Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases

Abstract

The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.1.3.48) are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors. The most promising molecules proved to inhibit CDC25 isoforms at single digit micromolar concentration, becoming valuable tools in chemical biology investigations and profitable leads for further optimization.

Keywords:

• CDC25
• enzyme inhibitors
• quinonoid
• organic synthesis
• molecular modeling

Acknowledgements

Authors are sincerely grateful to Dr. Nadine Martinet for her networking efforts and profitable discussions. The authors wish to acknowledge networking contribution by the COST Actions CM1106 “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells” and CM1407 “Challenging organic syntheses inspired by nature – from natural products chemistry to drug discovery”. The authors wish to thank the OpenEye Free Academic Licensing Program for providing a free academic license for molecular modeling and chemoinformatics software.

Disclosure statement

The authors report no conflicts of interest.