Extensive efforts have been made to identify nucleoside reverse transcriptase inhibitors (NRTIs). Eight NRTIs have now been approved for clinical use; however, variants of HIV-1 resistant to these antiviral agents have emerged in patients even when they are treated with combinations [highly active antiretroviral therapy (HAART)]. Thus, the development of novel compounds that are active against drug-resistant HIV-1 variants and that prevent or delay the emergence of resistant HIV-1 variants is urgently needed. Previously, 4′-C-substituted nucleosides (4′-SNs) were designed as new types of NRTIs. They were synthesized and examined as potential therapeutic agents against HIV infection. Among them, several 4′-substituted-2′-deoxynucleosides (4′-SdNs), especially those that bear an ethynyl group, were shown to be active against various laboratory and clinical HIV-1 strains including known drug-resistant variants. These results were recently reported by our collaborators. In this review, we summarize the design, synthesis and demonstrations of the anti-HIV activity of 4′-SNs, and then consider 4′-SNs as potential therapeutic agents for HIV-1.
BeachJWJeongLSAlvesAJPohlDKimHOChangC-NDoongS-LSchinaziRFChengY-C & ChuCK (1992) Synthesis of enantiomerically pure (2′R, 5′S)-(-)-1-[2-(hydroxymethyl)oxathiolan-5-yl]cytosine as a potent antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV). Journal of Organic Chemistry57: 2217–2219.
2.
ChenMSSuttmannRTPappECannonPDMcRobertsMJBachCCopelandWC & WangTS (1993) Selective action of 4′-azidothymidine triphosphate on reverse transcriptase of human immunodeficiency virus type 1 and human DNA polymerases alpha and beta. Biochemistry32: 6002–6010.
3.
CrichD & HaoX (1999) Asymmetric synthesis of C4′α-carboxylated 2′-deoxynucleosides. Preparation of oxetanone derivatives and influence of solvent on the stereochemistry of base introduction. Journal of Organic Chemistry64: 4016–4024.
4.
HaraguchiKItohYTakedaSHonmaYTanakaHNitandaTBabaMDutschmanGE & ChengY-C (2004) Synthesis of anti-HIV activity of agent 4′-cyano-2′, 3′-didehydro-3′-deoxythymidine. Nucleosides Nucleotides & Nucleic Acids23: 647–654.
5.
HaraguchiKTakedaSTanakaHNitandaTBabaMDutschmanGE & ChengY-C (2003) Synthesis of a highly active new anti-HIV agent 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine. Bioorganic & Medicinal Chemistry Letters13: 3775–3777.
6.
HaraguchiKTanakaHItoYSaitoS & MiyasakaT (1992) Stereoselective synthesis of 4′-C-branched 2′,3′-didehydro-2′,3′-dideoxy nucleosides based on SnCl4-promoted allylic rearrangement. Tetrahedron Letters33: 2841–2844.
7.
HrebabeckyH & HolyA (1993) Synthesis of 1-(3-azido-2, 3-dideoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)thymine, 1-(2,3-dideoxy-4-C-hydroxymethyl-α-L-glyceropentofuranosyl)thymine and 1-(2,3-dideoxy-4-C-hydroxymethyl-α-L-glycero-pent-2-enofuranosyl)thymine. Collection of Czechoslovak Chemical Communications58: 409–420.
8.
ImanishiT & ObikaS (1999) Syntheses and properties of novel conformationally restrained nucleoside analogues. Journal of Synthetic Organic Chemistry Japan57: 969–980.
9.
JenkinsIDVerheydenJPH & MoffattJG (1976) 4′-Substituted nucleosides. 2. Synthesis of the nucleosides antibiotic nucleocidine. Journal of the American Chemical Society98: 3346–3357.
10.
JohnsonCREskerJL & Van ZandtMC (1994) Chemoenzymatic synthesis of 4-substituted riboses. S-(4′-methyladenosyl)-L-homocysteine. Journal of Organic Chemistry59: 5854–5855.
11.
JonesGHTaniguchiMTeggD & MoffattJG (1979) 4′-Substituted nucleosides. 4. Synthesis of some 4′-hydroxymethyl nucleosides. Journal of Organic Chemistry44: 1309–1317.
12.
JungME & ToyotaA (2001) Preparation of 4′-substituted thymidines by substitution of the thymidine 5′-esters. Journal of Organic Chemistry66: 2624–2635.
13.
KatoKSuzukiHTanakaH & MiyasakaT (1998) Enantio- and diastereoselective synthesis of 4′-a-substituted carbocyclic nucleosides. Tetrahedron: Asymmetry9: 911–914.
14.
KitanoKMacHidaHMiuraS & OhruiH (1999) Synthesis of novel 4′-C-methyl-pyrimidine nucleosides and their biological activities. Bioorganic & Medicinal Chemistry Letters9: 827–830.
15.
KitanoKMiuraSOhruiH & MeguroH (1997) Synthesis of 4′-C-fluoromethylnucleosides as potential antineoplastic agents. Tetrahedron53: 13315–13322.
16.
