Novel [2‘,5‘-Bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]- 3‘-spiro-5‘ ‘-(4‘ ‘-amino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide) Derivatives with Anti-HIV-1 and Anti-Human-Cytomegalovirus Activity

Abstract

New [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-d-ribofuranosyl]-3'-spiro-5' '-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives substituted at the 4' '-amino group of the spiro moiety with different carbonyl functionalities have been designed and synthesized. Various synthetic procedures, on the scarcely studied reactivity of the 3'-spiroaminooxathioledioxide moiety, have been explored. The compounds were evaluated for their inhibitory effect on both wild-type and TSAO-resistant HIV-1 strains, in cell culture. The presence of a methyl ester (10) or amide groups (12) at the 4''-position conferred the highest anti-HIV-1 activity, while the free oxalyl acid derivative (11) was 10- to 20-fold less active against the virus. In contrast, the presence at this position of (un)substituted ureido or acyl groups markedly diminished or annihilated the anti-HIV-1 activity. Surprisingly, some of the target compounds also showed inhibition of human cytomegalovirus (HCMV) replication at subtoxic concentrations. This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity.

Reactivity of the 4‐Amino‐5H‐1,2‐Oxathiole‐2,2‐Dioxide Heterocyclic System: A Combined Experimental and Theoretical Study

“…Thus, reaction of 5 a with chlorosulfonyl isocyanate in acetonitrile, followed by treatment with aqueous NaHCO 3 www.chemeurj.org longed reaction time (4 days) at room temperature. When this reaction was carried out in a pressure reaction vessel at 80 8C (general N-acylation conditions used in TSAO nucleoside derivatives), [14] the initially observed N-acyl group of 23 underwent migration to the enaminic C-3 carbon to give the C-acylated product 24 after three hours, in good yield (69 %). It should be noted that N-acylation of the b-aminog-sultone heterocyclic system at room temperature or C-acylation with acyl chlorides has never been observed previously in TSAO nucleoside derivatives.…”

“…It should be noted that N-acylation of the b-aminog-sultone heterocyclic system at room temperature or C-acylation with acyl chlorides has never been observed previously in TSAO nucleoside derivatives. [14] Other carbonyl electrophiles such as aldehydes (previously unexplored in TSAO nucleoside substrates) react with model sultone derivatives 5 a,b exclusively at the C-3 position of the enamine system (Scheme 3). Reaction of 5 b with benzaldehyde in dry THF in the presence of NaH at low temperature (À78 8C) afforded the 3-hydroxyphenylmethyl derivative 25 in low yield.…”

“…Modifications at the 4-position of the b-amino-g-sultone heterocyclic system, which have been previously reported to work smoothly in this system, such as acid hydrolysis of the enamino system, [6, 10a, 12] or substitution of this amino group by other amines through transamination reactions [14] were next addressed in our substrates (Scheme 5). In good agreement with previous results, hydrolysis of compounds 5 a,b with 1 n HCl in methanol afforded the expected b-keto-gsultone derivatives 32 a,b (Scheme 5) in good yields (85 and 76 %, respectively).…”

“…[13,14] However, the presence of tert-butyldimethylsilyl groups (TBDMS) at positions 2' and 5', sensitive to basic and acid media, respectively, but essential for the antiviral efficacy of the TSAO compounds, restricted the selection of smooth reaction conditions compatible with such groups. The corresponding b-keto-g-sultone, obtained by hydrolysis, [6, 10a] has been transformed to bamino and b-keto sulfonic acids by reductive opening of the ring.…”

Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: A single mode of inhibition for the three HIV enzymes?

“…Studies on the effect of these 3 -TSAO modified compounds on RT dimerization indicate that compound 2 seems to have a higher destabilizing effect dimerization than TSAO-T (unpublished results). In the series of TSAO compounds bearing different carbonyl functionalities at the 4 -position (de Castro et al, 2005), many analogues showed high anti-HIV-1 activity against viral replication, but these 4 -TSAO modified compounds did not show any improvement over the parent TSAO-T as dimerization inhibitors (unpublished results). On the other hand, substitutions at the N-3 position of the thymine base led to compounds endowed with a greater impact on RT dimerization (Bonache et al, 2005) suggesting that interactions with one or more of the dimer interface residues close to the TSAO binding site (Glu138) may help destabilize the RT dimer by disrupting key interface interactions.…”