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

Emilie Evain-Bana,Lucie Schiavo,Christophe Bour,Don Antoine Lanfranchi,Simone Berardozzi,Francesca Ghirga,Denyse Bagrel,Bruno Botta,Gilles Hanquet,Mattia Mori

doi:10.1080/14756366.2016.1238364

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.

Highlights

Protein tyrosine phosphatases (E.C. 3.1.3.48) are a large family of enzymes that catalyze the removal of the phosphate group from tyrosine residues, and are widely expressed in mammals and other organisms[1,2]
Expression and activity of these enzymes are tightly regulated in physiological conditions, whereas abnormal expression of CDC25 has been detected in many high-grade tumors, such as breast, prostate, ovarian, endometrial, colorectal, esophageal, thyroid, gastric and hepatocellular cancers, glioma, neuroblastoma, non-Hodgkin lymphoma and acute myeloid leukemia[5,6,7]
Overexpression of CDC25 induces a bypass of cell cycle phases controls, allowing malignant cells to get through the phases and to divide, and has been correlated with tumor aggressiveness, high grade tumors and low vital prognosis for patients[8,9,10]

Summary

Introduction

Protein tyrosine phosphatases (E.C. 3.1.3.48) are a large family of enzymes that catalyze the removal of the phosphate group from tyrosine residues, and are widely expressed in mammals and other organisms[1,2]. Overexpression of CDC25 induces a bypass of cell cycle phases controls, allowing malignant cells to get through the phases and to divide, and has been correlated with tumor aggressiveness, high grade tumors and low vital prognosis for patients[8,9,10] Taken together, these evidences suggest that CDC25 phosphatases are promising targets for the development of anti-cancer therapies. A number of CDC25 inhibitors have been described in the literature[11,12,13], and some of them proved to be rather efficient[14] These compounds belong to various chemical classes, such as quinonoids, electrophilic inhibitors, thiophenic derivatives, phosphate surrogates and coumarins15,16) and were obtained by multiple sources, including organic synthesis, or marine organisms extraction[17]. It is worth mentioning that Georgantea et al have recently identified two CDC25 inhibitors among 21 sesquiterpenes isolated from the Caribbean soft coral Pseudopterogogia rigida[18]

Methods

Results

Conclusion