Esther Lobaton

Novel Series of [ddN]-[TSAO-T] Heterodimers as Potential Bi-Functional Inhibitors of HIV-1 RT. Studies in the Linker and ddN Region

Novel series of [ddN]-(CH2)n-[TSAO-T] heterodimers have been prepared and tested for their anti-HIV-1 and HIV-2 activity. The most active compound of this series was the [d4T]-(CH2)3-[TSAO-T] heterodimer (EC50 = 0.018 +/- 0.03 microM).

4″-H-TSAO-T, A NOVEL PROTOTYPE IN THE HIV-1 SPECIFIC TSAO FAMILY

The first TSAO derivative that lacks the amino group at the 3′-spiro moiety has been prepared. This molecule retained its HIV-1 specificity (NNRTI characteristic) but did not select for any of the classical NNRTI-specific mutations in the NNRTI binding pocket, including 138-Lys (TSAO resistant strain).

“SECOND GENERATION” OF TSAO COMPOUNDS DIRECTED AGAINST HIV-1 TSAO-RESISTANT STRAINS

A “second generation” of TSAO molecules directed against TSAO-resistant strains have been prepared. The presence of two neighboring carbonyl groups at the 4″ position of the 3′-spiro moiety seems to be important for the anti-HIV-1 activity against both wild type and TSAO-resistant strains. NMR conformational studies in solution and theoretical calculations of the novel compounds have also been carried out.

Structure-activity relationship studies on a novel family of specific HIV-1 reverse transcriptase inhibitors.

We have previously reported the discovery and preliminary structure-activity relationships of a new class of specific HIV-1 reverse transcriptase (RT) inhibitors whose prototype compound is the 1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-[(carboxy) methyl]-thymine. In an attempt to increase the inhibitory efficacy against HIV-1 RT of this new class of nucleosides, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on the prototype compound. These include substitution of the tert-butyldimethylsilyl groups by other liphophilic groups, replacement of the carboxy group at the N-3 position of the nucleobase by other functional groups, change in the length of the spacer between the thymine and the carboxylic acid residue and substitution of the thymine moiety by other pyrimidine (uracil, 5-ethyluracil) or purine (hypoxanthine) nucleobases. In addition, the most salient structural features of this new class of HIV-1-specific nucleosides have been incorporated into classical HIV RT nucleoside inhibitors such as ddI, AZT, d4T. Our studies demonstrate that both the carboxymethyl moiety at the nucleobase and tert-butyldimethylsilyl groups at the sugar are important structural components since deletion of either of them is detrimental to the antiviral activity.

Identification of a novel family of nucleosides that specifically inhibit HIV-1 reverse transcriptase

N-3-Benzyloxycarbonylmethyl- and N-3-carboxymethyl-TBDMS-substituted nucleosides were synthesized and evaluated for activity against HIV replication. It was found that the N-3-carboxymethyl-TBDMS-substituted nucleosides were specific inhibitors of HIV-1 replication. They should be considered as members of a novel and original class of NNRTIs.

UNEXPECTED RESULTS IN THE REACTION OF 5'-TOSYL TSAO-M3T WITH AMINES

Abstract We report our strategies to prepare TSAO compounds carrying at 5′-position groups, such as amines, that may be positively charged at physiological conditions, unexpectedly, cyclic TSAO-derivatives were obtained. A possible mechanism for the formation of these unexpected compounds is advanced.