ISSN:
1434-193X
Keywords:
AZT
;
cycloSal-pro-nucleotide
;
Prodrugs
;
Nucleotide delivery
;
HIV chemotherapy
;
Chemistry
;
General Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The application of our cycloSaligenyl- (cycloSal) pronucleotide concept to the approved anti-HIV dideoxynucleoside 3′-azido-3′-deoxythymidine AZT (1) is reported. This pro-nucleotide concept has been designed to deliver the corresponding 3′-azido-3′-deoxythymidine monophosphate AZTMP (2) by selective chemical hydrolysis from the lipophilic precursors cycloSal-AZTMP 4a-h. All derivatives 4a-h were synthesized using differently substituted salicyl alcohols 7a-h as starting materials. In hydrolysis studies, compounds 4 decomposed selectively releasing AZTMP (2) and the salicyl alcohols 7 following the designed tandem reaction. Furthermore, due to the electronic properties introduced by substituents, the half-lives of the triesters 4 could be ajusted over a wide range. Phosphotriesters 4 exhibited considerable biological activity in HIV-1 and HIV-2 infected wild-type human T-lymphocyte (CEM/O) cells, whereas, contrary to our expectations, nearly all activity was lost in HIV-2 infected thymidine-kinase-deficient CEM cells.
Type of Medium:
Electronic Resource