Design, synthesis, and biological evaluation of potent quinoline and pyrroloquinoline ammosamide analogues as inhibitors of quinone reductase 2.
A variety of ammosamide B analogues have been synthesized and evaluated as inhibitors of quinone reductase 2 (QR2). The potencies of the resulting series of QR2 inhibitors range from 4.1 to 25,200 nM. The data provide insight into the structural parameters necessary for QR2 inhibitory activity. The natural product ammosamide B proved to be a potent QR2 inhibitor, and the potencies of the analogues generally decreased as their structures became more distinct from that of ammosamide B. Methylation of the 8-amino group of ammosamide B was an exception, resulting in an increase in quinone reductase 2 inhibitory activity from an IC(50) of 61 nM to IC(50) 4.1 nM.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
P V Narasimha
PV
Reddy
Katherine C
KC
Jensen
Andrew D
AD
Mesecar
Phillip E
PE
Fanwick
Mark
M
Cushman
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011758:Pyrroles; D011804:Quinolines; C534623:ammosamide B; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases