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Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors.
Bioorg Med Chem Lett. 2021 09 01; 47:128169.BM

Abstract

Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Shen H
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
Ge Y
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
Wang J
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
Li H
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
Xu Y
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: xyg64@126.com.
Zhu Q
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: zhuqihua@vip.126.com.

MeSH

Antineoplastic AgentsCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorHumansMolecular StructurePoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsStructure-Activity Relationship

Pub Type(s)

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

Language

eng

PubMed ID

34091044

Citation

Shen, Hui, et al. "Design, Synthesis and Biological Evaluation of Novel Molecules as Potent PARP-1 Inhibitors." Bioorganic & Medicinal Chemistry Letters, vol. 47, 2021, p. 128169.
Shen H, Ge Y, Wang J, et al. Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors. Bioorg Med Chem Lett. 2021;47:128169.
Shen, H., Ge, Y., Wang, J., Li, H., Xu, Y., & Zhu, Q. (2021). Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 47, 128169. https://doi.org/10.1016/j.bmcl.2021.128169
Shen H, et al. Design, Synthesis and Biological Evaluation of Novel Molecules as Potent PARP-1 Inhibitors. Bioorg Med Chem Lett. 2021 09 1;47:128169. PubMed PMID: 34091044.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors. AU - Shen,Hui, AU - Ge,Yiran, AU - Wang,Junwei, AU - Li,Hui, AU - Xu,Yungen, AU - Zhu,Qihua, Y1 - 2021/06/06/ PY - 2021/04/08/received PY - 2021/05/19/revised PY - 2021/05/29/accepted PY - 2021/6/7/pubmed PY - 2022/1/5/medline PY - 2021/6/6/entrez KW - Antitumor drug KW - DNA repair KW - Drug design KW - PARP-1 inhibitors SP - 128169 EP - 128169 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 47 N2 - Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/34091044/Design_synthesis_and_biological_evaluation_of_novel_molecules_as_potent_PARP_1_inhibitors_ DB - PRIME DP - Unbound Medicine ER -