title: Design, synthesis, and biological evaluation of indenoisoquinoline rexinoids with chemopreventive potential.
abstract: Nuclear receptors, such as the retinoid X receptor (RXR), are proteins that regulate a myriad of cellular processes. Molecules that function as RXR agonists are of special interest for the prevention and control of carcinogenesis. The majority of these ligands possess an acidic moiety that is believed to be key for RXR activation. This communication presents the design, synthesis, and biological evaluation of both acidic and nonacidic indenoisoquinolines as new RXR ligands. In addition, a comprehensive structure-activity relationship study is presented that identifies the important features of the indenoisoquinoline rexinoids. The ease of modification of the indenoisoquinoline core and the lack of the necessity of a carboxyl group for activity make them an attractive and unusual family of RXR agonists. This work establishes a structural foundation for the design of new and novel rexinoid cancer chemopreventive agents.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Beck
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.forename: Trung X
authors.initials: TX
authors.lastname: Nguyen
authors.forename: Bingjie
authors.initials: B
authors.lastname: Hu
authors.forename: Lian
authors.initials: L
authors.lastname: Chen
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: White
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016588:Anticarcinogenic Agents; D007546:Isoquinolines; D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha