title: Myristoylated derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine) bi-functional prodrugs with potent anti-HIV-1 activity and low cytotoxicity.
abstract: BACKGROUND
  To improve in vitro antiviral activity and selectivity of stavudine (d4T), a range of its bi-functional prodrugs, 5'-O-myristoylated derivatives, have been synthesized.
  
  
  METHODS
  Stavudine 5'-O-myristoylated esters were synthesized using modified Parang's procedure. The cytotoxicity and anti-HIV activity was evaluated in the established MT-4 cell line. The level of p24 protein in culture medium was assayed, and EC50 and EC90 values were determined.
  
  
  RESULTS
  Excellent anti-HIV activity was obtained for stavudine derivatives 2',3'-didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine, 2',3'-didehydro-2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine and 5'-O-(12-azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine with C10 and C11 alkyl chains bearing thioethyl- and azido- substituents. These prodrugs were more potent than the parent stavudine, as is clear from their EC50 values: 2',3'-didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine (R=CO(CH2)10SC2H5, EC50 0.06 μM), 2',3'-didehydro-2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine (R=CO(CH2)11SC2H5, EC50 0.09 μM) and 5'-O-(12-azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine (R=CO(CH2)11N3, EC50 0.06 μM), while 50% cytotoxic concentration was >16.65 μM, >7.5 μM and >18.53 μM, respectively.
  
  
  CONCLUSIONS
  Overall data demonstrate that compounds 2',3'-didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine, 2',3'-didehydro-2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine and 5'-O-(12-azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine are very potent and selective anti-HIV agents and could be useful in treatment of HIV infections of the central nervous system.
authors.affiliation: Nucleic Acids & Antiviral Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, India. rksinghsrk@gmail.com.
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Singh
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Miazga
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Dąbrowska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Lipniacki
authors.forename: Andrzej
authors.initials: A
authors.lastname: Piasek
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Kulikowski
authors.forename: David
authors.initials: D
authors.lastname: Shugar
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D011355:Prodrugs / Q000378:metabolism*; D018119:Stavudine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D018119:Stavudine