Ring-expanded (Fat) purine nucleosides and nucleotides are of chemical, biochemical, biophysical and medicinal interest. From a chemical standpoint, their synthesis, structure, stability, acid-base properties, aromaticity, and tautomeric equilibria are interesting. From a biochemical perspective, they are an abundant source of substrates or inhibitors of enzymes of purine metabolism, as well as of those requiring energy cofactors. In biophysical terms, they are potentially excellent probes for nucleic acid structure, function, and metabolism. Medicinally, they offer a unique source of opportunities for anticancer and antiviral therapy. With regard to this latter aspect, a number of """"""""fat"""""""" nucleosides have recently exhibited potent, broad-spectrum antiviral and anticancer activities in vitro with little toxicity, if any, to the host cell lines. The antiviral activities include hepatitis B and C virus (HBV and HCV), West Nile virus (WNV), Epstein-Barr virus (EBV), Vericella Zoster virus (VZV), Japanese Encephalitis virus (JEV), Rhino virus (RV), Herpes Simplex (HSV-1 and HSV-2) viruses, and Measles virus (MV). The in vitro anticancer activities include leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. However, this proposal specifically focuses on the West Nile Virus (WNV) in light of the current health scare of this virus in US. The proposal concerns mechanistic investigations of viral replication employing a few """"""""fat"""""""" nucleosides that have exhibited potent in vitro anti-WNV activity. Two specific modes viral inhibition, which are deemed most viable, will be explored. Appropriate synthetic strategies have been put in place for further structural modifications of """"""""fat"""""""" nucleosides and nucleotides, contingent upon the outcome of the proposed mechanistic investigations, so as to eventually discover most potent antivirals against WNV with dismal, if any, human toxicity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Tseng, Christopher K
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University of Maryland Balt CO Campus
Schools of Arts and Sciences
United States
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Ujjinamatada, Ravi K; Phatak, Pornima; Burger, Angelika M et al. (2008) Inhibition of adenosine deaminase by analogues of adenosine and inosine, incorporating a common heterocyclic base, 4(7)-amino-6(5)H-imidazo[4,5-d]pyridazin-7(4)one. J Med Chem 51:694-8
Zhang, Peng; Zhang, Ning; Korba, Brent E et al. (2007) Structure-activity relationship studies on anti-HCV activity of ring-expanded ('fat') nucleobase analogues containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system. Bioorg Med Chem Lett 17:2225-8
Zhang, Peng; Zhang, Ning; Buckwold, Victor E et al. (2007) Chemical and biological effects of substitution of the 2-position of ring-expanded ('fat') nucleosides containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system: the role of electronic and steric factors on glycosidic bond stability and anti-HCV a Bioorg Med Chem 15:4933-45
Ujjinamatada, Ravi K; Baier, Andrea; Borowski, Peter et al. (2007) An analogue of AICAR with dual inhibitory activity against WNV and HCV NTPase/helicase: synthesis and in vitro screening of 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1-beta-D-ribofuranoside. Bioorg Med Chem Lett 17:2285-8
Ujjinamatada, Ravi K; Bhan, Anila; Hosmane, Ramachandra S (2006) Design of inhibitors against guanase: synthesis and biochemical evaluation of analogues of azepinomycin. Bioorg Med Chem Lett 16:5551-4
Ujjinamatada, Ravi K; Paulman, Robin L; Ptak, Roger G et al. (2006) Nucleosides with self-complementary hydrogen-bonding motifs: synthesis and base-pairing studies of two nucleosides containing the imidazo[4,5-d]pyridazine ring system. Bioorg Med Chem 14:6359-67
Ujjinamatada, Ravi K; Agasimundin, Yankanagouda S; Zhang, Peng et al. (2005) A novel imidazole nucleoside containing a diaminodihydro-S-triazine as a substituent: inhibitory activity against the West Nile virus NTPase/helicase. Nucleosides Nucleotides Nucleic Acids 24:1775-88
Zhang, Peng; Zhang, Ning; Korba, Brent E et al. (2005) Synthesis and in vitro anti-hepatitis B and C virus activities of ring-expanded ('fat') nucleobase analogues containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system. Bioorg Med Chem Lett 15:5397-401
Reayi, Ayub; Hosmane, Ramachandra S (2004) Inhibition of adenosine deaminase by novel 5:7 fused heterocycles containing the imidazo[4,5-e][1,2,4]triazepine ring system: a structure-activity relationship study. J Med Chem 47:1044-50
Reayi, Ayub; Hosmane, Ramachandra S (2004) Inhibitors of adenosine deaminase: continued studies of structure-activity relationships in analogues of coformycin. Nucleosides Nucleotides Nucleic Acids 23:263-71

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