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
Free accessResearch articleFirst published online December, 1998
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
Several 5-N-alkyl and 5-N,N-dialkylcarbamoyl substituted analogues of the anti-human immunodeficiency virus (HIV) type 1 lead compound[1-[2‘,5’-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-5-(N,N-dimethylcarbamoyl)-1,2,3-triazole]-3‘-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide) have been prepared and evaluated as inhibitors of HIV-1 replication. A new regiospecific synthetic procedure is described. The compounds were prepared by cycloaddition of the appropriate glycosylazide to 2-oxo-alkylidentriphenyl-phosphoranes, followed by treatment with primary or secondary amines, to yield, exclusively, 5-substituted 1,2,3-triazole-TSAO analogues. Several 5-substituted 1,2,3-triazole-TSAO derivatives proved to be potent inhibitors of HIV-1 replication with higher antiviral selectivity than that of the parent TSAO prototype.
AlonsoRCamarasaMJAlonsoG & De las HerasFG (1980) Alkylating nucleosides. 5. Synthesis and cytostatic activity of N-ribosyl-halomethyl-1,2,3-triazoles. European Journal of Medicinal Chemistry15: 105–109.
2.
AlvarezRJimenoMLPérez-PérezMJDe ClercqEBalzariniJ & CamarasaMJ (1997) Synthesis and anti-human immunodeficiency virus type 1 activity of novel 3′-spiro nucleoside analogues of TSAO-T. Antiviral Chemistry & Chemotherapy8: 507–509.
3.
AlvarezRJimenoMLGagoFBalzariniJPérez-PérezMJ & CamarasaMJ (1998) Novel 3′-spiro nucleoside analogues of TSAO-T. Part II. A comparative study based on NMR conformational analysis in solution and theoretical calculations. Antiviral Chemistry & Chemotherapy9: 123–133.
4.
AlvarezRVelázquezSSan-FélixAAquaroSDe ClercqEPernoC-FKarlssonABalzariniJ & CamarasaMJ (1994) 1,2,3-Triazole-[2′,5′-bis-O-(tert-butyldimethylsilyl-β-d-ribofuranosyl]-3′-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide) (TSAO) analogues. Synthesis and anti-HIV-1 activity. Journal of Medicinal Chemistry37: 4185–4194.
5.
BalzariniJPérez-PérezMJSan-FélixACamarasaMJBathurstICBarrPJ & De ClercqE (1992a) 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-(t-butyldimethylsilyl)-3′-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide) thymine (TSAO-T). Journal of Biological Chemistry267: 11831–11838.
6.
BalzariniJPérez-PérezMJSan-FélixAScholsDPernoCFVandammeAMCamarasaMJ & De ClercqE (1992b) 2,5′-Bis-O-(tert-butyldimethylsilyl)-3′-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide)pyrimidine (TSAO) nucleoside analogues: Highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proceedings of the National Academy of Sciences, USA89: 4392–4396.
7.
BalzariniJPérez-PérezMJSan-FélixAVelázquezSCamarasaMJ & De ClercqE (1992c) [2,5′-Bis-O-(tert-butyldimethylsilyl)]-3′-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide) (TSAO) derivatives of purine and pyrimidine nucleosides as potent and selective inhibitors of human immunodeficiency virus type 1. Antimicrobial Agents and Chemotherapy36: 1073–1080.
8.
BalzariniJKarlssonAPérez-PérezMJVrangLWalbersJZhangHÖbergBVandammeAMCamarasaMJ & De ClercqE (1993a) HIV-1-specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase. Virology192: 246–253.
9.
BalzariniJCamarasaMJ & KarlssonA (1993b) TSAO derivatives: Highly specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors. Drugs of the Future18: 1043–1055.
10.
BalzariniJKleimJPRiessGCamarasaMJDe ClercqE & KarlssonA (1994) Sensitivity of (138 GLU→ LYS) mutated human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to HIV-1-specific RT inhibitors. Biochemical and Biophysical Research Communications201: 1305–1312.
11.
