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

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

Volume: 25

Author(s): Mohamed Badr, Elshaymaa I. Elmongy*, Ibrahim El Tantawy El Sayed*, Yasmine S. Moemen, Ashraf Khalil, Doaa Elkhateeb, Reem Binsuwaidan and Hadeer Ali

Affiliation:

• Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, P.O. Box 11795, Egypt

• Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom, Egypt

Keywords: Indoloquinoline, anticancer agents, apoptosis, molecular docking, topoisomerase inhibitors, MV4-11 leukemia cells.

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.

Cite this article as:

Badr Mohamed, Elmongy I. Elshaymaa*, Sayed El Tantawy El Ibrahim*, Moemen S. Yasmine, Khalil Ashraf, Elkhateeb Doaa, Binsuwaidan Reem and Ali Hadeer, Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors, Anti-Cancer Agents in Medicinal Chemistry 2025; 25 () . https://dx.doi.org/10.2174/0118715206360700241219065917