Conformational effects of purine N3 electronic properties on drug design and cyclic nucleotide metabolism

Abstract

The conformational effect of variations in electronic properties at the N3 position of purines, purine analogs, and cyclic AMP analogs are related to their biological properties. The effect of glycosidic conformation is demonstrated for the adenosine analogs 2-azaadenosine and 2-fluoroadenosine by both theoretical calculations and T1 relaxation measurements. For these two analogs there is increased preference for the high anti conformations. The high anti conformation is considered to be required of purine substrates by the enzymes adenosine kinase and deoxycytidine kinase as well as adenylate cyclase activating adenosine receptors. Protein kinase II is considered as requiring an anti conformation for activation by cyclic AMP analogs, and an anti conformation may also be required at adenylate cyclase inhibiting adenosine receptors. The selective activation approach for designing nucleoside analogs is described. Selective therapeutic potential as antiparasitic, antiviral, antibacterial, or anticancer agents can be achieved with nucleoside analogs. The successful implementation of the selective activation approach depends on a precise understanding of the conformation and electronic specificity of normal versus disease associated nucleoside kinases and deoxynucleoside kinases. The conformation specificity of normal adenosine kinase and deoxycytidine kinase enzymes appears to be established. Less specific or alternative pathways leading to the formation of toxic nucleotide analogs are known to exist in bacteria, parasites, virus infections, and cancer. If the conformational, electronic, and functional group requirements for normal enzyme activation are removed in a nucleoside analog, then it can be selectively activated to a toxic form by the enzyme mechanisms available to a target disease. The target disease, by converting a nucleoside analog to a toxic form, will destroy itself with little or no damage anticipated for the host.