Studies on enzyme-cleavable dialkoxymethyl-cyclosaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates.
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.
Gisch
Nicolas
N
Organic Chemistry, Department of Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Balzarini
Jan
J
Meier
Chris
C
D000478:Alkylation; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001592:Benzyl Alcohols / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D054306:Dideoxynucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004798:Enzymes / Q000378:metabolism*; D006868:Hydrolysis; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014961:X-Ray Diffraction
C113124:2',3'-dideoxy-2',3'-didehydrothymidine monophosphate; D019380:Anti-HIV Agents; D001592:Benzyl Alcohols; D054306:Dideoxynucleotides; D004798:Enzymes; D018119:Stavudine; C010631:salicyl alcohol