Novel Tricyclic Poly(ADP-ribose) Polymerase-1 Inhibitors with Potent Anticancer Chemopotentiating Activity:  Design, Synthesis, and X-ray Cocrystal Structure

• Published in: Journal of medicinal chemistry Vol. 45; no. 23; pp. 4961 - 4974
• Main Authors: Canan Koch, Stacie S, Thoresen, Lars H, Tikhe, Jayashree G, Maegley, Karen A, Almassy, Robert J, Li, Jianke, Yu, Xiao-Hong, Zook, Scott E, Kumpf, Robert A, Zhang, Cathy, Boritzki, Theodore J, Mansour, Rena N, Zhang, Kanyin E, Ekker, Anne, Calabrese, Chris R, Curtin, Nicola J, Kyle, Suzanne, Thomas, Huw D, Wang, Lan-Zhen, Calvert, A. Hilary, Golding, Bernard T, Griffin, Roger J, Newell, David R, Webber, Stephen E, Hostomsky, Zdenek
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 07.11.2002
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Crystallography, X-Ray; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Drug Design; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Medical sciences; NAD - metabolism; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - metabolism; Structure-Activity Relationship; Temozolomide; Topotecan - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Drug combination; Enzyme; Nitrogen heterocycle; Transferases; Glycosyltransferases; Lactam; Enzyme inhibitor; Topotecan; Tricyclic compound; In vitro; Synergism; Pyrrolidine derivatives; NAD; Structure activity relation; ADP-ribosyltransferase; Benzenic compound; Aromatic compound; Drug interaction; Temozolomide; Chemical synthesis; Pentosyltransferases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020259n

A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.