, moderate enantiomeric purity and the use of toxic reagents.…”