Potential Multifunctional Inhibitors of HIV-1 Reverse Transcriptase. Novel [AZT]-[TSAO-T] and [d4T]-[TSAO-T] Heterodimers Modified in the Linker and in the Dideoxynucleoside Region

Abstract

In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer on activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important for the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was approximately 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Thus, Velázquez et al prepared AZT, d4T, and thymidine heterodimers with TSAO-T as potential inhibitors of HIV-1 reverse transcriptase. 222 Thymidine aryloxyphosphoramidate prodrug formation was performed using 2 equiv of phosphorochloridate 340 and 6 equiv of NMI (Scheme 132). The corresponding nucleoside phosphoramidate underwent N 3 -alkylation with 1,3-dibromopropane, and 444 was then coupled to TSAO-T using potassium carbonate.…”

A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity

“…The improvements in activity over d4T (stauvidine) were marginal, but some activity against nevirapine resistant and HIV-2 virus' were observed. The compounds were approximately ten-fold less active against HIV IIIB in MT-4 [92]. The most potent of these analogs had an EC 50 = 0.04 µM in MT-4 cells.…”

Synthesis and EPR Studies of 2′‐Deoxyuridines with Alkynyl, Rodlike Linkages

“…For example, DNA duplexes with interstrand cross-linkers, [i],[ii],[iii],[iv],[v],[vi] hydrogen (Watson-Crick) base pair bonding models (Figure 1), [vii],[viii] inhibitors of ribonucleotide reductase [ix] or HIV reverse transcriptase, [x] a model of the mechanism for the repair of DNA photolesion, [xi] supramolecular self-assembly, [xii] as well as protein binding [8] have all been studied with their aid. Some of the interstrand cross-linked oligonucleotides exhibit interesting biological properties such as thrombin inhibition.…”