BeslerBHMerzKM & KollmanPA (1990) Atomic charges derived from semiempirical methods. Journal of Computational Chemistry11: 431–439.
12.
BastideJHamelinJTexierF & QuangYV (1973) Cycloaddition dipolaire-1,3 aux alcynes. Bulletin de la Societe Chimique de France2998–3003.
13.
BoyerPLDingJArnoldE & HughesSH (1994) Subunit specificity of mutations that confer resistance to nonnucleoside inhibitors in human immunodeficiency virus type 1 reverse transcriptase. Antimicrobial Agents and Chemotherapy38: 1909–1914.
14.
CamarasaMJPérez-PérezMJSan-FélixABalzariniJ & De ClercqE (1992) 3′-Spironucleosides (TSAO derivatives), a new class of specific human immunodeficiency virus type 1 inhibitors: Synthesis and antiviral activity of 3′-spiro-5“-[4”-amino-1“,2”-oxathiole-2“,2”-dioxide]pyrimidine nucleosides. Journal of Medicinal Chemistry35: 2721–12727.
15.
CamarasaMJPérez-PérezMJVelázquezSSan-FélixAAlvarezAIngateSJimenoMLKarlssonADe ClercqE & BalzariniJ (1995) TSAO derivatives: Highly specific inhibitors of human immunodeficiency virus type-1 (HIV-1) replication. Nucleosides and Nucleotides14: 585–594.
16.
De ClercqE (1993) HIV-1 specific RT inhibitors: Highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Medicinal Research Reviews13: 229–258.
17.
De ClercqE (1995) Towards improved anti-HIV chemotherapy: Therapeutic strategies for intervention with HIV infections. Journal of Medicinal Chemistry38: 2491–2517.
18.
De ClercqE (1996) Nonnucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: Strategies to overcome drug resistance development. Medicinal Research Reviews16: 125–157.
19.
DewarMJSZoebischEGHealyE F & StewartJJP (1985) AM1: A new general purpose quantum mechanical molecular model. Journal of the American Chemical Society107: 3902–3909.
20.
EsnoufRMRenJHopkinsALRossCKJonesEYStammersDK & StuartDI (1997) Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proceedings of the National Academy of Sciences, USA94: 3984–3989.
21.
García-LópezMTGarcía-MuñozGIglesiasJ & MadroñeroR (1969) Heterocyclic N-glycosides. III. Synthesis of N-glycosyl-v-triazoles from glycosyl azides and phenylacetylenes. Journal of Heterocyclic Chemistry6: 639–642.
22.
GoodfordPJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. Journal of Medicinal Chemistry28: 849–857.
23.
GoodsellDS & OlsonAJ (1990) Automated docking of substrates to proteins by simulated annealing. Proteins Structure Function and Genetics8: 195–202.
24.
GoodsellDSMorrisGM & OlsonAJ (1996) Docking of flexible ligands: Applications of autoDock. Journal of Molecular Recognition9: 1–15.
25.
HarveyGR (1966) The reactions of phosphorous compounds. XII. A new synthesis of 1,2,3-triazoles and diazo esters from phosphorous ylids and azides. Journal of Organic Chemistry31: 1587–1590.
26.
HammerschmidtFPolstererJP & ZbiralE (1995) Synthesis of 1-(D-apio-β-D-furanosyl)-1,2,3-triazoles. Synthesis415–418.
27.
Jacobo-MolinaADingJNanniRGClarkADJrLuXTantilloCWilliamsRLKamerGFerrisALClarkPHiziAHughesSH & ArnoldE (1993) Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proceedings of the National Academy of Sciences, USA90: 6320–6324.
28.
JonckheereHTaymansJMBalzariniJVelázquezSCamarasaMJDesmyterJDe ClercqE & AnnéJ (1994) 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. Journal of Biological Chemistry269: 25255–25258.
29.
KatzRA & SkalkaAM (1993) The retroviral enzymes. Annual Review of Biochemistry63: 133–173.
30.
L'abbéG & HassnerA (1971) Stereochemistry XLIV. Regiochemistry in cycloaddition reactions of vinylazides with phenylacetylene. Bulletin des Societes Chimiques Belges80: 209–210.
