Design, Synthesis, and Anti-Cancer Evaluation of Novel Cyclic Phosphate Prodrug of Gemcitabine.

ProTide and cyclic phosphate ester are two successful prodrug technologies to overcome the limitations of nucleoside drugs, among which the cyclic phosphate ester strategy has not been widely used in the optimization of gemcitabine. Herein, we designed a series of novel ProTide and cyclic phosphate ester prodrugs of gemcitabine. Cyclic phosphate ester derivative exhibits much higher anti-proliferative activity than positive control NUC-1031 with ICs of 3.6-19.2 nM on multiple cancer cells. The metabolic pathway of demonstrates that 's bioactive metabolites prolong its anti-tumor activity. More importantly, we separated the two P chiral diastereomers of gemcitabine cyclic phosphate ester prodrugs for the first time, revealing their similar cytotoxic potency and metabolic profile. displays significant in vivo anti-tumor activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results suggest that compound is a promising anti-tumor candidate for treating human castration-resistant prostate and pancreatic cancer.