Pointer 4'-Ethynylstavudine (4'-Ed4T) Has Potent Anti-HIV-1 Activity with Reduced Toxicity and Shows a Unique Activity Profile against Drug-Resistant Mutants
Free accessResearch articleFirst published online August, 2005
Pointer 4'-Ethynylstavudine (4'-Ed4T) Has Potent Anti-HIV-1 Activity with Reduced Toxicity and Shows a Unique Activity Profile against Drug-Resistant Mutants
A nucleoside analogue 4'-ethynylstavudine (4'-Ed4T) was recently synthesized during chemical studies directed towards the development of a new route to 4' -carbon-substituted nucleosides. This compound was found to be more anti-HIV-1 active than the parent compound stavudine (d4T) and much less toxic to various cells and also to mitochondrial DNA synthesis. It became apparent that 4' -Ed4T is a better substrate for human thymidine kinase than d4T, and very much more resistant to catabolism by thymidine phosphorylase. The study of 4' -Ed4T against various drug-resistant HIV-1 mutants has disclosed its unique activity profile.
ChoiYGeorgeCCominMJBarchiJJJr.KimHSJacobsonKABalzariniJMitsuyaHBoyerPLHughesSHMarquezVE (2003) A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude. Journal of Medical Chemistry46: 3292–3299.
2.
DutschmanGEGrillSPGullenEAHaraguchiKTakedaSTanakaHBabaMChengYC (2004) Novel 4′-substituted stavudine analog with improved anti-human immunodeficiency virus activity and decreased cytotoxicity. Antimicrobial Agents & Chemotherapy48: 1640–1646.
3.
HaraguchiKTanakaHItohYYamaguchiKMiyasakaT (1996) Allylic substitution of 3′,4′-unsaturated nucleosides: Organosilicon-based stereoselective access to 4′-C-branched 2′,3′-didehydro-2′,3′-dideoxyribonucleosides. Journal of Organic Chemistry61: 851–858.
4.
HaraguchiKTakedaS & TanakaH (2003a) Ring opening of 4′,5′-epoxynucleosides: A novel stereoselective entry to 4′-C-branched nucleosides. Organic Letters5: 1399–1402.
5.
HaraguchiKTakedaSTanakaHNitandaTBabaMDutschmanGE & ChengYC (2003b) Synthesis of a highly active anti-HIV agent 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine. Bioorganic & Medicinal Chemistry Letters13: 3775–3777.
6.
HaraguchiKItohYTakedaSHonmaYTanakaHNitandaTBabaMDutschmanGE & ChengYC (2004) Synthesis and anti-HIV activity of 4′-cyano-2′,3′-didehydro-3′-deoxythymidine. Nucleosides, Nucleotides & Nucleic Acids23: 647–654.
7.
HayakawaHKohgoSKitanoKAshidaNKodamaEMitsuyaH & OhruiH (2004) Potential of 4′-C-substituted nucleosides for the treatment of HIV. Antiviral Chemistry & Chemotherapy15: 169–187.
8.
KumamotoHKatoKHaraguchiKTanakaHNitandaTBabaMDutschmanGE & ChengYC (2005) Synthesis of (±)-4′-ethynyl and 4′-cyano carbocyclic analogues of stavudine (d4T). Nucleosides, Nucleotides & Nucleic Acids24: 73–83.
9.
LarderBA & KempSD (1989) Multiple mutations in HIV-1 reverse transcriptase confer high level resistance to zidovudine (AZT). Science246: 1155–1158.
10.
MaagHRydzewskiRMMcRobertsMJCrawford-RuthDVerheydenJPH & PrisbeEJ (1992) Synthesis and anti-HIV activity of 4′-azido- and 4′-methoxynucleosides. Journal of Medical Chemistry35: 1440–1451.
11.
MullarMD (2004) K65R, TAMs and tenofovir. AIDS Reviews6: 22–33.
12.
O-YangCWuHYFraser-SmithEB & WalkerAM (1992) Synthesis of 4′-cyanothymidine and analogs as potent inhibitors of HIV. Tetrahedron Letters33: 37–40.
13.
NitandaTWangXKumamotoHHaraguchiKTanakaHChengY-C & BabaM (2005) Anti-human immunodeficiency virus type 1 activity and resistance profile of 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine in vitro. Antimicrobial Agents & Chemotherapy49: In press.
14.
PrisbeEJMaagHVerheydenJPH & RydzewskiRM (1993) Structure-activity relationships among HIV-inhibitory 4′-substituted nucleosides. In Nucleosides & Nucleotides as Antitumor & Antiviral Agents, pp. 101–113. Edited by ChuCK & BakerDC. New York: Plenum Press.
15.
ShirasakaTKavlickMFUenoTGaoWYKojimaEAlcaideMLChokekijchaiSRoyBMArnoldEYarchoanR & MitsuyaH (1995) Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proceedings of the National Academy of Sciences, USA92: 2398–2402.
16.
ShutoSKanazakiMIchikawaSMinakawaN & MatsudaA (1998) Stereo- and regioselective introduction of 1- or 2-hydroxyethyl group via intramolecular radical cyclization reaction with a novel silicon-containing tether. An efficient synthesis of 4′-branched 2′-deoxyadenosines. Journal of Organic Chemistry63: 746–754.
17.
SugimotoIShutoS & MatsudaA (1999) A one-pot method for the stereoselective introduction of a vinyl group via an atom-transfer radical-cyclization reaction with a diphenylvinylsilyl group as a temporary connecting tether. Synthesis of 4′-C-vinylthymidine, a potent antiviral nucleoside. Journal of Organic Chemistry64: 7153–7157.
18.
WhiteKLMargotNAWrinTPetropoulosCJMillerMD & NaegerLK (2002) Molecular mechanisms of resistance to human immunodeficiency virus type 1 with reverse transcriptase mutations K65R and K65R+M184V and their effects on enzyme function and viral replication capacity. Antimicrobial Agents & Chemotherapy41: 3437–3446.
