Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators

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.

Two series of 1-(4-dialkylaminoethyl)phenylmethyl-2-naphthol analogs were designed, synthesized and evaluated as potential selective estrogen receptor modulators against breast cancer cells.Figure optionsDownload as PowerPoint slideHighlights
► Several rationally designed compounds belonging to 3 series were evaluated as potential SERMs.
► In-silico docking studies were used to optimize the ligand structure.
► A series of 1-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalen-2-ols emerged as potent cytotoxics for breast cancer cells.
► A most potent compound showed strong antagonistic effects against estrogen receptor-α.