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Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation.
Bioorg Med Chem Lett. 2015 Oct 15; 25(20):4557-61.BM

Abstract

A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Xie Z
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Zhou Y
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Zhao W
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 21009, China.
Jiao H
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Chen Y
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Yang Y
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 21009, China.
Li Z
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China. Electronic address: zhiyuli@cpu.edu.cn.

MeSH

Cell Line, TumorCell ProliferationCell SurvivalDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorHumansIndolesMolecular StructurePoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26342868

Citation

Xie, Zhouling, et al. "Identification of Novel PARP-1 Inhibitors: Drug Design, Synthesis and Biological Evaluation." Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 20, 2015, pp. 4557-61.
Xie Z, Zhou Y, Zhao W, et al. Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation. Bioorg Med Chem Lett. 2015;25(20):4557-61.
Xie, Z., Zhou, Y., Zhao, W., Jiao, H., Chen, Y., Yang, Y., & Li, Z. (2015). Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation. Bioorganic & Medicinal Chemistry Letters, 25(20), 4557-61. https://doi.org/10.1016/j.bmcl.2015.08.060
Xie Z, et al. Identification of Novel PARP-1 Inhibitors: Drug Design, Synthesis and Biological Evaluation. Bioorg Med Chem Lett. 2015 Oct 15;25(20):4557-61. PubMed PMID: 26342868.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation. AU - Xie,Zhouling, AU - Zhou,Youli, AU - Zhao,Wei, AU - Jiao,He, AU - Chen,Yu, AU - Yang,Yong, AU - Li,Zhiyu, Y1 - 2015/08/22/ PY - 2015/05/28/received PY - 2015/07/26/revised PY - 2015/08/22/accepted PY - 2015/9/7/entrez PY - 2015/9/8/pubmed PY - 2016/6/1/medline KW - BRCA1/2-deficient KW - DNA damage KW - Inhibitor KW - Molecular docking KW - Poly ADP-ribose polymerase-1 (PARP-1) SP - 4557 EP - 61 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 25 IS - 20 N2 - A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-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. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/26342868/Identification_of_novel_PARP_1_inhibitors:_Drug_design_synthesis_and_biological_evaluation_ DB - PRIME DP - Unbound Medicine ER -