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Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors.
J Enzyme Inhib Med Chem. 2019 Dec; 34(1):150-162.JE

Abstract

A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer's disease.

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Authors+Show Affiliations

a Hubei Province Key Laboratory of Occupational Hazard Identification and Control , Wuhan University of Science and Technology , Wuhan , China.

a Hubei Province Key Laboratory of Occupational Hazard Identification and Control , Wuhan University of Science and Technology , Wuhan , China.

a Hubei Province Key Laboratory of Occupational Hazard Identification and Control , Wuhan University of Science and Technology , Wuhan , China.

a Hubei Province Key Laboratory of Occupational Hazard Identification and Control , Wuhan University of Science and Technology , Wuhan , China.

b College of Pharmacy , Shanghai University of Medicine & Health Sciences , Shanghai , China.

a Hubei Province Key Laboratory of Occupational Hazard Identification and Control , Wuhan University of Science and Technology , Wuhan , China.

c Barshop Institute for Longevity and Aging Studies , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.

d College of Life Science and Health , Wuhan University of Science and Technology , Wuhan , China.

a Hubei Province Key Laboratory of Occupational Hazard Identification and Control , Wuhan University of Science and Technology , Wuhan , China. c Barshop Institute for Longevity and Aging Studies , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.

MeSH

AcetylcholinesteraseAnimalsAntineoplastic AgentsButyrylcholinesteraseCell Line, TumorCell ProliferationCholinesterase InhibitorsDose-Response Relationship, DrugDrug Screening Assays, AntitumorElectrophorusHorsesHumansMolecular Docking SimulationMolecular StructurePhthalazinesPiperazinesPoly (ADP-Ribose) Polymerase-1Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30427217

Citation

Gao, Cheng-Zhi, et al. "Synthesis, Preliminarily Biological Evaluation and Molecular Docking Study of New Olaparib Analogues as Multifunctional PARP-1 and Cholinesterase Inhibitors." Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 34, no. 1, 2019, pp. 150-162.

Gao CZ, Dong W, Cui ZW, et al. Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors. J Enzyme Inhib Med Chem. 2019;34(1):150-162.

Gao, C. Z., Dong, W., Cui, Z. W., Yuan, Q., Hu, X. M., Wu, Q. M., Han, X., Xu, Y., & Min, Z. L. (2019). Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1), 150-162. https://doi.org/10.1080/14756366.2018.1530224

Gao CZ, et al. Synthesis, Preliminarily Biological Evaluation and Molecular Docking Study of New Olaparib Analogues as Multifunctional PARP-1 and Cholinesterase Inhibitors. J Enzyme Inhib Med Chem. 2019;34(1):150-162. PubMed PMID: 30427217.

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

TY - JOUR T1 - Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors. AU - Gao,Cheng-Zhi, AU - Dong,Wei, AU - Cui,Zhi-Wen, AU - Yuan,Qiong, AU - Hu,Xia-Min, AU - Wu,Qing-Ming, AU - Han,Xianlin, AU - Xu,Yao, AU - Min,Zhen-Li, PY - 2018/11/15/entrez PY - 2018/11/15/pubmed PY - 2018/12/19/medline KW - AChE KW - Alzheimer's Disease KW - BChE KW - Olaparib KW - PARP-1 inhibitor SP - 150 EP - 162 JF - Journal of enzyme inhibition and medicinal chemistry JO - J Enzyme Inhib Med Chem VL - 34 IS - 1 N2 - A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer's disease. SN - 1475-6374 UR - https://www.unboundmedicine.com/medline/citation/30427217/Synthesis_preliminarily_biological_evaluation_and_molecular_docking_study_of_new_Olaparib_analogues_as_multifunctional_PARP_1_and_cholinesterase_inhibitors_ DB - PRIME DP - Unbound Medicine ER -