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 18c exhibits much higher anti-proliferative
activity than positive control NUC-1031 with IC50s of 3.6–19.2
nM on multiple cancer cells. The metabolic pathway of 18c demonstrates that 18c’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. 18c displays significant in vivo anti-tumor
activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results
suggest that compound 18c is a promising anti-tumor candidate
for treating human castration-resistant prostate and pancreatic cancer.