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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

Lookup NU author(s): Dr Christopher Calabrese, Professor Nicola Curtin, Suzanne Kyle, Huw Thomas, Lan Wang, Professor Alan Calvert, Professor Bernard Golding, Professor Roger Griffin, Professor Herbie Newell

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Abstract

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.


Publication metadata

Author(s): Tikhe J, Webber S, Hostomsky Z, Maegley K, Ekkers A, Li J, Yu X, Almassy R, Kumpf R, Boritzki T, Zhang C, Calabrese C, Curtin NJ, Kyle S, Thomas HD, Wang L, Calvert AH, Golding B, Griffin RJ, Newell DR

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2004

Volume: 47

Issue: 22

Pages: 5467-5481

Print publication date: 21/10/2004

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm030513r

DOI: 10.1021/jm030513r

PubMed id: 15481984


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