TSAO-T Analogues Bearing Amino Acids at Position N-3 of Thymine: Synthesis and Anti-Human Immunodeficiency Virus Activity

Novel analogues of the anti-HIV-1 lead compound [1-[2‘,5’-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3‘-spiro-5’-(4“-amino-1”,2“-oxathiole-2‘,2’-dioxide) (TSAO-T) bearing different amino acids at position N-3 of thymine were prepared and evaluated as inhibitors of HIV replication. The synthesis of the target compounds was accomplished by coupling of the appropriate TSAO intermediate with a conveniently protected (L) amino acid in the presence of BOP and triethylamine, followed by depro-tection of the amino acid moiety. Several TSAO derivatives, bearing at N-3 position of the thymine base an L-amino acid retaining the free carboxylic acid, acquired activity against HIV-2, in addition to their inhibitory effect on HIV-1.

[1]  E. De Clercq,et al.  Regiospecific Synthesis and Anti-Human Immunodeficiency Virus Activity of Novel 5-Substituted N-Alkylcarbamoyl and N,N-Dialkyl Carbamoyl 1,2,3-Triazole-TSAO Analogues , 1998, Antiviral chemistry & chemotherapy.

[2]  E. De Clercq,et al.  Abasic analogues of TSAO-T as the first sugar derivatives that specifically inhibit HIV-1 reverse transcriptase. , 1998, Journal of medicinal chemistry.

[3]  R. Lee,et al.  The p51 subunit of human immunodeficiency virus type 1 reverse transcriptase is essential in loading the p66 subunit on the template primer. , 1998, Biochemistry.

[4]  J. Balzarini,et al.  TSAO DERIVATIVES: HIGHLY SPECIFIC INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 (HIV-1) REPLICATION , 1995 .

[5]  D. Patel,et al.  “BOP” as a Reagent for Mild and Efficient Preparation of Esters. , 1994 .

[6]  E. De Clercq,et al.  1,2,3-Triazole-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole 2",2"-dioxide) (TSAO) analogues: synthesis and anti-HIV-1 activity. , 1994, Journal of medicinal chemistry.

[7]  E. De Clercq,et al.  Resistance of HIV-1 reverse transcriptase against [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino-1'',2''- oxathiole-2'',2''-dioxide)] (TSAO) derivatives is determined by the mutation Glu138-->Lys on the p51 subunit. , 1994, The Journal of biological chemistry.

[8]  P. Boyer,et al.  Subunit specificity of mutations that confer resistance to nonnucleoside inhibitors in human immunodeficiency virus type 1 reverse transcriptase , 1994, Antimicrobial Agents and Chemotherapy.

[9]  E. De Clercq,et al.  Sensitivity of (138 Glu-->Lys) mutated human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to HIV-1-specific RT inhibitors. , 1994, Biochemical and biophysical research communications.

[10]  E. De Clercq,et al.  Novel series of TSAO-T derivatives. Synthesis and anti-HIV-1 activity of 4-, 5-, and 6-substituted pyrimidine analogues. , 1994, Journal of medicinal chemistry.

[11]  E. De Clercq,et al.  TSAO analogues. 3. Synthesis and anti-HIV-1 activity of 2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl 3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) purine and purine-modified nucleosides. , 1993, Journal of medicinal chemistry.

[12]  J. Balzarini,et al.  TSAO derivatives: highly specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors , 1993 .

[13]  J. Balzarini,et al.  TSAO Analogues. Stereospecific Synthesis and Anti‐HIV‐1 Activity of 1‐( 2′,5′‐Bis‐O‐(tert‐butyldimethylsilyl)‐β‐D‐ribofuranosyl)‐3′‐spiro‐ 5′′‐(4′′‐amino‐1′′,2′′‐oxathiole 2′′,2′′‐dioxide)pyrimidine and Pyrimidine‐Modified Nucleosides. , 1992 .

[14]  J. Balzarini,et al.  3′-Spiro Nucleosides, a New Class of Specific Human Immunodeficiency Virus Type 1 Inhibitors: Synthesis and Antiviral Activity of (2′,5′- Bis-O-(tert-butyldimethylsilyl)-β-D-xylo- and -ribofuranose)-3′- spiro-5′′-(4′′-amino-1′′,2′′-oxathiole 2′′,2′′-Dioxide) (TSAO) Pyrimidine Nucleosides. , 1992 .

[15]  E. De Clercq,et al.  TSAO analogues. 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. , 1992, Journal of medicinal chemistry.

[16]  E. De Clercq,et al.  3'-Spiro nucleosides, a new class of specific human immunodeficiency virus type 1 inhibitors: synthesis and antiviral activity of [2'-5'-bis-O-(tert-butyldimethylsilyl)-beta-D-xylo- and -ribofuranose]-3'-spiro-5"-[4"-amino-1",2"-oxathiole 2",2"-dioxide] (TSAO) pyrimidine nucleosides. , 1992, Journal of medicinal chemistry.

[17]  E. De Clercq,et al.  Kinetics of inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by the novel HIV-1-specific nucleoside analogue [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5 "- (4"-amino-1",2"-oxathiole-2",2"-dioxide)thymine (TSAO-T). , 1992, The Journal of biological chemistry.

[18]  E. De Clercq,et al.  2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino-1'',2''- oxathiole-2'',2'-dioxide)pyrimidine (TSAO) nucleoside analogues: highlyselective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[19]  E. De Clercq,et al.  [2',5'-Bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives of purine and pyrimidinenucleosides as potent and selective inhibitors of human immunodeficiency virus type 1 , 1992, Antimicrobial Agents and Chemotherapy.

[20]  C. Selve,et al.  Reactifs de couplage peptidique I (1) - l'hexafluorophosphate de benzotriazolyl N-oxytrisdimethylamino phosphonium (B.O.P.) , 1975 .