Synthesis and biological evaluation of new cross-conjugated dienone marine prostanoid analogues.
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.
Kuhn
Cyrille
C
Institut Curie, Section Recherche, Laboratoire de Pharmacochimie, 26 rue d'Ulm, 75248 Paris, Cedex 05, France.
Roulland
Emmanuel
E
Madelmont
Jean-Claude
JC
Monneret
Claude
C
Florent
Jean-Claude
JC
D000447:Aldehydes / Q000138:chemical synthesis; D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D051379:Mice; D011453:Prostaglandins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D000447:Aldehydes; D000475:Alkenes; D003517:Cyclopentanes; D011453:Prostaglandins