Identification, synthesis, and biological evaluation of the metabolites of 3-amino-6-(3'-aminopropyl)-5h-indeno[1,2- c]isoquinoline-5,11-(6h)dione (AM6-36), a promising rexinoid lead compound for the development of cancer chemotherapeutic and chemopreventive agents

Lian Chen, Martin Conda-Sheridan, P. V.Narasimha Reddy, Andrew Morrell, Eun Jung Park, Tamara P. Kondratyuk, John M. Pezzuto, Richard B. Van Breemen, Mark Cushman

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3′-aminopropyl)-5H- indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.

Original languageEnglish (US)
Pages (from-to)5965-5981
Number of pages17
JournalJournal of Medicinal Chemistry
Volume55
Issue number12
DOIs
StatePublished - Jun 28 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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