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.

KEYWORDS:

• Antiproliferative activity
• drug resistance
• HIF1α activity suppression
• hypoxia
• quinoxaline-2-carbonitrile-1,4-dioxide

Acknowledgments

The authors thank Dr. Yu. N. Luzikov, Dr. A. M. Korolev, N. Maliutina (Gause Institute of New Antibiotics) for NMR, ESI HRMS and HPLC analyses. The HRE-LUC and P53-LUC plasmid were kindly provided by Dr. Giovanni Melillo and Prof. Victor Adler, respectively. We thank Dr. Irina Zhitnyak for consulting and kindly help with fluorescence microscopy.

Declaration of interest

The authors report no conflicts of interest.

Additional information

Funding

The biology experiments of the research were supported by RSF 14-15-00362.