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 |
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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 |
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Affiliation: | Pfizer Global R&D--La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. jayashree.tikhe@pfizer.com |
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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 gamma-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. |
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