title: Synthesis of casimiroin and optimization of its quinone reductase 2 and aromatase inhibitory activities.
abstract: An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogues has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Arup
authors.initials: A
authors.lastname: Maiti
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.forename: Megan
authors.initials: M
authors.lastname: Sturdy
authors.forename: Laura
authors.initials: L
authors.lastname: Marler
authors.forename: Scott D
authors.initials: SD
authors.lastname: Pegan
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mesecar
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000737:chemistry; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052117:Benzodioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D032081:Casimiroa / Q000737:chemistry*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005638:Fruit / Q000737:chemistry; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D052117:Benzodioxoles; D015363:Quinolones; C540179:6-methoxy-9-methyl-(1,3)dioxolo(4,5-h)quinolin-8(9H)-one; D001141:Aromatase; D011808:Quinone Reductases