Myristoylated derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine) bi-functional prodrugs with potent anti-HIV-1 activity and low cytotoxicity.
Antivir Chem Chemother
; 23(6): 231-5, 2014 Dec 16.
Article
em En
| MEDLINE
| ID: mdl-23985753
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
HIV-1
/
Estavudina
/
Fármacos Anti-HIV
Idioma:
En
Revista:
Antivir Chem Chemother
Assunto da revista:
QUIMICA
/
TERAPIA POR MEDICAMENTOS
/
VIROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Índia