Synthetic studies to access carbanucleosides targeting adenosine receptors.

RODRIGUEZ, JUAN BAUTISTA; DE DIEGO SAADIA, SHEILA I.; SZAJNMAN, SERGIO HERNÁN

Lisboa

Simposio; 29th International Carbohydrate Symposium (ICS 2018); 2018

International Carbohydrate Organization

The aglycone of a specific nucleoside unit exists in a dynamic equilibrium between Northern geometry and the respective antipodal Southern conformation according to the pseudorotational cycle defined by Altona.[1] On the other hand, biological activity of nucleosides is toughly influenced by sugar conformation, which is modulated not only by the anomeric effect but also by the nature and the stereochemistry of the functional groups present in the sugar moiety affecting shaping and puckering of the ring. Hence, this conformation does control and facilitate reactions between nucleosides and specific enzymes involved in the sequence of activation leading to active metabolites triphosphates. However, the difficult of relating the favored sugar conformation in solution by an enzyme is its flexibility not found in the crystal state. For example, the crystal structure of dideoxycytidine is observed in the Southern geometry, whereas in solution is found in close to 80% in the Northern conformation. Nevertheless, cyclopentenyl nucleosides that are conformationally locked into either the N- or the S-geometry have been employed to study the preferred conformation for molecular recognition,[2] bearing in mind that a three-membered ring (cyclopropane, epoxide, thiirane) fused to a cyclopentane moiety, in an appropriate position, proved to be a suitable pseudosugar that fixes the conformation of a carbocyclic nucleoside in one of the extreme antipodes. [1] W. Saenger in Principles of Nucleic Acid Structure, Springer-Verlag, New York, 1983, pp. 51104.[2] J. B. Rodriguez, M. J. Comin. Mini Rev. Med. Chem. 2003, 3, 95?114.[3] K. A. Jacobson, D. K. Tosh, K. S. Toti, A. Ciancetta. Drug Discov. Today 2017, 22, 1782?1791.