Synthesis and biological activity of N-2,3-dihydroxypropyl-N-4-chlorobutyl nucleoside phosphoramidate prodrugs.
N-2,3-dihydroxypropyl-N-4-chlorobutyl phosphoramidate prodrugs of thymidine and 5-fluoro-2'-deoxyuridine (5-FdU) 2-4 were synthesized as analogues of the known prodrugs 1a,b to assess the effects of the dihydroxypropyl moiety on prodrug activation, log P, and growth inhibitory activity in vitro. The thymidine analogues 2 and 3 were prepared as model compounds for kinetics and log P studies. 31P NMR kinetics following hydrogenolysis of 2 showed that the thymidine N-dihydroxypropyl phosphoramidate released thymidine monophosphate with a half-life of 212 min under model physiologic conditions compared to approximately 2 min for the corresponding N-methyl phosphoramidate reported previously. The measured log P for compound 3 was 1.1 log units lower than that of the analogous 1b, confirming that the dihydroxypropyl group significantly decreased prodrug lipophilicity. The dihydroxypropyl prodrug 4 showed cell growth inhibition activity in the NCI 60 cell line panel similar to that of the N-methyl analogue 1a previously reported.
Wu
Weidong
W
Department of Medicinal Chemistry and Molecular Pharmacology and Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Borch
Richard F
RF
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; D000970:Antineoplastic Agents; D010756:Phosphoric Acids; D011355:Prodrugs; D005467:Floxuridine; C011067:phosphoramidic acid; D013936:Thymidine