Synthesis and biological evaluation of new cross-conjugated dienone marine prostanoid analoguesElectronic supplementary information (ESI) available: 1H NMR, COSY and NOESY spectra. See http://www.rsc.org/suppdata/ob/b4/b404016c/

Abstract

The synthesis of a series of brominated cross-conjugated dienones, marine prostanoid analogues, was considered using two cyclopentannelation processes, from enamine (by a domino 3-aza Claisen/Mannich reaction) and from dioxolane ester alkylation followed by intramolecular Wittig reaction. All the compounds synthesized featured the same cross-conjugated dienone system, with a vicinal syn or anti diol on the omega-chain. The replacement of the omega-side-chain of the natural prostanoids with a 1-hydroxyphenyl-butyl moiety gave new prostanoids (32-34) with good cytotoxicities. In a second series of products, the possibility of a shorter alpha-side-chain bearing a simple phenyl ester was investigated. The results indicated a dramatic increase in the cytotoxicity (39, 40, 43, 44). Finally, in a third series, the omega-1-hydroxyphenyl-butyl was replaced by a 1-hydroxymethyloxybenzyl chain. These simpler compounds (45, 46, 47, 48, 60) are still highly cytotoxic, in the medium range of 60 nM, close to the value of natural punaglandins.