Design, Synthesis and Evaluation of 1,3,2 Diazaphosphorin[4,5- b]Quinoxaline-5,10-di-N-oxide Derivatives as Novel VEGFR-2 and SRC Kinase Inhibitors in the Treatment of Prostate Cancer

ABSTRACT

Prostate cancer remains a significant public health problem, with limited therapeutic options. Recently, new approaches in prostate cancer treatment have been developed, inhibition of the proangiogenic VEGFR kinase and SRC kinase, involved in progression and metastasis of prostate cancer were investigated. A new series of 1,3,2diazaphosphorin[4,5-b]quinoxaline-5,10-di-N-oxide was synthesized using Lawson’s reagent in a reaction that provides a rare example of the incorporation of phosphorous. The structure of the new compounds was confirmed by spectroscopic data. The new synthesized compounds were evaluated for their in-vitro prostate cancer cell line (PC3). Compounds 7a and 8a possessed remarkable antitumor activity more active than the known drug Doxorubicin with IC50= 0.12, 0.36 and 0.63 μM respectively. Evaluation of the new synthesized compounds on VEGFR-2 and SRC kinases showed that compound 7a was the most effective with IC50= 18μM. On the other hand, weak inhibitory effect was observed by the compounds on SRC kinase. Docking study was performed for compound 7a into ATP binding site of VEGFR-2 kinase.

Keywords:

Diazaphosphorin, quinoxaline 1,4-di-N-oxides, prostate cancer.