title: Enzymatically activated cycloSal-d4T-monophosphates: The third generation of cycloSal-pronucleotides.
abstract: The third generation of cycloSal-pronucleotides, 5-diacetoxymethyl-cycloSal-d4T-monophosphates (5-di-AM-cycloSal-d4TMPs), is reported as a new class of "lock-in"-modified cycloSal-pronucleotides. These compounds bear an esterase-cleavable geminal dicarboxylate (acylal) attached to the aromatic ring of the saligenyl unit. The conversion into a strong acceptor group (aldehyde) leads to a strong decrease in hydrolytic stability. As a consequence, a fast release of a nucleoside monophosphate (i.e., d4TMP) follows. The concept of this enzymatic activation is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations showed the conversion of the acylal group into a polar aldehyde by enzymatic cleavage. Besides, antiviral activities against HIV are presented.
authors.affiliation: Department of Chemistry, Organic Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gisch
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054306:Dideoxynucleotides; D006801:Humans; D006868:Hydrolysis; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D013942:Thymine Nucleotides
chemical_list: D019380:Anti-HIV Agents; C415254:Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate; D054306:Dideoxynucleotides; D010755:Organophosphates; D013942:Thymine Nucleotides; D018119:Stavudine; D013936:Thymidine