Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, ACTIVE NUCLEOSIDE MONOPHOSPHATES, DELIVERY, PRONUCLEOTIDES, NUCLEOTIDES, CYCLOSAL-D4TMP, COMPLEXES, CHEMISTRY, D4TMP, Alkylation, Anti-HIV Agents, Benzyl Alcohols, Chromatography, High Pressure Liquid, Dideoxynucleotides, Enzymes, Hydrolysis, Methylation, Models, Molecular, Molecular Structure, Stavudine, Structure-Activity Relationship, Substrate Specificity, X-Ray Diffraction, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

Recently we reported on conceptually new enzymatically activated cycloSal-pronucleotides. Now, we developed this concept further with new compounds of this type. The basic idea is fast intracellular cleavage of a functionalized group at the cycloSal residue that results in a rapid delivery of the nucleotide and thus an intracellular enrichment of the nucleotide. The introduction of a higher alkylated acylal group, the di- iso-butyryloxymethyl group, to the aromatic ring led to the expected higher stability of these prodrugs against enzymatic cleavage but also entailed surprisingly a decrease in hydrolysis stabilities and solubility problems. For some compounds, a separation of the two diastereomeric forms ( R P or S P) was achieved. By X-ray structure analysis, the absolute configuration at the P-atom was assigned. For all separated diastereomers the ( S P) form showed better antiviral activity than the ( R P) form.