4′-Ethynylstavudine (4′-Ed4T) has potent anti-HIV-1 activity with reduced toxicity and shows a unique activity profile against drug-resistant mutants

Antiviral Chemistry and Chemotherapy

Volumn 16, Issue 4, 2005, Pages 217-221

  Tanaka, Hiromichi ^a   Haraguchi, Kazuhiro ^a   Kumamoto, Hiroki ^a   Baba, Masanori ^b   Cheng, Yung Chi ^c  

^a SHOWA UNIVERSITY   (Japan)

^b KAGOSHIMA UNIVERSITY   (Japan)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

4 substituted nucleoside; Anti HIV agent; Drug resistant mutants; NRTI; Reverse transcriptase; Stavudine analogue

Indexed keywords

4' ALLYLSTAVUDINE; 4' CYANOSTAVUDINE; 4' ETHYNYLSTAVUDINE; 4' METHYLETHYNYLSTAVUDINE; 4' METHYLSTAVUDINE; 4' VINYLSTAVUDINE; LAMIVUDINE; MITOCHONDRIAL DNA; NUCLEOSIDE ANALOG; STAVUDINE; TENOFOVIR; THYMIDINE; THYMIDINE KINASE 1; THYMIDINE PHOSPHORYLASE; UNCLASSIFIED DRUG; 4'-ETHYNYLSTAVUDINE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DRUG DERIVATIVE; THYMIDINE KINASE;

ANTIVIRAL ACTIVITY; CELL GROWTH; CONCENTRATION RESPONSE; CYTOTOXICITY; DNA CONTENT; DNA SYNTHESIS; DRUG METABOLISM; DRUG POTENCY; DRUG SENSITIVITY; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; PRIORITY JOURNAL; REVIEW; STRUCTURE ACTIVITY RELATION; VIRUS MUTANT; VIRUS STRAIN; ANTIBIOTIC RESISTANCE; ARTICLE; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; COMPARATIVE STUDY; DRUG EFFECT; ENZYME SPECIFICITY; GENETICS; METABOLISM; MUTATION;

ANTI-HIV AGENTS; CELL LINE; DNA, MITOCHONDRIAL; DRUG RESISTANCE, VIRAL; HIV-1; HUMANS; MOLECULAR STRUCTURE; MUTATION; STAVUDINE; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY; THYMIDINE KINASE; THYMIDINE PHOSPHORYLASE;

EID: 23744503171     PISSN: 09563202     EISSN: None     Source Type: Journal    
DOI: 10.1177/095632020501600402     Document Type: Review

References (18)

1. Choi Y, George C, Comin MJ, Barchi Jr. JJ, Kim HS, Jacobson KA, Balzarini J, Mitsuya H, Boyer PL, Hughes SH, Marquez VE (2003) A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude. Journal of Medical Chemistry 46:3292-3299.
2. Dutschman GE, Grill SP, Gullen EA, Haraguchi K, Takeda S, Tanaka H, Baba M, Cheng YC (2004) Novel 4′-substituted stavudine analog with improved anti-human immunodeficiency virus activity and decreased cytotoxicity. Antimicrobial Agents & Chemotherapy 48:1640-1646.
3. Haraguchi K, Tanaka H, Itoh Y, Yamaguchi K, Miyasaka T (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 Chemistry 61:851-858.
4. Haraguchi K, Takeda S & Tanaka H (2003a) Ring opening of 4′,5′-epoxynucleosides: a novel stereoselective entry to 4′-C-branched nucleosides. Organic Letters 5:1399-1402.
5. Haraguchi K, Takeda S, Tanaka H, Nitanda T, Baba M, Dutschman GE & Cheng YC (2003b) Synthesis of a highly active anti-HIV agent 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine. Bioorganic & Medicinal Chemistry Letters 13:3775-3777.
6. Haraguchi K, Itoh Y, Takeda S, Honma Y, Tanaka H, Nitanda T, Baba M, Dutschman GE & Cheng YC (2004) Synthesis and anti-HIV activity of 4′-cyano-2′,3′-didehydro-3′-deoxythymidine. Nucleosides, Nucleotides & Nucleic Acids 23:647-654.
7. Hayakawa H, Kohgo S, Kitano K, Ashida N, Kodama E, Mitsuya H & Ohrui H (2004) Potential of 4′-C-substituted nucleosides for the treatment of HIV. Antiviral Chemistry & Chemotherapy 15:169-187.
8. Kumamoto H, Kato K, Haraguchi K, Tanaka H, Nitanda T, Baba M, Dutschman GE & Cheng YC (2005) Synthesis of (±)-4′-ethynyl and 4′-cyano carbocyclic analogues of stavudine (d4T). Nucleosides, Nucleotides & Nucleic Acids 24:73-83.
9. Larder BA & Kemp SD (1989) Multiple mutations in HIV-1 reverse transcriptase confer high level resistance to zidovudine (AZT). Science 246:1155-1158.
10. Maag H, Rydzewski RM, McRoberts MJ, Crawford-Ruth D, Verheyden JPH & Prisbe EJ (1992) Synthesis and anti-HIV activity of 4′-azido- and 4′-methoxynucleosides. Journal of Medical Chemistry 35:1440-1451.
11. Mullar MD (2004) K65R, TAMs and tenofovir. AIDS Reviews 6:22-33.
12. O-Yang C, Wu HY, Fraser-Smith EB & Walker AM (1992) Synthesis of 4′-cyanothymidine and analogs as potent inhibitors of HIV. Tetrahedron Letters 33:37-40.
13. Nitanda T, Wang X, Kumamoto H, Haraguchi K, Tanaka H, Cheng Y-C & Baba M (2005) Anti-human immunodeficiency virus type 1 activity and resistance profile of 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine in vitro. Antimicrobial Agents & Chemotherapy 49:in press.
14. Prisbe EJ, Maag H, Verheyden JPH & Rydzewski RM (1993) Structure-activity relationships among HIV-inhibitory 4′-substituted nucleosides. In Nucleosides & Nucleotides as Antitumor & Antiviral Agents, pp. 101-113. Edited by CK Chu & DC Baker. New York: Plenum Press.
15. Shirasaka T, Kavlick MF, Ueno T, Gao WY, Kojima E, Alcaide ML, Chokekijchai S, Roy BM, Arnold E, Yarchoan R & Mitsuya H (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, USA 92:2398-2402.
16. Shuto S, Kanazaki M, Ichikawa S, Minakawa N & Matsuda A (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 Chemistry 63:746-754.
17. Sugimoto I, Shuto S & Matsuda A (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 Chemistry 64:7153-7157.
18. White KL, Margot NA, Wrin T, Petropoulos CJ, Miller MD & Naeger LK (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 & Chemotherapy 41:3437-3446.