RESUMEN
A concise enantiospecific synthesis of (-)-bakkenolide III was accomplished from (S)-(+)-carvone. The key step involved radical cyclization of an iodoketone intermediate which afforded the cis-hydrindanone skeleton. Further synthetic transformations generated bakkenolide III, which also constitutes the formal total synthesis of (-)-bakkenolides, B, C, H, L, V, and X.
Asunto(s)
4-Butirolactona/análogos & derivados , Indanos/síntesis química , Compuestos de Espiro/síntesis química , 4-Butirolactona/síntesis química , Ciclización , Monoterpenos Ciclohexánicos , Cetonas/química , Monoterpenos/química , Sesquiterpenos/síntesis químicaRESUMEN
In an systematic attempt to develop novel Selective Estrogen Receptor Modulators (SERMs), chiral 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were designed based on an accepted pharmacophore model. Simpler prototypes, viz. racemic 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ols, were first synthesized to develop kinetic resolution to pure enantiomers. Simultaneously, a series of racemic 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were evaluated against estrogen-responsive human MCF-7 breast cancer cells, but the compounds were found to be moderately active. The lack of potency could be due to the molecular bulk resulting in inadequate fit at the receptor. Subsequently, the molecular motif was modified to achiral 1-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalen-2-ols by removing the piperidinol moiety. Bioevaluation of this new series of compounds displayed significantly enhanced cytotoxicity against MCF-7 cells. A representative compound for this series showed estrogen receptor alpha binding activity and the action is that of an antagonist.