Intracellular trapping of cycloSal-pronucleotides: modification of prodrugs with amino acid esters.
A new class of d4TMP- cycloSal-pronucleotides bearing enzymatically cleavable amino acid esters is reported. These compounds are designed to trap the pronucleotide inside the cell by a fast conversion of a nonpolar ester group into a charged carboxylate. This should prevent efficient diffusion equilibrium across the cell membrane to the extracellular environment, leading to an intracellular accumulation of the compounds. This initial conversion is followed by a slow release of the nucleoside monophosphate (i.e., d4TMP). The concept is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations revealed a high sensitivity of some amino acid ester modifications to conversion by cellular extracts, resulting in the fast release of a charged intermediate, whereas no cleavage of the modification is found in phosphate buffer. In addition, antiviral activities against HIV are presented.
Jessen
Henning J
HJ
Chemistry Department, Organic Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Balzarini
Jan
J
Meier
Chris
C
D000596:Amino Acids / Q000737:chemistry*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002457:Cell Extracts; D002460:Cell Line; D003500:Cyclization; D004952:Esters / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009711:Nucleotides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018119:Stavudine / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000998:Antiviral Agents; D002457:Cell Extracts; D004952:Esters; D009711:Nucleotides; D011355:Prodrugs; D018119:Stavudine