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Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors.
Future Med Chem. 2020 10; 12(19):1691-1707.FM

Abstract

Aim: The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities. Results: A new series of novel phthalazinone derivatives were designed and synthesized. Among these, B1 and B16 displayed more potent PARP-1 inhibitory activities than olaparib. B16 gave an IC50 value of 7.8 nM against PARP-1, and a PF50 value of 3.4 in the sensitizing effect assay. The in vivo pharmacokinetic properties evaluation showed B16 displayed insufficient oral exposure, and it was also not stable in rat blood. Conclusion: The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compound B16 was a valuable lead compound with significant in vitro efficacy, deserving further optimization to develop anticancer drug candidate.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Xin M
Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No 76, Yanta West Road, Xi'an, 710061, PR China.
Sun J
Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No 76, Yanta West Road, Xi'an, 710061, PR China.
Huang W
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology & Health, College of Chemistry, Central China Normal University, Wuhan, 430079, PR China.
Tang F
Jiangsu Simcere Pharmaceutical Co. Ltd., No 699-18, Xuan Wu District, Nanjing, 210042, PR China.
Liu Z
Jiangsu Simcere Pharmaceutical Co. Ltd., No 699-18, Xuan Wu District, Nanjing, 210042, PR China.
Jin Q
Jiangsu Simcere Pharmaceutical Co. Ltd., No 699-18, Xuan Wu District, Nanjing, 210042, PR China.
Wang J
Jiangsu Simcere Pharmaceutical Co. Ltd., No 699-18, Xuan Wu District, Nanjing, 210042, PR China.

MeSH

AnimalsAntineoplastic AgentsCell Line, TumorCrystallography, X-RayDose-Response Relationship, DrugHumansMolecular Docking SimulationMolecular StructurePhthalazinesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsRatsRats, Sprague-DawleyStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33012191

Citation

Xin, Minhang, et al. "Design and Synthesis of Novel Phthalazinone Derivatives as Potent poly(ADP-ribose)polymerase 1 Inhibitors." Future Medicinal Chemistry, vol. 12, no. 19, 2020, pp. 1691-1707.
Xin M, Sun J, Huang W, et al. Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors. Future Med Chem. 2020;12(19):1691-1707.
Xin, M., Sun, J., Huang, W., Tang, F., Liu, Z., Jin, Q., & Wang, J. (2020). Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors. Future Medicinal Chemistry, 12(19), 1691-1707. https://doi.org/10.4155/fmc-2020-0009
Xin M, et al. Design and Synthesis of Novel Phthalazinone Derivatives as Potent poly(ADP-ribose)polymerase 1 Inhibitors. Future Med Chem. 2020;12(19):1691-1707. PubMed PMID: 33012191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors. AU - Xin,Minhang, AU - Sun,Jiajia, AU - Huang,Wei, AU - Tang,Feng, AU - Liu,Zhaoyu, AU - Jin,Qiu, AU - Wang,Jia, Y1 - 2020/10/05/ PY - 2020/10/6/pubmed PY - 2021/7/15/medline PY - 2020/10/5/entrez KW - PARP-1 inhibitors KW - lead compound KW - phthalazinone derivatives KW - potent KW - sensitizing effect SP - 1691 EP - 1707 JF - Future medicinal chemistry JO - Future Med Chem VL - 12 IS - 19 N2 - Aim: The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities. Results: A new series of novel phthalazinone derivatives were designed and synthesized. Among these, B1 and B16 displayed more potent PARP-1 inhibitory activities than olaparib. B16 gave an IC50 value of 7.8 nM against PARP-1, and a PF50 value of 3.4 in the sensitizing effect assay. The in vivo pharmacokinetic properties evaluation showed B16 displayed insufficient oral exposure, and it was also not stable in rat blood. Conclusion: The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compound B16 was a valuable lead compound with significant in vitro efficacy, deserving further optimization to develop anticancer drug candidate. SN - 1756-8927 UR - https://www.unboundmedicine.com/medline/citation/33012191/Design_and_synthesis_of_novel_phthalazinone_derivatives_as_potent_poly_ADP_ribose_polymerase_1_inhibitors_ DB - PRIME DP - Unbound Medicine ER -