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Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors.
Bioorg Med Chem. 2015 Feb 15; 23(4):681-93.BM

Abstract

Poly(ADP-ribose)polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. In this work, a novel series of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized as human PARP-1 inhibitors, structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values of single or double digit nanomolar level. Compound 7j was a potent PARP-1 and PARP-2 inhibitor and it could selectively kill the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, in comparison with homologous recombination proficient cell types such as breast cancer cells MDA-MB-231. In addition, compound 7j displayed the strongest potentiation effect on temozolomide in MX-1 cells (PF50=3.77) in this series of PARP-1 inhibitors.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Yao H
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Ji M
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Zhu Z
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Zhou J
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Cao R
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Chen X
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: chxg@imm.ac.cn.
Xu B
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: xubl@imm.ac.cn.

MeSH

Antineoplastic AgentsBreastBreast NeoplasmsCell Line, TumorEnzyme InhibitorsFemaleHumansMolecular Docking SimulationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesQuinazolinesStructure-Activity Relationship

Pub Type(s)

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

Language

eng

PubMed ID

25614115

Citation

Yao, Haiping, et al. "Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione Derivatives as Novel poly(ADP-ribose)polymerase-1 Inhibitors." Bioorganic & Medicinal Chemistry, vol. 23, no. 4, 2015, pp. 681-93.
Yao H, Ji M, Zhu Z, et al. Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors. Bioorg Med Chem. 2015;23(4):681-93.
Yao, H., Ji, M., Zhu, Z., Zhou, J., Cao, R., Chen, X., & Xu, B. (2015). Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors. Bioorganic & Medicinal Chemistry, 23(4), 681-93. https://doi.org/10.1016/j.bmc.2014.12.071
Yao H, et al. Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione Derivatives as Novel poly(ADP-ribose)polymerase-1 Inhibitors. Bioorg Med Chem. 2015 Feb 15;23(4):681-93. PubMed PMID: 25614115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors. AU - Yao,Haiping, AU - Ji,Ming, AU - Zhu,Zhixiang, AU - Zhou,Jie, AU - Cao,Ran, AU - Chen,Xiaoguang, AU - Xu,Bailing, Y1 - 2015/01/08/ PY - 2014/10/29/received PY - 2014/12/31/revised PY - 2014/12/31/accepted PY - 2015/1/24/entrez PY - 2015/1/24/pubmed PY - 2015/10/6/medline KW - Antitumor activity KW - PARP-1 inhibitor KW - PARP-2 inhibitor KW - Quinazoline-2,4(1H,3H)-dione SP - 681 EP - 93 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 23 IS - 4 N2 - Poly(ADP-ribose)polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. In this work, a novel series of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized as human PARP-1 inhibitors, structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values of single or double digit nanomolar level. Compound 7j was a potent PARP-1 and PARP-2 inhibitor and it could selectively kill the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, in comparison with homologous recombination proficient cell types such as breast cancer cells MDA-MB-231. In addition, compound 7j displayed the strongest potentiation effect on temozolomide in MX-1 cells (PF50=3.77) in this series of PARP-1 inhibitors. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25614115/Discovery_of_1_substituted_benzyl_quinazoline_24_1H3H__dione_derivatives_as_novel_poly_ADP_ribose_polymerase_1_inhibitors_ DB - PRIME DP - Unbound Medicine ER -
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