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Issue 84, 2016, Issue in Progress
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Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors

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Abstract

Two new series of 1H-indole-4-carboxamide derivatives were designed and synthesized as potent PARP-1 inhibitors. These compounds were further evaluated for PARP-1 enzyme and cellular inhibitory activity, resulting in the identification of compound LX15 with superior potency against both the PARP-1 (IC50 = 13 nM) and BRCA1 deficient cells (CC50 = 0.98 μM), and it is more potent than AG014699. In addition, LX15 displayed excellent selectivity between the BRCA1 deficient cells and wild type MCF-7 cells (CC50 = 0.98 μM vs. CC50 = 22 μM). The studies of the mechanism indicated that LX15 significantly caused the accumulation of DNA double-strand breaks and impaired the cell-cycle progression in BRCA1 deficient cells. Moreover, LX15 exhibited reasonable PK profiles and significantly potentiated the efficacy of temozolomide (TMZ) in MCF-7 cells in vitro and the B16F10 murine melanoma model in vivo. All results indicated that LX15 could be a promising drug candidate for further study.

Graphical abstract: Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors

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Publication details

The article was received on 17 May 2016, accepted on 20 Jul 2016 and first published on 26 Aug 2016


Article type: Paper
DOI: 10.1039/C6RA12591C
RSC Adv., 2016,6, 80784-80796

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    Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors

    Z. Xie, Y. Chen, P. Xu, Y. Zhou, Q. Zhao, H. Jiao and Z. Li, RSC Adv., 2016, 6, 80784
    DOI: 10.1039/C6RA12591C

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