5-(1-Acetoxyvinyl)-cycloSaligenyl-2',3'-dideoxy-2',3'- didehydrothymidine monophosphates, a second type of new, enzymatically activated cycloSaligenyl pronucleotides.
In our attempt to further develop the cycloSal pronucleotide concept, we report on 5-(1-acetoxyvinyl)-cycloSal-d4TMPs as a new type of enzyme-activated pronucleotides. These compounds were converted into 5-acetyl-cycloSal-d4TMPs by (carboxy)esterase cleavage inside the cells. The enzymatic reaction led to the formation of a strong electron-withdrawing substituent that strongly accelerates the chemical hydrolysis of the cycloSal nucleotide to give d4TMP. For some cycloSal-d4TMPs a separation into the diastereomers was achieved. The absolute configuration was assigned by correlation of circular dichroism spectra with similar compounds. Most of the compounds showed complete retention of antiviral activity in TK-deficient CEM/TK(-) cells, which proves the TK-bypass potential of this approach. Interestingly, (S(P))-isomers of cycloSal phosphate triesters showed better antiviral activity in HIV-2-infected thymidine-kinase deficient CEM/TK(-) cells than their (R(P))-counterparts.
Gisch
Nicolas
N
Organic Chemistry, Department of Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Pertenbreiter
Florian
F
Balzarini
Jan
J
Meier
Chris
C
D019380:Anti-HIV Agents / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D054306:Dideoxynucleotides / Q000138:chemical synthesis* / Q000737:chemistry*; D015195:Drug Design; D004583:Electrons; D015497:HIV-1 / Q000378:metabolism; D015498:HIV-2 / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009711:Nucleotides / Q000737:chemistry*; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013942:Thymine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry
C113124:2',3'-dideoxy-2',3'-didehydrothymidine monophosphate; D019380:Anti-HIV Agents; C415254:Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate; D054306:Dideoxynucleotides; D009711:Nucleotides; D013942:Thymine Nucleotides; D018119:Stavudine