Collect. Czech. Chem. Commun.
2006, 71, 1211-1220
https://doi.org/10.1135/cccc20061211
Polymeric Conjugates of 9-[2-(Phosphonomethoxy)ethyl]purine with Potential Antiviral and Cytostatic Activity
Michal Pechara,*, Alena Braunováa, Vladimír Šubra, Karel Ulbricha and Antonín Holýb
a Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, 162 06 Prague 6, Czech Republic
b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
Abstract
Syntheses and characterization of polymer conjugates of 9-[2-(phosphonomethoxy)ethyl] (PME) derivatives of adenine (PMEA), 2,6-diaminopurine (PMEDAP) and guanine (PMEG) are described. The phosphonate group of these acyclic nucleotide analogues was activated by reaction with triphenylphosphine and di(2-pyridyl) disulfide (TPP-PDS). The activated phosphonate reacted with a random copolymer containing N-(2-hydroxypropyl)methacrylamide (HPMA) and N-(3-methacrylamidopropanoyl)ethane-1,2-diamine (Ma-AP-ED) units. The phosphonamide bond between the nucleotide and polymer carrier proved to be relatively stable at physiological pH 7.4 while at pH 5.0 (corresponding to endosomal or lysosomal compartments of cells) underwent slow hydrolysis. The rate of hydrolysis (drug release) was shown to depend on the detailed structure of the heterocyclic base. The polymer-drug conjugates described in the paper represent a new family of antiviral and cytostatic drugs with potentially improved pharmacokinetics, sustained drug release and diminished non-specific toxicity.
Keywords: Drug delivery systems; Polymer-supported drugs; Cytostatics; Antivirals; Hydrolyses; Phosphonamide bond; HPMA copolymer; Acyclic nucleotide analogues; Acyclic nucleoside phosphonates.
References: 29 live references.
