Synthesis, chemistry and biochemistry of a family of """"""""fat"""""""" nucleosides and nucleotides possessing the following 5:7-fused heterocyclic base systems will be studied: I) imidazo(4,5,e)(1,3,4)triazepine; II) imidazo(4,5-e)(1,4)diazepine; and III) imidazo(4,5,d)(1,3)diazepine. The novel rearrangement discovered in the heterocyclic system of category I will be further explored for wide synthetic utility. The mono- and diphosphate derivatives of nucleosides of category II will be prepared. The diphosphates will be polymerized by using the enzyme polynucleotide phosphorylase and the resulting homopolymer templates will be evaluated for substrate/inhibitory activity against Moloney murine leukemia virus (M-MuLV) reverse transcriptase. These studies will be extended to """"""""fat"""""""" nucleoside/nucleotide systems of categories I & III. The target and intermediate nucleosides and heterocycles will be screened for potential antitumor activity by the National Cancer Institute. The ongoing collaborative arrangements with Professor E. De Clercq of Katholieke University, Leuven, Belgium will enable testing of the above compounds for antiviral activity in a broad range of viral assay systems. Preliminary studies on the 5:8-fused heterocylic systems will be continued. As a secondary goal, double helical complexes will be prepared by pairing the above """"""""fat"""""""" nucleotide homopolymers with appropriate pyrimidine counterparts, and investigated for stability, stacking interactions and conformational characteristics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071079-03
Application #
2733233
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Forry-Schaudies, Suzanne L
Project Start
1996-07-15
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Maryland Balt CO Campus
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21250
Borowski, Peter; Lang, Melanie; Haag, Annemarie et al. (2002) Characterization of imidazo[4,5-d]pyridazine nucleosides as modulators of unwinding reaction mediated by West Nile virus nucleoside triphosphatase/helicase: evidence for activity on the level of substrate and/or enzyme. Antimicrob Agents Chemother 46:1231-9
Sood, Ramesh K; Bhadti, Vishweshwar S; Fattom, Ali I et al. (2002) Novel ring-expanded nucleoside analogs exhibit potent and selective inhibition of hepatitis B virus replication in cultured human hepatoblastoma cells. Antiviral Res 53:159-64
Zhang, Ning; Chen, Huan-Ming; Sood, Ramesh et al. (2002) in vitro inhibition of the measles virus by novel ring-expanded ('fat') nucleoside analogues containing the imidazo[4,5-e]diazepine ring system. Bioorg Med Chem Lett 12:3391-4
Hosmane, Ramachandra S (2002) Ring-expanded (""Fat"") nucleosides as broad-spectrum anticancer and antiviral agents. Curr Top Med Chem 2:1093-109
Chen, H M; Hosmane, R S (2001) Acyclic nucleoside/nucleotide analogues with an imidazole ring skeleton. Nucleosides Nucleotides Nucleic Acids 20:1599-614
Gill, J K; Wang, L; Bretner, M et al. (2001) Potent in vitro anticancer activities of ring-expanded (""fat"") nucleosides containing the imidazo[4,5-e][1,3]diazepine ring system. Nucleosides Nucleotides Nucleic Acids 20:1043-5
Wang, L; Hosmane, R S (2001) A unique ring-expanded acyclic nucleoside analogue that inhibits both adenosine deaminase (ADA) and guanine deaminase (GDA; guanase): synthesis and enzyme inhibition studies of 4,6-diamino-8H-1-hydroxyethoxymethyl-8-iminoimidazo[4,5-e][1,3]diazepine. Bioorg Med Chem Lett 11:2893-6
Bretner, M; Beckett, D; Hosmane, R S (1999) Potent anti-hepatitis B viral activity and inhibition of bacteriophage T7 RNA polymerase by a ""fat"" nucleoside and its 5'-triphosphate derivative: synthetic, biochemical, and biological studies of 4,8-diamino-6-imino-6H-1-beta-D-ribofuranosyl-imidazo[4, Nucleosides Nucleotides 18:837-8
Chen, H M; Sood, R; Hosmane, R S (1999) An efficient, short synthesis and potent anti-hepatitis B viral activity of a novel ring-expanded purine nucleoside analogue containing a 5:7-fused, planar, aromatic, imidazo[4,5-e][1,3]diazepine ring system. Nucleosides Nucleotides 18:331-5
Rajappan, V P; Hosmane, R S (1999) Investigations into biochemical mode of inhibition of guanase by azepinomycin: synthesis and biochemical screening of several analogues of azepinomycin. Nucleosides Nucleotides 18:835-6

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