Vajja Krishna Rao, Subarno Paul, Mitchell Gulkis, Zhihang Shen, Haritha Nair, Amandeep Singh, Chenglong Li, Arun K. Sharma, Melike Çağlayan, Chinmay Das, Biswajit Das, Chanakya N. Kundu, Satya Narayan and Sankar K. Guchhait
{"title":"通过对 NSC-666719 进行分子编辑,发现可用作抗癌剂的苯并二噻二酮胍类化合物","authors":"Vajja Krishna Rao, Subarno Paul, Mitchell Gulkis, Zhihang Shen, Haritha Nair, Amandeep Singh, Chenglong Li, Arun K. Sharma, Melike Çağlayan, Chinmay Das, Biswajit Das, Chanakya N. Kundu, Satya Narayan and Sankar K. Guchhait","doi":"10.1039/D3MD00648D","DOIUrl":null,"url":null,"abstract":"<p >DNA polymerase β (Polβ) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent <strong>NSC-666719</strong> was investigated, which led to the development of new molecular motifs with Polβ inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent <strong>NSC-666719</strong> and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both <em>in vitro</em> reconstituted and <em>in vivo</em> intact cell systems. Compound <strong>10e</strong> demonstrated significant Polβ interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.5970,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents†\",\"authors\":\"Vajja Krishna Rao, Subarno Paul, Mitchell Gulkis, Zhihang Shen, Haritha Nair, Amandeep Singh, Chenglong Li, Arun K. Sharma, Melike Çağlayan, Chinmay Das, Biswajit Das, Chanakya N. Kundu, Satya Narayan and Sankar K. Guchhait\",\"doi\":\"10.1039/D3MD00648D\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >DNA polymerase β (Polβ) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent <strong>NSC-666719</strong> was investigated, which led to the development of new molecular motifs with Polβ inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent <strong>NSC-666719</strong> and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both <em>in vitro</em> reconstituted and <em>in vivo</em> intact cell systems. Compound <strong>10e</strong> demonstrated significant Polβ interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.</p>\",\"PeriodicalId\":88,\"journal\":{\"name\":\"MedChemComm\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5970,\"publicationDate\":\"2024-01-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"MedChemComm\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00648d\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Pharmacology, Toxicology and Pharmaceutics\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"MedChemComm","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00648d","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents†
DNA polymerase β (Polβ) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polβ inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polβ interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.