Solution Conformation of the Anti-HIV-Active Compound (S,S)-Isodideoxyadenosine

Abstract

In the design of novel dideoxynucleosides with anti-HIV activity, a variety of structure–activity correlations are being investigated, including the correlation of activity with conformation of the active compounds in solution. Using multiple 1-D and 2-D NMR techniques and computational analyses, the preferred conformation in solution of the anti-HIV active compound (S,S)-isodideoxyadenosine was determined. These studies showed that there are two preferred conformations of the carbohydrate moiety in solution. Almost 58% of the population is in the northern conformation (P = −43.3°, 1T2) of the pseudo-rotation cycle and 42% is in the southern hemisphere (P = 197.9°, 3E). The x-ray crystallographic data showed that the compound crystallized out in the 10T conformation (P = 108°). In addition, the NMR studies confirmed the anti conformation of the base about the ‘glycosidic’ bond and gave information on the orientation of the hydroxymethyl group [pγ+ = 0.49 (gg) with the remaining 51% being part γt(ap) and part γ].