title: Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators.
abstract: 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.
authors.affiliation: Department of Chemistry, Acadia University, 6 University Avenue, Wolfville, NS B4P 2R6, Canada.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Yadav
authors.forename: Erin D
authors.initials: ED
authors.lastname: Maclean
authors.forename: Annyt
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barden
authors.forename: Catherine K L
authors.initials: CK
authors.lastname: Too
authors.forename: Amitabh
authors.initials: A
authors.lastname: Jha
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020845:Selective Estrogen Receptor Modulators