Novel Quinoxaline-2-Carbonitrile-1,4-Dioxide Derivatives Suppress HIF1α Activity and Circumvent MDR in Cancer Cells

Abstract

A series of 3-aryl/hetarylquinoxaline-2-carbonitrile-1,4-dioxides was synthesized and evaluated against breast cancer cell lines in normoxia and hypoxia. Selected compounds in this series demonstrated better cytotoxicity and comparable hypoxia selectivity than tirapazamine. In contrast to Dox, quinoxaline-1,4-dioxides showed potent cytotoxicity against different MDR cells. Compound 2g inhibits of cancer cell growth through p53-independent mechanisms. Our results showed that compound 2g sensitized MCF-7 cells to metformin in hypoxia. Treatment with 2g results in the increase of ROS accumulation in cancer cells. Compound 2g can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents.

Synthesis of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: a way forward for targeting hypoxia and drug resistance of cancer cells

“…Selected derivatives have shown a high hypoxia selectivity and antiproliferative potency against a panel of wild-type and drug-resistant tumor cell lines. 9 Additionally, in an in-depth study of the Beirut reaction between monosubstituted benzofuroxans and benzoylacetonitrile, we identied isomeric 6(7)-monosubstituted quinoxaline-2carbonitrile 1,4-dioxide, 2, which demonstrated signicant differences in biological activity. Thus, in search for new knowledge regarding the possibility of chemical modication of the quinoxaline scaffold and for further exploration of the structureactivity relationships for quinoxaline-2-carbonitrile 1,4-dioxides, a novel water-soluble derivative with residues of cyclic diamines was obtained.…”

“…Based on the structural similarity between TPZ and quinoxaline 1,4-dioxide, a series of quinoxaline-2-carbonitrile 1,4-dioxides, 2-4 (ref. [6][7][8][9], have been synthesized and evaluated. Selected derivatives have shown a high hypoxia selectivity and antiproliferative potency against a panel of wild-type and drug-resistant tumor cell lines.…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…The faster release of MET enhances the cytotoxicity of DOX by reducing hypoxic stress in vivo and in vitro. MET diminished the cell oxygen consumption and inhibited the expression of HIF1α and P-glycoprotein (Pgp) in vitro [179]. In addition, the dual-drug loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, indicating that the tumor reoxygenation effect of MET promotes its synergistic effect with DOX to combat MCF7/ADR xenografts.…”

Novel Water-Soluble Far-Red Nitroreductase-Responsive Bodipy-Based Fluorescent Probe for the Detection of Hypoxic Status in A549 Non-Small Cell Lung Cancer Cells

“…Previously, we modified the method, in order to provide a more stable and reliable fluorescence signal in molecular biology experiments. 25,26 The advantage of this method is the rapid processing of NBB-containing cells with a PBS/DMSO (9:1, v/v) solution. The prepared samples were transferred to black 96-well plates and analyzed at 610/680 nm using the microplate reader.…”