title: Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer.
abstract: In a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1-yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERα. Two representative compounds were also evaluated for in vitro membrane permeability, plasma stability as well as in-vivo toxicity in mice. The compounds displayed well-acceptable drug-like in vitro membrane permeability as well as plasma stability and were well-tolerated in experimental mice at 300 mg/kg dose.
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada. Electronic address: ajha@acadiau.ca.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Jha
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada; Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Yadav
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada.
authors.forename: Ajay B
authors.initials: AB
authors.lastname: Naidu
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada; Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: V Kameswara
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: MacDonald
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Canada.
authors.forename: Catherine K L
authors.initials: CK
authors.lastname: Too
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Toronto Western Research Institute, Toronto M5T 2S8, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barden
authors.affiliation: Department of Chemistry, Dalhousie University, Halifax B3H 4R2, Canada.
authors.forename: T Stanley
authors.initials: TS
authors.lastname: Cameron
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000602731:6-(4-hydroxypiperidino)naphthalen-2-ol; D000970:Antineoplastic Agents; D009284:Naphthols; D010880:Piperidines; D011960:Receptors, Estrogen
keywords: 1-(4-Dialkylaminoethoxy)phenylmethyl-6-(4-hydroxypiperidino)naphthalen-2-ols; Anticancer; Breast cancer; Cytotoxic; Pharmacokinetics; SERM