Design, Synthesis, and Evaluation of 3,4-Dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as Inhibitors of Poly(ADP-Ribose) Polymerase

• Published in: Journal of medicinal chemistry 2004-10, Vol.47 (22), p.5467-5481
• Main Authors: Tikhe, Jayashree G, Webber, Stephen E, Hostomsky, Zdenek, Maegley, Karen A, Ekkers, Anne, Li, Jianke, Yu, Xiao-Hong, Almassy, Robert J, Kumpf, Robert A, Boritzki, Theodore J, Zhang, Cathy, 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
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Drug Design; Drug Resistance, Neoplasm; Drug Synergism; General aspects; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerase Inhibitors; Structure-Activity Relationship; Topoisomerase I Inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030513r

The design, synthesis, and biological evaluation of potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are reported. A novel series of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones were designed using a combination of protein structure-based drug design, molecular modeling, and structure−activity relationships (SAR). These novel submicromolar inhibitors possess a tricyclic ring system conformationally restricting the benzamide in the preferred cis orientation. The compounds were designed to optimize space-filling and atomic interactions within the NAD+ binding site of PARP-1. Previously described and newly adapted methods were applied to syntheses of these tricyclic inhibitors. Various modifications were made to the diazepinoindolones at the 6- and 7-positions in order to study this region of the active site and optimize noncovalent interactions. The electron density of derivative 28 bound to chicken PARP-1 revealed that the oxime makes a tight hydrogen bond with the catalytic γ-carboxylate of glutamic acid (Glu) 988 in accordance with our original designs and models. Most of the compounds have been evaluated for inhibition of human PARP-1. Selected inhibitors were also tested for the ability to potentiate the cytotoxic effect of the DNA-damaging agent Topotecan.