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Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity.
Org Biomol Chem. 2018 05 02; 16(17):3189-3202.OB

Abstract

Novel quinazoline-2,4(1H,3H)-dione derivatives bearing a 3-amino pyrrolidine moiety were designed and synthesized as PARP-1/2 inhibitors. Structure-activity relationships were examined which revealed a number of potent PARP-1/2 inhibitors with moderate selectivity toward PARP-1 over PARP-2. These compounds had IC50 values against PARP-1 at the 10-9 M level and against PARP-2 at the 10-8 M level. Among all the synthesized compounds, compounds 10 and 11 displayed strong cytotoxicities which are either used as a single agent or in combination with temozolomide (TMZ) in MX-1 cells (10, IC50 < 3.12 μM, PF50 > 10; 11, IC50 = 3.02 μM, PF50 ≈ 10). In vivo tumor growth inhibition was investigated using compound 11 in combination with TMZ, and it was demonstrated that compound 11 could strongly potentiate the cytotoxicity of TMZ in a MX-1 xenograft tumor model. The co-crystal structure of compound 11 complexed with PARP-1 was achieved and demonstrated a unique binding mode.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Zhou J
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100050, China. xubl@imm.ac.cn.
Ji M
No affiliation info available
Yao H
No affiliation info available
Cao R
No affiliation info available
Zhao H
No affiliation info available
Wang X
No affiliation info available
Chen X
No affiliation info available
Xu B
No affiliation info available

MeSH

AnimalsAntineoplastic AgentsBreast NeoplasmsCell Line, TumorDrug DesignFemaleHumansMiceMolecular Docking SimulationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesQuinazolinesStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29648554

Citation

Zhou, Jie, et al. "Discovery of quinazoline-2,4(1H,3H)-dione Derivatives as Novel PARP-1/2 Inhibitors: Design, Synthesis and Their Antitumor Activity." Organic & Biomolecular Chemistry, vol. 16, no. 17, 2018, pp. 3189-3202.
Zhou J, Ji M, Yao H, et al. Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity. Org Biomol Chem. 2018;16(17):3189-3202.
Zhou, J., Ji, M., Yao, H., Cao, R., Zhao, H., Wang, X., Chen, X., & Xu, B. (2018). Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity. Organic & Biomolecular Chemistry, 16(17), 3189-3202. https://doi.org/10.1039/c8ob00286j
Zhou J, et al. Discovery of quinazoline-2,4(1H,3H)-dione Derivatives as Novel PARP-1/2 Inhibitors: Design, Synthesis and Their Antitumor Activity. Org Biomol Chem. 2018 05 2;16(17):3189-3202. PubMed PMID: 29648554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of quinazoline-2,4(1H,3H)-dione derivatives as novel PARP-1/2 inhibitors: design, synthesis and their antitumor activity. AU - Zhou,Jie, AU - Ji,Ming, AU - Yao,Haiping, AU - Cao,Ran, AU - Zhao,Hailong, AU - Wang,Xiaoyu, AU - Chen,Xiaoguang, AU - Xu,Bailing, PY - 2018/4/13/pubmed PY - 2019/2/20/medline PY - 2018/4/13/entrez SP - 3189 EP - 3202 JF - Organic & biomolecular chemistry JO - Org Biomol Chem VL - 16 IS - 17 N2 - Novel quinazoline-2,4(1H,3H)-dione derivatives bearing a 3-amino pyrrolidine moiety were designed and synthesized as PARP-1/2 inhibitors. Structure-activity relationships were examined which revealed a number of potent PARP-1/2 inhibitors with moderate selectivity toward PARP-1 over PARP-2. These compounds had IC50 values against PARP-1 at the 10-9 M level and against PARP-2 at the 10-8 M level. Among all the synthesized compounds, compounds 10 and 11 displayed strong cytotoxicities which are either used as a single agent or in combination with temozolomide (TMZ) in MX-1 cells (10, IC50 < 3.12 μM, PF50 > 10; 11, IC50 = 3.02 μM, PF50 ≈ 10). In vivo tumor growth inhibition was investigated using compound 11 in combination with TMZ, and it was demonstrated that compound 11 could strongly potentiate the cytotoxicity of TMZ in a MX-1 xenograft tumor model. The co-crystal structure of compound 11 complexed with PARP-1 was achieved and demonstrated a unique binding mode. SN - 1477-0539 UR - https://www.unboundmedicine.com/medline/citation/29648554/Discovery_of_quinazoline_24_1H3H__dione_derivatives_as_novel_PARP_1/2_inhibitors:_design_synthesis_and_their_antitumor_activity_ DB - PRIME DP - Unbound Medicine ER -
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