{"title":"评估 1,10-菲罗啉基羟酰胺衍生物作为组蛋白去乙酰化酶/核糖核苷酸还原酶双重抑制剂的抗肿瘤活性","authors":"Manasa Gangadhar Shetty, Padmini Pai, Bipasa Dey, Kapaettu Satyamoorthy, Suranjan Shil, Usha Yogendra Nayak, Ashwini T, Babitha Kampa Sundara","doi":"10.1007/s40199-024-00514-1","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The <i>N</i><sup>1</sup>-hydroxy-<i>N</i><sup>8</sup>-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC<sub>50</sub> of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC<sub>50</sub> values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>","PeriodicalId":10888,"journal":{"name":"DARU Journal of Pharmaceutical Sciences","volume":"30 1","pages":""},"PeriodicalIF":2.5000,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities\",\"authors\":\"Manasa Gangadhar Shetty, Padmini Pai, Bipasa Dey, Kapaettu Satyamoorthy, Suranjan Shil, Usha Yogendra Nayak, Ashwini T, Babitha Kampa Sundara\",\"doi\":\"10.1007/s40199-024-00514-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Background</h3><p>Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy.</p><h3 data-test=\\\"abstract-sub-heading\\\">Objectives</h3><p>The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor.</p><h3 data-test=\\\"abstract-sub-heading\\\">Methods</h3><p>The <i>N</i><sup>1</sup>-hydroxy-<i>N</i><sup>8</sup>-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2.</p><h3 data-test=\\\"abstract-sub-heading\\\">Results</h3><p>The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC<sub>50</sub> of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC<sub>50</sub> values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7.</p><h3 data-test=\\\"abstract-sub-heading\\\">Conclusion</h3><p>The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.</p><h3 data-test=\\\"abstract-sub-heading\\\">Graphical Abstract</h3>\",\"PeriodicalId\":10888,\"journal\":{\"name\":\"DARU Journal of Pharmaceutical Sciences\",\"volume\":\"30 1\",\"pages\":\"\"},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-04-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"DARU Journal of Pharmaceutical Sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40199-024-00514-1\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"DARU Journal of Pharmaceutical Sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40199-024-00514-1","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities
Background
Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy.
Objectives
The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor.
Methods
The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2.
Results
The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7.
Conclusion
The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.
期刊介绍：
DARU Journal of Pharmaceutical Sciences is a peer-reviewed journal published on behalf of Tehran University of Medical Sciences. The journal encompasses all fields of the pharmaceutical sciences and presents timely research on all areas of drug conception, design, manufacture, classification and assessment.
The term DARU is derived from the Persian name meaning drug or medicine. This journal is a unique platform to improve the knowledge of researchers and scientists by publishing novel articles including basic and clinical investigations from members of the global scientific community in the forms of original articles, systematic or narrative reviews, meta-analyses, letters, and short communications.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
