Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors
[Display omitted] Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Am...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2021-09, Vol.47, p.128169-128169, Article 128169 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 47 |
| creator | Shen, Hui Ge, Yiran Wang, Junwei Li, Hui Xu, Yungen Zhu, Qihua |
| description | [Display omitted]
Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors. |
| doi_str_mv | 10.1016/j.bmcl.2021.128169 |
| format | Article |
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Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2021.128169</identifier><identifier>PMID: 34091044</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antitumor drug ; Cell Line, Tumor ; Cell Proliferation - drug effects ; DNA repair ; Dose-Response Relationship, Drug ; Drug Design ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; PARP-1 inhibitors ; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors ; Poly (ADP-Ribose) Polymerase-1 - metabolism ; Poly(ADP-ribose) Polymerase Inhibitors - chemical synthesis ; Poly(ADP-ribose) Polymerase Inhibitors - chemistry ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2021-09, Vol.47, p.128169-128169, Article 128169</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-e22868a84f646ecd0d30132ff9e25b586bde7e267d861053f27652f2414828e53</citedby><cites>FETCH-LOGICAL-c422t-e22868a84f646ecd0d30132ff9e25b586bde7e267d861053f27652f2414828e53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2021.128169$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34091044$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shen, Hui</creatorcontrib><creatorcontrib>Ge, Yiran</creatorcontrib><creatorcontrib>Wang, Junwei</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Xu, Yungen</creatorcontrib><creatorcontrib>Zhu, Qihua</creatorcontrib><title>Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. 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Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t1/2 of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34091044</pmid><doi>10.1016/j.bmcl.2021.128169</doi><tpages>1</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2021-09, Vol.47, p.128169-128169, Article 128169 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antitumor drug Cell Line, Tumor Cell Proliferation - drug effects DNA repair Dose-Response Relationship, Drug Drug Design Drug Screening Assays, Antitumor Humans Molecular Structure PARP-1 inhibitors Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors Poly (ADP-Ribose) Polymerase-1 - metabolism Poly(ADP-ribose) Polymerase Inhibitors - chemical synthesis Poly(ADP-ribose) Polymerase Inhibitors - chemistry Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Structure-Activity Relationship |
| title | Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors |
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