KodamaEKohgoSKitanoKMacHidaHGatanagaHShigetaSMatsuokaMOhruiH & MitsuyaH (2001) 4′-Ethynyl nucleoside analogs: Potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro. Antimicrobial Agents & Chemotherapy45: 1539–1546.
17.
KohgoSHorieH & OhruiH (1999) Synthesis of 4′-C-ethynyl-β-D-arabino- and 4′-C-ethynyL-2′-deoxy-β-D-ribo-pentofuranosyl pyrimidines, and their biological evaluation. Bioscience Biotechnology & Biochemistry63: 1146–1149.
18.
KohgoSKodamaEShigetaSSaneyoshiMMacHidaH & OhruiH (1999) Synthesis of 4′-substituted nucleosides and their biological evaluation. Nucleic Acids Symposium Series42: 127–128.
19.
KohgoSMitsuyaH & OhruiH (2001) Synthesis of the L-enantiomer 4′-C-ethynyl-2′-deoxycytidine. Bioscience Biotechnology & Biochemistry65: 1879–1882.
MaagHRydzewskiRMMcRobertsMJCrawford-RuthDVerheydenJPH & PrisbeEJ (1992) Synthesis and anti-HIV activity of 4′-azido- and 4′-methoxynucleosides. Journal of Medicinal Chemistry35: 1440–1451.
MurakamiKShirasakaTYoshiokaHKojimaEAokiSFordHJr.DriscollJSKelleyJA & MitsuyaH (1991) Escherichia coli mediated biosynthesis and in vitro anti-HIV activity of lipophilic 6-halo-2′,3′-dideoxypurine nucleosides. Journal of Medicinal Chemistry34: 1606–1612.
24.
NomuraMShutoSTanakaMSasakiTMoriSShigetaS & MatsudaA (1999) Nucleosides & Nucleotides 185. Synthesis and biological activities of 4′α-C-branched-chain sugar pyrimidine nucleosides. Journal of Medicinal Chemistry42: 2901–2908.
25.
O-YangCKurzWEuguiEMMcRobertsMJVerheydenJPHKurzLJ & WalkerKAM (1992) 4′-Substituted nucleosides as inhibitors of HIV: An unusual oxetane derivative. Tetrahedron Letters33: 41–44.
26.
O-YangCWuHYFraser-SmithEB & WalkerKAM (1992) Synthesis of 4′-cyanothymidine and analogs as potent inhibitors of HIV. Tetrahedron Letters33: 37–40.
27.
OhruiHKohgoSKitanoKSakataSKodamaEYoshimuraKMatsuokaMShigetaS & MitsuyaH (2000) Syntheses of 4′-C-ethynyl-β-D-arabino- and 4′-C-ethynyl-2′-deoxy-β-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity. Journal of Medicinal Chemistry43: 4516–4525.
28.
OhruiH & MitsuyaH (2001) 4′-C-Substituted-2′-deoxynucleosides: A family of retroviral agents which are potent against drug-resistant HIV variants. Current Drug Targets-Infectious Disorders1: 1–10.
29.
OhruiHNishizakiTWagaT & MeguroH (1991) Synthetic study on 4′-C-methylnucleosides: Part I, synthesis of 4-C-methyl-D-ribofuranose derivative. Nucleic Acids Symposium Series25: 1–2.
30.
OwenGRVerheydenJPH & MoffattJG (1976) 4′-Substituted nucleosides. 3. Synthesis of some 4′-fluorouridine derivatives. Journal of Organic Chemistry41: 1310–1317.
31.
PrisbeEJMaagHVerheydenJPH & RydzewskiRM (1993) Structure-activity relationships among HIV inhibitory 4′-substituted nucleosides. Nucleosides & Nucleotides as Antitumor & Antiviral Agents. Edited by ChuCK & BakerDC. New York: Plenum Press, pp. 101–113.
32.
SecristJAIII & WinterWJJr (1978) Carbon-carbon bond formation at C4' of a nucleoside. Synthesis and utilization of a uridine 4′, 5′-enamine. Journal of the American Chemical Society100: 2554–2555.
33.
SinghSKKumarR & WengelJ (1998) Synthesis of novel bicyclo[2.2.1]ribonucleosides: 2′-amino- and 2′-thio-LNA monomeric nucleosides. Journal of Organic Chemistry63: 6078–6079.
34.
SugimotoIShutoSMoriSShigetaS & MatsudaA (1999) Nucleosides & Nucleotides 183. Synthesis of 4′α-branched thymidines as a new type of antiviral agent. Bioorganic & Medicinal Chemistry Letters9: 385–388.
35.
SummererD & MarxA (2001) DNA polymerase selectivity: Sugar interactions monitored with high-fidelity nucleotides. Angewandte ChemieInternational Edition40: 3693–3695.
36.
ThraneHFensholdtJRengerM & WengelJ (1995) Novel linear and branched oligodeoxynucleotide analogues containing 4′-C-(hydroxymethyl)thymidine. Tetrahedron51: 10389–10402.
37.
VerheydenJPH & MoffattJG. (1975) 4′-Substituted nucleosides, 1. Synthesis of 4′-methoxyuridine and related compounds. Journal of the American Chemical Society97: 4386–4395.
