Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities.
Bioorg Med Chem. 2020 05 01; 28(9):115434.BM

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors have achieved great success in clinical application, especially for the prolonged survival of cisplatin-sensitive ovarian cancer patients. However, there are still many patients who do not respond to PARP inhibitors. Novel PARP inhibitors with higher activity are urgently needed. Herein we report a series of compounds by molecular hybridization PARP-1 inhibitor Olaparib (Ola) with HSP90 inhibitor C0817 (one curcumin derivative). All synthesized compounds were evaluated for their antiproliferative activity in vitro, and some were further assessed for their inhibitory activities of the PARP enzyme and HSP90 affinity. Our results indicated that compound 4 could bind to HSP90 and cause static quenching, indicating that compound 4 was able to bind to HSP90, moreover, downstream molecular breast cancer 1 (BRAC-1) was reduced. In conclusion, dual target inhibitors of PARP and HSP90 exhibited stronger selective cytotoxicities against cancer.

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Authors+Show Affiliations

Lin S

Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Institute of Materia Medica, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China.

Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China; Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China.

Xu J

Liu Y

Institute of Materia Medica, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China; Department of Pharmacochemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China. Electronic address: liuyang@fjmu.edu.cn.

Chen L

Wu L

MeSH

Antineoplastic AgentsCell Line, TumorCell ProliferationCurcuminDose-Response Relationship, DrugDrug Screening Assays, AntitumorHSP90 Heat-Shock ProteinsHumansMolecular StructurePhthalazinesPiperazinesPoly(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

32222339

Citation

Lin, Shanshan, et al. "Synthesis of Novel Dual Target Inhibitors of PARP and HSP90 and Their Antitumor Activities." Bioorganic & Medicinal Chemistry, vol. 28, no. 9, 2020, p. 115434.

Lin S, Zhang L, Zhang X, et al. Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities. Bioorg Med Chem. 2020;28(9):115434.

Lin, S., Zhang, L., Zhang, X., Yu, Z., Huang, X., Xu, J., Liu, Y., Chen, L., & Wu, L. (2020). Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities. Bioorganic & Medicinal Chemistry, 28(9), 115434. https://doi.org/10.1016/j.bmc.2020.115434

Lin S, et al. Synthesis of Novel Dual Target Inhibitors of PARP and HSP90 and Their Antitumor Activities. Bioorg Med Chem. 2020 05 1;28(9):115434. PubMed PMID: 32222339.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities. AU - Lin,Shanshan, AU - Zhang,LingYu, AU - Zhang,Xiao, AU - Yu,Zelei, AU - Huang,Xiuwang, AU - Xu,Jianhua, AU - Liu,Yang, AU - Chen,Limin, AU - Wu,Lixian, Y1 - 2020/03/13/ PY - 2019/12/25/received PY - 2020/03/10/revised PY - 2020/03/10/accepted PY - 2020/3/31/pubmed PY - 2021/5/29/medline PY - 2020/3/31/entrez KW - Antitumor KW - HSP90 KW - Multitarget KW - PARP SP - 115434 EP - 115434 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 28 IS - 9 N2 - Poly (ADP-ribose) polymerase (PARP) inhibitors have achieved great success in clinical application, especially for the prolonged survival of cisplatin-sensitive ovarian cancer patients. However, there are still many patients who do not respond to PARP inhibitors. Novel PARP inhibitors with higher activity are urgently needed. Herein we report a series of compounds by molecular hybridization PARP-1 inhibitor Olaparib (Ola) with HSP90 inhibitor C0817 (one curcumin derivative). All synthesized compounds were evaluated for their antiproliferative activity in vitro, and some were further assessed for their inhibitory activities of the PARP enzyme and HSP90 affinity. Our results indicated that compound 4 could bind to HSP90 and cause static quenching, indicating that compound 4 was able to bind to HSP90, moreover, downstream molecular breast cancer 1 (BRAC-1) was reduced. In conclusion, dual target inhibitors of PARP and HSP90 exhibited stronger selective cytotoxicities against cancer. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/32222339/Synthesis_of_novel_dual_target_inhibitors_of_PARP_and_HSP90_and_their_antitumor_activities_ DB - PRIME DP - Unbound Medicine ER -

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Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities.Bioorg Med Chem. 2020 05 01; 28(9):115434.BM