Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2018.1530224 |
| _version_ | 1818154625580138496 |
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| author | Cheng-Zhi Gao Wei Dong Zhi-Wen Cui Qiong Yuan Xia-Min Hu Qing-Ming Wu Xianlin Han Yao Xu Zhen-Li Min |
| author_facet | Cheng-Zhi Gao Wei Dong Zhi-Wen Cui Qiong Yuan Xia-Min Hu Qing-Ming Wu Xianlin Han Yao Xu Zhen-Li Min |
| author_sort | Cheng-Zhi Gao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T14:29:29Z |
| format | Article |
| id | doaj.art-5f4681bee0ed4cefb59b2ef92e696960 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-11T14:29:29Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-5f4681bee0ed4cefb59b2ef92e6969602022-12-22T01:02:30ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742019-01-0134115016210.1080/14756366.2018.15302241530224Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitorsCheng-Zhi Gao0Wei Dong1Zhi-Wen Cui2Qiong Yuan3Xia-Min Hu4Qing-Ming Wu5Xianlin Han6Yao Xu7Zhen-Li Min8Wuhan University of Science and TechnologyWuhan University of Science and TechnologyWuhan University of Science and TechnologyWuhan University of Science and TechnologyShanghai University of Medicine & Health SciencesWuhan University of Science and TechnologyUniversity of Texas Health Science Center at San AntonioWuhan University of Science and TechnologyWuhan University of Science and TechnologyA 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.http://dx.doi.org/10.1080/14756366.2018.1530224parp-1 inhibitorolaparibachebchealzheimer's disease |
| spellingShingle | Cheng-Zhi Gao Wei Dong Zhi-Wen Cui Qiong Yuan Xia-Min Hu Qing-Ming Wu Xianlin Han Yao Xu Zhen-Li Min 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 parp-1 inhibitor olaparib ache bche alzheimer's disease |
| title | Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors |
| title_full | Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors |
| title_fullStr | Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors |
| title_full_unstemmed | Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors |
| title_short | Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors |
| title_sort | synthesis preliminarily biological evaluation and molecular docking study of new olaparib analogues as multifunctional parp 1 and cholinesterase inhibitors |
| topic | parp-1 inhibitor olaparib ache bche alzheimer's disease |
| url | http://dx.doi.org/10.1080/14756366.2018.1530224 |
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