Synthesis of New Covalently Bound κ-Carrageenan−AZT Conjugates with Improved Anti-HIV Activities

This paper describes the first covalent synthesis of κ-carrageenan−3‘-azido-3‘-deoxythymidine (AZT) conjugates. A succinate diester spacer was used to covalently couple AZT onto κ-carrageenan, resulting in a tripartite prodrug. Two methods (UV and radioactive counting) are described and validated to...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2002-03, Vol.45 (6), p.1275-1283
Main Authors: Vlieghe, Patrick, Clerc, Thierry, Pannecouque, Christophe, Witvrouw, Myriam, De Clercq, Erik, Salles, Jean-Pierre, Kraus, Jean-Louis
Format: Article
Language:English
Subjects:
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Carbohydrate Sequence
Carrageenan - chemical synthesis
Carrageenan - chemistry
Cells, Cultured
Chemical Sciences
Drug Synergism
HIV-1 - drug effects
Humans
Medical sciences
Medicinal Chemistry
Molecular Sequence Data
Pharmacology. Drug treatments
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Zidovudine - chemical synthesis
Zidovudine - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:This paper describes the first covalent synthesis of κ-carrageenan−3‘-azido-3‘-deoxythymidine (AZT) conjugates. A succinate diester spacer was used to covalently couple AZT onto κ-carrageenan, resulting in a tripartite prodrug. Two methods (UV and radioactive counting) are described and validated to determine the AZT loading onto the κ-carrageenan carrier. This polymeric carrier, through its own intrinsic anti-HIV activity, is expected to act not only as a drug delivery agent but also as an anti-HIV agent. Synergism between the two drugs (κ-carrageenan and AZT) was demonstrated when MT-4 cells were preincubated with the κ-carrageenan−AZT conjugate prior to HIV-1-infection. A threshold of AZT loaded onto the κ-carrageenan was required to achieve this synergistic effect. Such κ-carrageenan−AZT conjugates could be of great therapeutic interest because these conjugates, which contain a low AZT concentration, present improved anti-HIV activities relative to free AZT. Moreover, κ-carrageenan is a well-tolerated biopolymer, already used in the food industry.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm010969d