This Is AuburnElectronic Theses and Dissertations

8-Alkyl Adenines and Their Nucleoside Derivatives




Abouelghit, Maha

Type of Degree



Chemistry and Biochemistry


S-adenosylhomocysteine hydrolase has become an important target in the design of antiviral drugs. It is the only known enzyme in eukaryotes that is responsible for the catabolism of S-adenosylhomocysteine into adenosine and L-homocysteine. S-adenosylhomocysteine is both a product and potent feedback inhibitor of methylation reactions involving S-adenosylmethionine as a methyl donor. By inhibition of the methylation reactions responsible for formation of the mRNA 5ʹ-cap required by most viruses for proper translation, the viral replication process is inhibited as well. Two carbocyclic nucleosides: aristeromycin and neplanocin have been shown to possess broad spectrum antiviral properties with severe toxicity. They have been used as templates for design of antiviral agents that retain the antiviral properties without the toxic side effects. Purine ribofuranosyl nucleosides substituted in the 8-position have shown usefulness as probes for the study of nucleoside structural conformations. Based on the nature of the purine 8-susbtituent, the nucleoside can exist in a syn/anti equilibrium that shifts from a preferred anti arrangement towards the syn conformation that may become purely syn depending on the 8-substituent. In this research, a group of purine carbocyclic nucleosides with variable alkyl substituents were studied theoretically and synthetically with the intent of exploring their conformational parameters that could lead to correlation with biological activity. A theoretical methodology, the density functional theory with various basis sets, was used to predict the structural parameters: phase angle of pseudorotation, the degree of pucker and the glycosyl torsion angle of the carbocyclic nucleosides. The results were compared to experimental data either obtained from the literature or generated within this research. The investigation was aimed at identifying the conformations that attribute to the observed experimental data as well as assessing the contribution of each conformation to the overall structure. The research also focused on studying the relationship between syn/anti conformation and the pseudorotation of the cyclopentyl moiety in carbocyclic nucleosides and extrapolating the findings from the 8-alkyl substituted carbocyclic nucleoside. A final aspect was providing the basis for uncovering a correlation between the syn/anti conformation and the biological activity of purine derived carbocyclic nucleosides, which was beyond the scope of this dissertation research. To avail authentic carbocyclic nucleoside samples for this study, synthetic procedures were developed that called upon pyrimidine and cyclopentane/cyclopentene precursors. In that effort the Mitsunobu and Luche reactions and the Grubbs metathesis procedures were employed. The required compounds were obtained in overall reasonable yields and their structures verified by x-ray crystallography and a thorough NMR analysis using contemporary, multi-dimensional methods.