31.
Le CorreM (1970) Nouvelle voie d'accés aux esters α-cétoniques β-éthyléniques. Comptes Rendus de L'Academie des Sciences Serie C270: 1312–11314.
32.
MorrisGMGoodsellDSHueyR & OlsonAJ (1996) AutoDock: Automated docking of flexible ligands to receptors, version 2.4. La Jolla: The Scripps Research Institute.
33.
NanniRGDingJJacobo-MolinaAHughesSH & ArnoldE (1993) Review of HIV-1 reverse transcriptase three-dimensional structure: Implications for drug design. Perspectives in Drug Discovery and Design1: 129–1150.
34.
Párez-PérezMJSan-FélixABalzariniJDe ClercqE & CamarasaMJ (1992) 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. Journal of Medicinal Chemistry35: 2988–2995.
35.
RenJSEsnoufRGarmanEJonesYSomersDRossCKirbyIKeelingJDarbyGStuartD & StammersD (1995) High resolution structure of HIV-1 RT: Insights from four RT—inhibitor complexes. Nature Structural Biology2: 293–302.
36.
SchörkuberW & ZbiralE (1980) Glycosylazide als Ausgangsbasis zur Gewinnung von Nucleosidanalogen. Liebigs Annalen1455–1469.
37.
SchörkuberW & ZbiralE (1981) Zur synthese von 5-(x-methyl)ribofuranosyl-1,2,3-triazol-nucleosides. Chemische Berichte114: 3165–3169.
38.
SmerdonSJJägerJWangJKohlstaedtLAChirinoAJFriedmanJMRicePA & SteitzTA (1994) Structure of the binding site for non-nucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proceedings of the National Academy of Sciences, USA91: 3911–3915.
39.
SchinaziRF (1993) Competitive inhibitors of human immunodeficiency virus reverse transcriptase. Perspectives in Drug Discovery and Design1: 151–180.
40.
StewartJJP (1993) MOPAC 93. Tokyo: Fujitsu.
41.
TantilloCDingJJacobo-MolinaANanniRGBoyerPLHughesSHPauwelsRAndriesKJanssenPAJ & ArnoldE (1994) Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. Journal of Molecular Biology243: 369–387.
42.
YoungS D (1993) Nonnucleoside inhibitors of HIV-1 reverse transcriptase. Perspectives in Drug Discovery and Design1: 181–192.
43.
VaishnavYN & Wong-StaalF (1991) The biochemistry of AIDS. Annual Review of Biochemistry60: 577–630.
44.
VelázquezSChamorroCPérez-PérezMJAlvarezRJimenoMLMartín-DomenechAPérezCGagoFDe ClercqEBalzariniJSan-FélixA & CamarasaMJ (1998) Abasic analogues of TSAO-T as the first sugar derivatives that specifically inhibit HIV-1 reverse tanscriptase. Journal of Medicinal Chemistry41: 4636–4647
45.
VelézquezSJimenoMLCamarasaMJ & BalzariniJ (1994) Synthesis of [1-[3′,5′-bis-O-(tert-butyldimethylsilyl-β-d-arabino-and ribofuranosyl]cytosine]-2′-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide). Analogues of the highly specific anti-HIV-1 agent TSAO-T. Tetrahedron50: 11013–11022.
46.
VelázquezSSan-FélixAPérez-PérezMJBalzariniJDe ClercqE & CamarasaMJ (1993) TSAO analogues. 3. Synthesis and anti-HIV-1 activity of [2′,5′-bis-O-(tert-butyldimethylsilyl-β-d-ribofuranosyl]-3′-spiro-5“-[4”-amino-1“,2”-oxathiole-2“,2”-dioxide] purine and purine-modified nucleosides. Journal of Medicinal Chemistry36: 3230–3239.
47.
ZbiralE (1974) Synthesen von heterocyclen mit hilfe von alkyliden-phosphoranen phosphin-imiden, vinyl phosphonium-salzen und vinylphosphin-oxiden. Synthesis775–800.
