Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors.

IF 3 4区医学 Q3 CHEMISTRY, MEDICINAL Anti-cancer agents in medicinal chemistry Pub Date : 2025-01-01 DOI:10.2174/0118715206360700241219065917

Mohamed Badr, Elshaymaa I Elmongy, Ibrahim El Tantawy El Sayed, Yasmine S Moemen, Ashraf Khalil, Doaa Elkhateeb, Reem Binsuwaidan, Hadeer Ali

{"title":"Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors.","authors":"Mohamed Badr, Elshaymaa I Elmongy, Ibrahim El Tantawy El Sayed, Yasmine S Moemen, Ashraf Khalil, Doaa Elkhateeb, Reem Binsuwaidan, Hadeer Ali","doi":"10.2174/0118715206360700241219065917","DOIUrl":null,"url":null,"abstract":"Background: The tetracyclic indoloquinoline ring system has attracted considerable interest in the recent past due to its broad spectrum of biological activities and its binding to various types of nucleic acids.Objective: This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II.Methods: Several compounds derived from 6-amino-11H-indolo[3,2-c]quinoline with diverse groups on the quinoline ring have been successfully synthesized according to a previously established protocol where all the synthesized indolo[3,2-c]quinoline derivatives were evaluated in vitro against A549, HCT-116, BALB/3T3, and MV4-11 cell lines using MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl- tetrazolium bromide) assay. These derivatives were then screened for their topo I and II inhibitory activities.Results: The tested compounds were more effective at killing MV4-11 leukemia cells than the standard cancer drug cisplatin, as shown by the fact that their IC50 values were less than 0.9 μM. On the other hand, cisplatin revealed an IC50 value of 2.36 μM. Moreover, they exhibited inhibitory activity against both Topoisomerase (Topo) I and II. The most potent compound, 5g, demonstrated a suppressive impact on topoisomerase I, with an IC50 value of 2.9 μM compared to the positive control Camptothecin (IC50 1.64 μM) and compound 8 displayed remarkable topoisomerase II inhibitory activity with an IC50 of 6.82 μM compared to the positive control Doxorubicin (IC50 6.49 μM). The cell cycle study for compounds 5g and 8 revealed that cell cycle arrest occurred at the G1/S and S phases, respectively. Compounds 5g and 8 showed a high selectivity index, which suggests that they could be used to develop low-toxicity chemotherapeutic agents.Conclusion: The results of this study demonstrate that compounds 5g and 8 can be considered promising candidates for further anti-cancer drug development, which might be related to inhibiting TOPO I and TOPO II activities.","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":"1029-1040"},"PeriodicalIF":3.0000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anti-cancer agents in medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0118715206360700241219065917","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: The tetracyclic indoloquinoline ring system has attracted considerable interest in the recent past due to its broad spectrum of biological activities and its binding to various types of nucleic acids.

Objective: This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II.

Methods: Several compounds derived from 6-amino-11H-indolo[3,2-c]quinoline with diverse groups on the quinoline ring have been successfully synthesized according to a previously established protocol where all the synthesized indolo[3,2-c]quinoline derivatives were evaluated in vitro against A549, HCT-116, BALB/3T3, and MV4-11 cell lines using MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl- tetrazolium bromide) assay. These derivatives were then screened for their topo I and II inhibitory activities.

Results: The tested compounds were more effective at killing MV4-11 leukemia cells than the standard cancer drug cisplatin, as shown by the fact that their IC₅₀ values were less than 0.9 μM. On the other hand, cisplatin revealed an IC₅₀ value of 2.36 μM. Moreover, they exhibited inhibitory activity against both Topoisomerase (Topo) I and II. The most potent compound, 5g, demonstrated a suppressive impact on topoisomerase I, with an IC₅₀ value of 2.9 μM compared to the positive control Camptothecin (IC₅₀ 1.64 μM) and compound 8 displayed remarkable topoisomerase II inhibitory activity with an IC₅₀ of 6.82 μM compared to the positive control Doxorubicin (IC₅₀ 6.49 μM). The cell cycle study for compounds 5g and 8 revealed that cell cycle arrest occurred at the G1/S and S phases, respectively. Compounds 5g and 8 showed a high selectivity index, which suggests that they could be used to develop low-toxicity chemotherapeutic agents.

Conclusion: The results of this study demonstrate that compounds 5g and 8 can be considered promising candidates for further anti-cancer drug development, which might be related to inhibiting TOPO I and TOPO II activities.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

作为拓扑异构酶抑制剂的吲哚并[3,2-c]喹啉类化合物的设计、合成和分子对接研究

背景：四环吲哚喹啉环系由于其广泛的生物活性和与多种核酸的结合，近年来引起了人们的极大兴趣。目的：研究它们与DNA的相互作用及其对拓扑异构酶（TOPO） I和II的影响。方法：采用MTT（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四唑）法，对所有合成的吲哚[3,2-c]喹啉衍生物在A549、HCT-116、BALB/3T3和MV4-11细胞系进行体外评价，成功合成了喹啉环上具有不同基团的6-氨基- 11h -吲哚[3,2-c]喹啉衍生物。然后筛选这些衍生物的topo I和II抑制活性。结果：所试化合物对MV4-11白血病细胞的杀伤效果优于标准抗癌药物顺铂，IC50值均小于0.9 μM。而顺铂的IC50值为2.36 μM。此外，它们对拓扑异构酶（Topo） I和II都有抑制活性。其中，化合物5g对拓扑异构酶I的抑制作用最强，IC50值为2.9 μM，高于阳性对照喜树碱（IC50值为1.64 μM）；化合物8对拓扑异构酶I的抑制作用最强，IC50值为6.82 μM，高于阳性对照阿霉素（IC50值为6.49 μM）。化合物5g和8的细胞周期研究表明，细胞周期阻滞分别发生在G1/S期和S期。化合物5g和8表现出较高的选择性指数，表明它们可用于开发低毒化疗药物。结论：化合物5g和8可能与抑制TOPO I和TOPO II活性有关，具有进一步开发抗癌药物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL

CiteScore

5.10

自引率

3.60%

发文量

323

审稿时长

4-8 weeks

期刊介绍： Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.