Free accessResearch articleFirst published online 1998-10
An Approach towards the Synthesis of Potential Metal-Chelating TSAO-T Derivatives as Bidentate Inhibitors of Human Immunodeficiency virus Type 1 Reverse Transcriptase
Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.
AlthausIWChouJJGonzalesAJDeibelMRChouCKKezdyFJRomeroDLAristoffPATarpleyWG & ReusserF (1993) Steady-state kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-87201E. Journal of Biological Chemistry268:6119–6124.
2.
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.
3.
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.
4.
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.
5.
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.
6.
BalzariniJCamarasaMJ & KarlssonA (1993b) TSAO derivatives: highly specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors. Drugs of the Future18:1043–1055.
7.
BrogdenPJGabbuttCD & HepworthJD (1984) Pyrans and fused pyrans: (i) structure. In Comprehensive Heterocyclic Chemistryvol. 3, pp. 573–645. Edited by BoultonAJ and McKillopAOxford: Pergamon Press.
8.
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 Chemistry35:2721–2727.
9.
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.
10.
CativielaCSerranoJL & ZurbanoMM (1995) Synthesis of 3-substituted pentane-2,4-diones: valuable intermediates for liquid crystals. Journal of Organic Chemistry60:3074–3083.
11.
ChoudharyA & BaumstarkAL (1989) Convenient, high-yield method for the methylation of 1,3-diketones. Synthesis688–690.
12.
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.
13.
De ClercqE (1996a) What can be expected from non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections?Reviews in Medical Virology6:97–117.
14.
De ClercqE (1996b) Non-nucleoside 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.
15.
DianaGDSalvadorUJZalayESCarabateasPMWilliamsGLCollinsJC & PancicF (1977) Antiviral activity of some β-dike-tones. 2. Aryloxy alkyl diketones. In vitro activity against both RNA and DNA viruses. Journal of Medicinal Chemistry20:757–761.
16.
DianaGDCarabateasPMSalvadorUJWilliamsGLZalayESPancicFSteinbergBA & CollinsJC (1978) Antiviral activity of some β-diketones. 3. Aryl Bis (β-diketones). Antiherpetic activity. Journal of Medicinal Chemistry21:689–692.
17.
D'IncanE & VioutP (1975) Orientation de l'alkylation d'anions ambidents par les sels d'ammonium quaternaire dans les conditions de la catalyse par transfert de phase. Tetrahedron31:159–164.
18.
DingJDasKMoereelsHKoymansLAndriesKJanssenPAJHughesSH & ArnoldE (1995a) Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse non-nucleoside inhibitors. Nature Structural Biology2:407–415.
19.
DingJDasKTantilloCZhangWClarkADJJessenSLuXHsiouYJacobo-MolinaAAndriesKPauwelsRMoereelsHKoymansLJanssenPAJSmithRHJKroeger KoepkeRMichejdaCJHughesSHArnoldE (1995b) Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R95845 at 2.8 Å resolution. Structure3:365–379.
20.
FrankKBNollGJConnellEV & SimIS (1991) Kinetic interaction of human immunodeficiency virus type 1 reverse transcriptase with the antiviral tetrahydroimidazo[4,5,1-jk]-[1,4]-benzodiazepine-2-(1H)-thione compound R82150. Journal of Biological Chemistry266:14231–14236.
21.
HopkinsALRenJEsnoufRMWillcoxBEJonesYRossCMiyasakaTWalkerRTTanakaHStammersDK & StuartDI (1996) Complexes of HIV-1 reverse transcriptase with inhibitors of HEPT series reveal conformational changes relevant to the design of potent non-nucleosides inhibitors. Journal of Medicinal Chemistry39:1589–1600.
22.
HouseHO (1965) The alkylation of active methylene compounds. In Modern Synthetic Reactions, pp. 163–215. Edited by BenjaminWA. New York and Amsterdam: Elsevier.
23.
HutchinsonDW (1985) Metal chelators as potential antiviral agents. Antiviral Research5:193–205.
24.
JackmanLM & LangeBC (1977) Structure and reactivity of alkali metal enolates. Tetrahedron33:2737–2769.
25.
KirmseW & SchnurrO (1977) Pathways from nitrosooxazolidones to vinyl azides. Journal of the Americal Chemical Society99:3539–3541.
26.
