title: Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation.
abstract: The prodrug strategy has been explored frequently for a number of marked drugs to obtain better pharmaceutical properties and efficacy and safety profiles. For gemcitabine, a nucleoside analog that has been used widely as a chemotherapeutic agent for the treatment of a variety of cancers, the protection of the amino group from extensive deamination and increase of permeability have been used for oral prodrug development. In the present study, several novel and proprietary monophosphate ester prodrugs of gemcitabine representing different "tail" structures were evaluated for their antiproliferation activities in various tumor cell lines. As compared to LY2334737, a prototype oral prodrug of gemcitabine, the monophosphate ester prodrugs exhibited superior in vitro antiproliferation activity. Among those, compound-3 emerged as a promising prodrug candidate. Data revealed that cellular concentrations of compound-3 were correlated well with its antiproliferation activity and its cellular uptake did not involve human equilibrative nucleoside transporter, suggesting a potential to treat gemcitabine resistant tumors. Compound-3 demonstrated equal or better antitumor efficacy after oral administration as compared to intraperitoneally injected gemcitabine. Taken together, compound-3 has the potential for further development as an orally active antitumor agent.
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Qi
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Li
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Yedong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center For Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Electronic address: zhanghongjian@suda.edu.cn.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004952:Esters; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004952:Esters; D011355:Prodrugs; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: antiproliferation; gemcitabine; hENT; monophosphate ester; prodrug