Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation. Issue 20 (15th October 2015)

• Record Type: Journal Article
• Authors: Xie, Zhouling; Zhou, Youli; Zhao, Wei; Jiao, He; Chen, Yu; Yang, Yong; Li, Zhiyu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 20(2015)
• Page Start: 4557
• Page End: 4561
• Publication Date: 2015-10-15
• Subjects: CWEDJXYOHUIUML-UHFFFAOYSA-N -- CIRHWLRJJAMSEL-UHFFFAOYSA-N -- JKTIWQKWRMMZOA-UHFFFAOYSA-N -- PYDPELONKUWGFG-UHFFFAOYSA-N -- HCDRGKUOZOZNLB-UHFFFAOYSA-N -- BWBCZUIOZISGAA-UHFFFAOYSA-N -- JHKQQJFNVQMWOX-UHFFFAOYSA-N -- DKBLZGASANDIHM-UHFFFAOYSA-N -- CGZHCBPBPMDDBM-UHFFFAOYSA-N -- ZQOZVYMUXRFTNB-UHFFFAOYSA-N -- OBMAFOSIVNPHRQ-UHFFFAOYSA-N; Poly ADP-ribose polymerase-1 (PARP-1) -- Inhibitor -- Molecular docking -- DNA damage -- BRCA1/2-deficient; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.060
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of AG014699 derivatives containing a novel scaffold of 2, 3-dihydro-1 H -[1, 2]diazepino[4, 5, 6- cd ]indole-1, 4(6 H )-dione were synthesized and evaluated for their inhibitory activities toward PARP-1 enzyme and two cell lines, MCF-7 cells and the BRCA1 -deficient MDA-MB-436 cells. Our results demonstrated that of all AG014699 derivatives synthesized in this work, compounds 6 and 7 showed strong PARP-1 inhibitory activity (IC50 = 3.5 nM and 2.4 nM, respectively), only four and three times less potent than AG014699. Compound 6 also had significantly cell inhibitory activity against both MCF-7 cells (CC50 = 25.8 μM) and the BRCA1 -deficient MDA-MB-436 cells (CC50 = 5.4 μM), nearly as good as AG014699, indicating that it can be a promising compound for further evaluation.