RESUMEN
A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.
Asunto(s)
Adipatos/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , Imitación Molecular , Péptidos/química , Adipatos/química , Adipatos/farmacología , Animales , Línea Celular , Cristalografía por Rayos X , Proteasa del VIH/biosíntesis , Proteasa del VIH/aislamiento & purificación , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/enzimología , Ratones , Relación Estructura-ActividadRESUMEN
In order to obtain rigidity within the sugar moiety of nucleosides, some bicyclic pyrimidine nucleoside analogues were synthesized starting from cyclopentanone. The C-3' is fused to C-4' via a propylene linker in order to obtain a [3.3.0]-bicyclic ring system wherein the sugar moiety should be restricted to mainly the C-1'-exo conformation.