Synthesis and antiviral activity of aryl phosphoramidate derivatives of beta-D- and beta-L-C-5-substituted 2',3'-didehydro-2',3'-dideoxy-uridine bearing linker arms.
We have previously reported the synthesis and evaluation of potent anti-human immunodeficiency virus compounds based on beta-D-d4T analogues bearing a tether attached at the C-5 position and their beta-L-counterparts. Initial study revealed a requirement for an alkyl side-chain with an optimal length of 12 carbons for a weak antiviral activity. As a continuation of that work, we have now prepared the corresponding phosphoramidate derivatives as possible membrane-permeable prodrugs. Phosphorochloridate chemistry gave the target phosphoramidates which were tested for anti-human immunodeficiency virus type 1 activity; unfortunately, they were devoid of anti-HIV activity.
Ladurée
Daniel
D
Centre d'Etudes et de Recherche sur le Médicament de Normandie, U. F. R. des Sciences Pharmaceutiques, 5, Rue Vaubénard, F-14032, Caen Cedex, France. daniel.laduree@unicaen.fr
Fossey
Christine
C
Delbederi
Zoica
Z
Sugeac
Elena
E
Schmidt
Sylvie
S
Laumond
Geraldine
G
Aubertin
Anne-Marie
AM
D000577:Amides / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry
D000577:Amides; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D014542:Uridine Monophosphate