Design and Synthesis of New Quinoxaline Derivatives as Anticancer Agents and Apoptotic Inducers

Abstract

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.

Novel Synthetic Routes to Prepare Biologically Active Quinoxalines and Their Derivatives: A Synthetic Review for the Last Two Decades

“…The antitumor activity of kinase inhibitors comprising diaryl urea has earned immense attention because of its binding mode. Owing to its beneficial anticancer properties, Abouzid et al [ 60 ] synthesized an array of quinoxaline-based compounds with amide, urea, thiourea, and sulfonamide moieties. Quinoxalines is derived from the reaction of o-phenylenediamine and α-keto-carboxylic acids [ 61 ].…”

“…The C2 chlorine is replaced by an ether linkage affixed to a benzene ring having a free aldehyde or amine group. The reaction Scheme 18, expounds the synthetic pathway to prepare 4-(2-methyl quinoxaline-3-yloxy)benzaldehyde (60) and N-((4-(2-methylquinoxaline-3yloxy)phenyl)methylene)-4-substituted benzenamine (63) using 2-chloro-3-methyl quinoxaline (59). A mixture of ( 59) and 4-hydroxy benzaldehyde was refluxed in acetonitrile for 30 h to afford (60) as an intermediate.…”

Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses

“…Quinoxaline and quinazoline and their derivatives are considered as important synthetic targets in anticancer drug discovery [ 19 , 20 , 21 , 22 , 23 , 24 ]. Quinazoline derivatives have been reported to exhibit cytotoxic activity against different cancer types via various mechanisms, including the inhibition of; epidermal growth factor receptor (EGFR) [ 25 ], or kinesin spindle protein (KSP) [ 26 ], interfering with: Wnt signaling pathway [ 27 ] and phosphatidylinositol-3-kinase (PI3K) [ 28 ], in addition to the downregulation of the antiapoptotic proteins Bcl2 and BclxL [ 29 ].…”

Cytotoxic Activity of Piperazin-2-One-Based Structures: Cyclic Imines, Lactams, Aminophosphonates, and Their Derivatives

“…For example, quinoxaline derivatives were studied as anticancer agents and apoptotic inducers against three lines of cancer cells, HCT116, HepG1, and MCF-7. The lead compound was found to cause a noticeable disruption in the cell cycle profile, and induced cell cycle arrest at the G2/M phase boundary [ 20 ]. On the other hand, in the investigation on antiproliferative activity of aminophosphonates by Huang et al, the authors concluded that the most promising derivative may induce apoptosis of SK-OV-3 cells through mitochondrion pathways [ 21 ].…”