TSAO analogs. Stereospecific synthesis and anti-HIV-1 activity of 1-[2',5'-bis-O-(tert-butyldimethylsilyl)-.beta.-D-ribofuranosyl]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)pyrimidine and pyrimidine-modified nucleosides

Abstract

Several analogues of a new lead for anti-HIV-1 agents [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-thymine] -3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO) modified at positions N-3, O-4 and C-5 of the thymine moiety, have been prepared and evaluated as inhibitors of HIV-1 replication. A new stereoselective synthetic procedure is described. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with pyrimidine bases, followed by treatment with Cs2CO3 afforded stereoselectively, beta-D-ribofuranosyl-3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO derivatives. Only those analogues having a tBDMSi group at both the C-5' and C-2' positions of the ribose moiety showed potent anti-HIV-1 activity. The activity ranged from 0.060 microM to 1.0 microM. Introduction of an alkyl or alkenyl function at N-3 of the thymine ring markedly decreased cytotoxicity without affecting the antiviral activity. While markedly active against HIV-1, the TSAO derivatives had no activity against HIV-2 or SIV. They represent the first example of nucleoside analogues with an intact ribose moiety that discriminate between HIV-1 and other retroviruses.

Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives).

“…Synthesis of TSAO-m3T has been described (11,12 (13,14). The first set of primers (5'-GTAGAATTCT-GTTGACTCAGATTGG-3' and 5'-TTCTGCCAGTTCTA-GCTCTGCTTCT-3') gave a 900-bp product of the proviral RT gene.…”

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: Strategies to overcome drug resistance development

“…The thymine moiety of TSAO-T can be replaced by a number of pyrimidines, purines, and triazoles without marked decrease of activity.76J7 In particular, 5-substituted amido-, methylamido-, and dimethylamido-l,2,3-triazole derivatives are endowed with potent anti-HIV-1 activity, comparable to that of TSAO-T.77 Introduction of a lipophilic (i.e., methyl, ethyl or allyl) entity at the N-3 of the thymine ring or N-1 of the purine ring results in a significant decrease of cytotoxicity, without concomitant decrease of anti-HIV-1 activity, thus yielding derivatives (i.e., TSAO-m3T) with increased selectivity (relative to TSAO-T). 13,14,72,74 Within the a-APA series,*6 both 0-nitro-and 0-acetyl substituted anilino derivatives were found to inhibit HIV-1 replication at concentrations that were 1,000-to 100,000-fold lower than the cytotoxic concentration. In all cases the (-)enantiomers were considerably more active than the (+)enantiomers.…”

Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives

“…Among them, the [2',5'-bis-O-(tert-butyldimethylsilyl)-t3-Dribofu ra nosyl]-3'-spi ro-5"-[4"-a mino-1 ",2"-oxathiole-2",2"-dioxide]pyrimidines and -purines (TSAO; Fig. 12) are the only structures that closely resemble the nucleoside structure [110][111][112][113][114][115]. All these structurally different classes of anti-HIV compounds, including TSAO, have the following properties in common that discriminate them from the previously discussed 2',3'-dideoxynucleosides and acyclic nucleoside phosphonates: 9 they are potent and selective inhibitors of HIV-1, but not of HIV-2 or other (retro)viruses; 9 they are targeted at HIV-1 reverse transcriptase at a non-substrate-binding site and they prefer the artificial template poly(C).oligo(dG) over the other artificial templates; 9 they do not inhibit other viral or cellular DNA polymerases such as the DNA polymerases (~, /3, % 9 they are relatively non-toxic to human cells; 9 their antiviral selectivity index (ratio of cytotoxic concentration to antivirally effective concentration) in cell culture is very high (up to 100,000), and they rapidly select for highly resistant HIV-1 strains both in vitro and in vivo.…”