Sulfonyl-containing nucleoside phosphotriesters and phosphoramidates as novel anticancer prodrugs of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP).
A series of sulfonyl-containing 5-fluoro-2'-deoxyuridine (FdU) phosphotriester and phosphoramidate analogues were designed and synthesized as anticancer prodrugs of FdUMP. Stability studies have demonstrated that these compounds underwent pH dependent beta-elimination to liberate the corresponding nucleotide species with half-lives in the range of 0.33-12.23 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 degrees C. Acceleration of the elimination was observed in the presence of human plasma. Compounds with an FdUMP moiety (4-9) were considerably more potent than those without (1-3) as well as 5-fluorouracil (5-FU) against Chinese hamster lung fibroblasts (V-79 cells) in vitro. Addition of thymidine (10 microM) reversed the growth inhibition activities of only 5-FU and the compounds with an FdUMP moiety, but had no effect on those without. These results are consistent with thymidylate synthase as the target of the prodrugs.
Sun
Yuan-Wan
YW
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439, USA.
Chen
Kun-Ming
KM
Kwon
Chul-Hoon
CH
D000586:Amination; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D004952:Esters / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D010758:Phosphorus / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000970:Antineoplastic Agents; D004952:Esters; C435305:FdUMP(10); D009705:Nucleosides; D011355:Prodrugs; D005468:Fluorodeoxyuridylate; D010758:Phosphorus; D005461:Fluorine; D013936:Thymidine