Document 0422
 DOCN  M9620422
 TI    Design, synthesis, and structure-activity relationship of novel
       dinucleotide analogs as agents against herpes and human immunodeficiency
       viruses.
 DT    9602
 AU    Hakimelahi GH; Moosavi-Movahedi AA; Sadeghi MM; Tsay SC; Hwu JR;
       Organosilicon and Synthesis Laboratory, Institute of Chemistry,;
       Academia Sinica, Nankang, Taipei, Taiwan, Republic of China.
 SO    J Med Chem. 1995 Nov 10;38(23):4648-59. Unique Identifier : AIDSLINE
       MED/96068833
 AB    A new acyclic nucleoside phosphonate (13) containing an adenine moiety
       was synthesized, which acted as an excellent inhibitor of calf mucosal
       adenosine deaminase. This inhibitory property allows it to exert great
       synergistic effect on certain antiviral agents (e.g., ara-A, 37).
       Phosphonate 13 was not phosphorylated by the bovine brain guanylate
       kinase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of
       biologically active nucleotide phosphonate 40 and its phosphonoamidate
       derivative 42 were accomplished, which showed remarkable activity
       against herpes viruses and exhibited low host cell toxicity.
       3'-Azido-nucleoside phosphonate 20 and 3'-fluoronucleoside phosphonate
       32, as well as the corresponding dinucleotide analogs 47 and 48, and
       their respective phosphonoamidates 53-56 were also synthesized as new
       compounds, among which phosphonoamidates 53-56 showed potent activity
       against human immunodeficiency virus. Phosphonoamidates 55 and 56
       bearing a methyl D-alaninate moiety exhibited less cellular toxicity
       than 53 and 54 bearing a methyl L-alaninate moiety. Nucleotide
       phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found
       susceptible to degradation by phosphodiesterases. Their respective
       phosphonoamidates 42 and 53-56, however, were completely resistant to
       snake venom and spleen enzymes.
 DE    Adenosine Deaminase/ANTAGONISTS & INHIB  Animal  Antiviral
       Agents/CHEMISTRY/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Brain/ENZYMOLOGY
       Cattle  Dinucleoside Phosphates/CHEMISTRY/*CHEMICAL SYNTHESIS/
       PHARMACOLOGY  *Drug Design  Drug Synergism  Enzyme
       Inhibitors/PHARMACOLOGY  Guanylate Cyclase/METABOLISM
       Herpesviridae/*DRUG EFFECTS  Herpesvirus 1, Human/DRUG EFFECTS
       Herpesvirus 2, Human/DRUG EFFECTS  HIV-1/*DRUG EFFECTS  Kinetics
       Molecular Structure  Phosphonic Acids/CHEMICAL SYNTHESIS  Phosphoric
       Diester Hydrolases/METABOLISM  Phosphorylation  Ribose-Phosphate
       Pyrophosphokinase/METABOLISM  Structure-Activity Relationship  Support,
       Non-U.S. Gov't  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).