KohlstaedtLAWangJFriedmanJMRicePA & SteitzTA (1992) Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science256:1783–1790.
27.
KurtsALGenkinaNKMaciasABeletskayaIP & ReutovOA (1971) Reactivity of ambident anions. Hardness of alkyl groups and symbiotic effect in alkylation of ambident anions. Tetrahedron27:4777–4785.
28.
Le NobleWJ & Frank MorrisH (1969) O vs. C alkylation of ethyl acetoacetate. Journal of Organic Chemistry6:1969–1973.
29.
MarchJ (1985) Delocalized chemical bonding. Tautomerism. In Advanced Organic Chemistry, 3rd edn, pp.66–68 Edited by MarchJ. New York: John Wiley & Sons.
30.
Martell & Calvin (1953) Chelate stability constants. In Chemistry of the Metal Chelate Compounds, pp. 514–561. Edited by LatimerWM. New York: Prentice-Hall.
31.
NanniRGDingJJacobo-MolinaAHughesSH & ArnoldE (1993) Review of HIV-1 reverse transcriptase three-dimensional structure: implications for drug design. Perspectives in Drug Discovery and Design1:129–150.
32.
PascualCMeierJ & SimonW (1966) Regel zur abschätzung der chemischen verschiebung von protonen an einer doppelbindung. Helvetica Chemica Acta49:164–168.
33.
PelletierHSawayaMAKumarAWilsonSH & KrantJ (1994) Structures of ternary complexes of rat DNA polymerase β, a DNA template-primer, and ddCTP. Science264:1891–1893.
34.
Pérez-PérezMJSan-FélixABalzariniJDe ClercqE & CamarasaMJ (1992) TSAO-analogues. Stereospecific synthesis and anti-HIV-1 activity of 1-[2′,5′-Bis-O-(tert-butyldimethylsilyl)-β-d-ribo-furanosyl]-3′-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide) pyrimidine and pyrimidine-modified nucleosides. Journal of Medicinal Chemistry35:2988–2995.
35.
PerrinDD (1979) Stability constants of metalion complexes: part B organic ligands. In IUPAC Chemical Data Series, number 22, pp. 273–280 and 1019–1020. Edited by PerrinDD. Oxford: Pergamon Press.
36.
RatnerLHaseltineWPatarcaRLivakKJStarcichBJosephsSFDoranERRafalskiJAWhitehornEABaumeisterKIvanoffLPettewaySRJrPearsonMLLautenbergJAPapasTSGhrayebJChangNTGalloRC & Wong-StaalF (1985) Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature313:277–284.
37.
RenJSEsnoufRGarmanEJonesYSomersDRossCKirbyIKeelingJDarbyGStuartD & StammersD (1995a) High resolution structure of HIV-1 RT: insights from four RT-inhibitor complexes. Nature Structural Biology2:293–302.
38.
RenJSEsnoufRHopkinsARossCJonesYStammersD & StuartD (1995b) The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design. Structure3:915–926.
39.
RosemeyerH & SeeleF (1990) Configuraional and conformational analysis of regular and modified nucleosides by 1D-NOE difference spectroscopy. Nucleosides and Nucleotides9:417–418.
40.
SmerdonSJJägerJWangJKohlstaedtLAChirinoAJFriedmanJMRicePA & SteizTA (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.
41.
SpenceRAKatiWMAndersonKS & JohnsonKA (1995) Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science267:988–993.
42.
SteitzTA (1993) DNA and RNA-dependent DNA polymerases. Current Opinion in Structural Biology3:31–38.
43.
VelázquezSAlvarezASan-FélixAJimenoMLDe ClercqEBalzariniJ & CamarasaMJ (1995) Synthesis and anti-HIV-1 activity of [AZT]-[TSAO-T] and [AZT]-[HEPT] dimers as potential multifunctional inhibitors of HIV-1 reverse transcriptase. Journal of Medicinal Chemistry38:1641–1649.
44.
WuJCWarrenTCAdamsJProudfootJSkilesJRaghavanPPerryCPotockiIFarinaRR & GrobPM (1991) A novel dipyridodi-azepinone inhibitor of HIV-1 reverse transcriptase acts through a non-substrate binding site. Biochemistry30:2022–2026.
45.
YoungSD (1993) Non-nucleoside inhibitors of HIV-1 reverse transcriptase. Perspectives in Drug Discovery and Design1:181–192.
