Kholoud Heshmat, Asmaa T. Mohamed, Samah A. Loutfy, Ramy Mohamed AbdElaziz, Mehrez E. El-Naggar, Mohamed A. Hamed, Mohamed Atef, Elbadawy A. Kamoun, Ibrahim El-Tantawy El-Sayed, Yasmine S. Moemen
{"title":"Synthesis, antiproliferative activity and molecular docking studies of neo- and isocryptolepine conjugates","authors":"Kholoud Heshmat, Asmaa T. Mohamed, Samah A. Loutfy, Ramy Mohamed AbdElaziz, Mehrez E. El-Naggar, Mohamed A. Hamed, Mohamed Atef, Elbadawy A. Kamoun, Ibrahim El-Tantawy El-Sayed, Yasmine S. Moemen","doi":"10.1007/s13738-024-03078-8","DOIUrl":null,"url":null,"abstract":"<div><p>A series of twelve conjugates <b>9a-c, 10a-c</b>, <b>11a-c,</b> and <b>12a-c</b> based on naturally occurring neo- and isocryptolepines <b>I</b> and <b>II</b> were synthesized and characterized. The synthetic pathways involved nucleophilic substitution reaction of the preprepared amines <b>4a-c</b> and <b>5a-c</b> with 1-(4-bromobutyl)indole derivatives <b>8a</b> and <b>8b</b>, respectively, in aprotic solvent under heating. The structures of the synthesized conjugates were elucidated by <b>FTIR, </b><sup><b>1</b></sup><b>H NMR</b>, <sup><b>13</b></sup><b>C NMR,</b> and <b>MS</b> spectrometry and showed data consistence with the expected structures. The antiproliferative activity of <b>9a-c, 10a-c, 11a-c</b> and <b>12a-c</b> was evaluated against HepG-2 and HCT-116 cancer cell lines using normal cells and reference drug paclitaxel. The screening results revealed that <b>9b</b> and <b>9c</b> were the most active conjugates against HepG-2 and HCT-116 cancer cell lines with IC<sub>50</sub>: 8.49, 9.52, 16.87, 21.75 µM, respectively, using <i>paclitaxel</i> as a reference drug. It is worth noting that <b>9b</b> and <b>9c</b> were more selective toward cancer cells versus normal Vero cells. To rationalize the anticancer activity and selectivity of <b>9b</b> and <b>9c,</b> we have performed molecular docking study against human topoisomerases I and II for better understanding of their anticancer activities in atomic level. Molecular docking studies revealed that the presence of planar indoloquinoline fused four rings and a flexible side chain pharmacophores together improve DNA-intercalation and inhibition of DNA-Topo isomerases activity.</p></div>","PeriodicalId":676,"journal":{"name":"Journal of the Iranian Chemical Society","volume":null,"pages":null},"PeriodicalIF":2.2000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the Iranian Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s13738-024-03078-8","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
A series of twelve conjugates 9a-c, 10a-c, 11a-c, and 12a-c based on naturally occurring neo- and isocryptolepines I and II were synthesized and characterized. The synthetic pathways involved nucleophilic substitution reaction of the preprepared amines 4a-c and 5a-c with 1-(4-bromobutyl)indole derivatives 8a and 8b, respectively, in aprotic solvent under heating. The structures of the synthesized conjugates were elucidated by FTIR, 1H NMR, 13C NMR, and MS spectrometry and showed data consistence with the expected structures. The antiproliferative activity of 9a-c, 10a-c, 11a-c and 12a-c was evaluated against HepG-2 and HCT-116 cancer cell lines using normal cells and reference drug paclitaxel. The screening results revealed that 9b and 9c were the most active conjugates against HepG-2 and HCT-116 cancer cell lines with IC50: 8.49, 9.52, 16.87, 21.75 µM, respectively, using paclitaxel as a reference drug. It is worth noting that 9b and 9c were more selective toward cancer cells versus normal Vero cells. To rationalize the anticancer activity and selectivity of 9b and 9c, we have performed molecular docking study against human topoisomerases I and II for better understanding of their anticancer activities in atomic level. Molecular docking studies revealed that the presence of planar indoloquinoline fused four rings and a flexible side chain pharmacophores together improve DNA-intercalation and inhibition of DNA-Topo isomerases activity.
期刊介绍:
JICS is an international journal covering general fields of chemistry. JICS welcomes high quality original papers in English dealing with experimental, theoretical and applied research related to all branches of chemistry. These include the fields of analytical, inorganic, organic and physical chemistry as well as the chemical biology area. Review articles discussing specific areas of chemistry of current chemical or biological importance are also published. JICS ensures visibility of your research results to a worldwide audience in science. You are kindly invited to submit your manuscript to the Editor-in-Chief or Regional Editor. All contributions in the form of original papers or short communications will be peer reviewed and published free of charge after acceptance.