Mohamed Badr, Elshaymaa I Elmongy, Ibrahim El Tantawy El Sayed, Yasmine S Moemen, Ashraf Khalil, Doaa Elkhateeb, Reem Binsuwaidan, Hadeer Ali
{"title":"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","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":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6000,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. 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Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors.
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.
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.
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