ABASIC ANALOGS OF TSAO-T AS THE FIRST SUGAR-DERIVATIVES THAT SPECIFICALLY INHIBIT HIV-1 REVERSE-TRANSCRIPTASE

With the aim of assessing the role that the thymine base of TSAO-T may play in the interaction of TSAO compounds with HIV-1 reverse transcri ptase (RT), we have designed, synthesized, and evaluated for their ant i-HIV-1 activity a series of 3-spiro sugar derivatives substituted at the anomeric position with nonaromatic rings or with amine, amide, ure a, or thiourea moieties that mimic parts or the whole thymine base of TSAO-T. Also, a dihydrouracil TSAO analogue and O-glycosyl S-spiro sug ar derivatives substituted at the anomeric position with methyloxy or benzyloxy groups have been prepared. Compounds substituted at the anom eric position with an azido, amino, or methoxy group, respectively, we re devoid of marked antiviral activity (EC50: 10-200 mu M). However, t he substituted urea sugar derivatives led to an increase in antiviral potency (EC50: 0.35-4 mu M), among them those urea derivatives that mi mic most closely the intact TSAO-T molecule retained the highest antiv iral activity. Also, the dihydrouracil TSAO derivative retained pronou nced anti-HIV-1 activity. None of the compounds showed any anti-HIV-2 activity. The results described herein represent the first examples of sugar derivatives that interact in a specific manner with HIV-1 RT. M olecular modeling studies carried out with a prototype urea derivative indicate that a heteroaromatic ring is not an absolute requirement fo r a favorable interaction between TSAO-T and HIV-1 RT. Urea derivative s, which can mimic to a large extent both the shape and the electrosta tic potential of a thymine ring, can effectively replace this nucleic acid base when incorporated into a TSAO molecular framework with only moderate loss of activity.