This project involves the synthesis and biochemical/biophysical investigations of novel ring-expanded (""""""""fat"""""""") purine and ring-contracted (""""""""slim"""""""") pyrimidine nucleosides and nucleotides. With judicious atom insertion at the ring loci and functionalization of the ring periphery, these """"""""fat"""""""" and """"""""slim"""""""" nucleotides are potentially capable of Watson-Crick base-pair hydrogen bonding with appropriate pyrimidine partners. Because of their unique structures, these aberrant nucleotides are excellent probes for nucleic acid structure, function, and metabolism. Our studies are directed toward a) synthesizing various """"""""fat"""""""" and """"""""slim"""""""" nucleosides and nucleotides and constructing double helices, b) investigations of base-pairing and stacking interactions of homo- and heteropolymer duplexes incorporated with """"""""fat"""""""" or """"""""slim"""""""" nucleotides, c) explorations of structural and spatial limitations of formation of double helices, as well as of helical structure, stability and conformations, d) biochemical investigations to determine the potential of """"""""fat"""""""" and """"""""slim"""""""" nucleosides and nucleotides to act as substrates or inhibitors of various enzymes of nucleic acid metabolism. Using these analogs, base-mispairing accompanied by considerable deviation of base-sugar bond deviation from the natural array can potentially result in chain termination of the developing DNA during reverse transcription of a retroviral RNA genome such as that of the human immunodeficiency virus (HIV), the etiologic agent causing the acquired immunodeficiency syndrome (AIDS). """"""""Fat"""""""" and """"""""slim"""""""" nucleosides and nucleotides, are, therefore, potential chain terminators operating by this mechanism. Low-resolution and high-resolution FAB-MS has been used extensively to characterize these synthetic products.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR000480-27
Application #
5220562
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
27
Fiscal Year
1996
Total Cost
Indirect Cost
Peri, S P; Bhadti, V S; Somerville-Armstrong, K S et al. (1999) Affinity reagents for cross-linking hemoglobin: bis(phenoxycarbonylethyl)phosphinic acid (BPCEP) and bis(3-nitrophenoxycarbonylethyl)phosphinic acid (BNCEP). Hemoglobin 23:1-20
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
Bretner, M; Beckett, T D; Sood, R K et al. (1999) Substrate/inhibition studies of bacteriophage T7 RNA polymerase with the 5'-triphosphate derivative of a ring-expanded ('fat') nucleoside possessing potent antiviral and anticancer activities. Bioorg Med Chem 7:2931-6
Rajappan, V P; Hosmane, R S (1998) Analogues of azepinomycin as inhibitors of guanase. Nucleosides Nucleotides 17:1141-51
Agasimundin, Y S; Mumper, M W; Hosmane, R S (1998) Inhibitors of glycogen phosphorylase b: synthesis, biochemical screening, and molecular modeling studies of novel analogues of hydantocidin. Bioorg Med Chem 6:911-23
Hosmane, R S; Peri, S P; Bhadti, V S et al. (1998) Bis[2-(4-carboxyphenoxy)carbonylethyl]phosphinic acid (BCCEP): a novel affinity reagent for the beta-cleft modification of human hemoglobin. Bioorg Med Chem 6:767-83
Hosmane, R S; Hong, M (1997) How important is the N-3 sugar moiety in the tight-binding interaction of coformycin with adenosine deaminase? Biochem Biophys Res Commun 236:88-93
Lopez-Lara, I M; Orgambide, G; Dazzo, F B et al. (1993) Characterization and symbiotic importance of acidic extracellular polysaccharides of Rhizobium sp. strain GRH2 isolated from acacia nodules. J Bacteriol 175:2826-32
Watson, J T; Kayganich, K (1989) Novel sample preparation for analysis by electron capture negative ionization mass spectrometry. Biochem Soc Trans 17:254-7
Kassel, D B; Kayganich, K A; Watson, J T et al. (1988) Utility of ion source pretreatment with chlorine-containing compounds for enhanced performance in gas chromatography/negative ionization mass spectrometry. Anal Chem 60:911-7

Showing the most recent 10 out of 11 publications