Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer

Amitabh Jha; Yogesh Yadav; Ajay B Naidu; V Kameswara Rao; Anil Kumar; Virinder S Parmar; William J MacDonald; Catherine K L Too; Jan Balzarini; Christopher J Barden; T Stanley Cameron

doi:10.1016/j.ejmech.2014.12.037

Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer

Eur J Med Chem. 2015 Mar 6:92:103-14. doi: 10.1016/j.ejmech.2014.12.037. Epub 2014 Dec 23.

Authors

Affiliations

¹ Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada. Electronic address: [email protected].
² Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada; Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
³ Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada.
⁴ Department of Chemistry, Acadia University, Wolfville, NS B4P 2R6, Canada; Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
⁵ Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
⁶ Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
⁷ Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Canada.
⁸ Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
⁹ Toronto Western Research Institute, Toronto M5T 2S8, Canada.
¹⁰ Department of Chemistry, Dalhousie University, Halifax B3H 4R2, Canada.

PMID: 25544690
DOI: 10.1016/j.ejmech.2014.12.037

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.

Keywords: 1-(4-Dialkylaminoethoxy)phenylmethyl-6-(4-hydroxypiperidino)naphthalen-2-ols; Anticancer; Breast cancer; Cytotoxic; Pharmacokinetics; SERM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
HeLa Cells
Humans
MCF-7 Cells
Mice
Models, Molecular
Molecular Structure
Naphthols / chemical synthesis
Naphthols / chemistry
Naphthols / pharmacology*
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Receptors, Estrogen / antagonists & inhibitors*
Receptors, Estrogen / metabolism
Structure-Activity Relationship

Substances

6-(4-hydroxypiperidino)naphthalen-2-ol
Antineoplastic Agents
Naphthols
Piperidines
Receptors, Estrogen