Synthesis and in vitro chemical and enzymatic stability of glycosyl 3'-azido-3'-deoxythymidine derivatives as potential anti-HIV agents.
New glycosyl derivatives of 3'-azido-3'-deoxythymidine (AZT) (1 and 2) were synthesized in order to improve AZT retention in the blood and to guarantee its sustained release, overcoming the necessity of multiple drug administrations. The esters synthesized (1 and 2) link AZT, by a succinyl linker, to the C-3 position of glucose and to C-6 of galactose. Furthermore, the chemical and enzymatic stabilities of esters 1 and 2 were evaluated in order to determine both their stability in aqueous medium and their feasibility to undergo enzymatic cleavage by esterase to regenerate the original drug. The pharmacokinetic profiles of esters 1 and 2, obtained after systemic administration, showed an interesting controlled release, in particular for ester 2, compared to the pharmacokinetic profile of AZT.
Bonina
Francesco
F
Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Catania, Viale A. Doria 6, 95125, Catania, Italy. boninaf@mbox.unict.it
Puglia
Carmelo
C
Rimoli
Maria Grazia
MG
Avallone
Lucia
L
Abignente
Enrico
E
Boatto
Giampiero
G
Nieddu
Maria
M
Meli
Rosaria
R
Amorena
Michele
M
de Caprariis
Paolo
P
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004795:Enzyme Stability; D004950:Esterases / Q000378:metabolism; D006031:Glycosylation; D008297:Male; D011355:Prodrugs / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D011355:Prodrugs; D015215:Zidovudine; D004950:Esterases