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.
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439, USA.
Yuan-Wan
YW
Sun
Kun-Ming
KM
Chen
Chul-Hoon
CH
Kwon
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