QUINOXALINE DERIVATIVES: DUAL INHIBITION OF MTOR AND PI3K PATHWAYS IN CANCER CELLS

Abstract

Purpose: mTOR and PI3K are crucial enzymes that regulate cell growth, survival, and metabolism. Dysregulation of these enzymes is linked to various cancers, including breast, lung, prostate, and colorectal cancer. Targeting mTOR and PI3K simultaneously could be a promising strategy to overcome drug resistance and enhance anticancer efficacy.

Methods: Quinoxaline derivatives were synthesized using commercially available 2,3-dichloroquinoxaline and substituted benzene sulfonamide. Molecular docking studies were conducted using Auto Dock Vina, Chimera, and BIOVIA Discovery Studio to evaluate the binding affinity with the active sites of mTOR and PI3K. The in vitro anticancer activity of the synthesized compounds was assessed against human cancer cell lines: MCF-7 (breast cancer), HCT-116 (colon cancer), and HepG-2 (liver cancer) using the MTT assay.

Results: The synthesized compounds exhibited characteristic peaks of the quinoxaline ring at 1600–1500 cm−1 and 1400–1300 cm−1 in IR spectra. The ( ^1H ) NMR spectra showed signals of aromatic protons at 7.0–8.5 ppm and aliphatic protons at 0.8–4.5 ppm. Compound 5 demonstrated the highest binding affinity for both mTOR (−8.4 kcal/mol) and PI3K (−7.6 kcal/mol). Additionally, Compound 5 exhibited the lowest IC50 values for the cell lines, ranging from 0.89 to 1.12 μM, indicating its potential as an effective anticancer agent.

Conclusion: This study provides new insights into the development of quinoxaline-based dual inhibitors of mTOR and PI3K as novel anticancer therapeutics

Purpose: mTOR and PI3K are crucial enzymes that regulate cell growth, survival, and metabolism. Dysregulation of these enzymes is linked to various cancers, including breast, lung, prostate, and colorectal cancer. Targeting mTOR and PI3K simultaneously could be a promising strategy to overcome drug resistance and enhance anticancer efficacy.

Methods: Quinoxaline derivatives were synthesized using commercially available 2,3-dichloroquinoxaline and substituted benzene sulfonamide. Molecular docking studies were conducted using Auto Dock Vina, Chimera, and BIOVIA Discovery Studio to evaluate the binding affinity with the active sites of mTOR and PI3K. The in vitro anticancer activity of the synthesized compounds was assessed against human cancer cell lines: MCF-7 (breast cancer), HCT-116 (colon cancer), and HepG-2 (liver cancer) using the MTT assay.

Results: The synthesized compounds exhibited characteristic peaks of the quinoxaline ring at 1600–1500 cm−1 and 1400–1300 cm−1 in IR spectra. The ( ^1H ) NMR spectra showed signals of aromatic protons at 7.0–8.5 ppm and aliphatic protons at 0.8–4.5 ppm. Compound 5 demonstrated the highest binding affinity for both mTOR (−8.4 kcal/mol) and PI3K (−7.6 kcal/mol). Additionally, Compound 5 exhibited the lowest IC50 values for the cell lines, ranging from 0.89 to 1.12 μM, indicating its potential as an effective anticancer agent.

Conclusion: This study provides new insights into the development of quinoxaline-based dual inhibitors of mTOR and PI3K as novel anticancer therapeutics.