Doubly loaded cycloSaligenyl-pronucleotides - 5,5'-Bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates).
Recently, we reported on 3,3'-bis-(cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates) (3,3'-bis-(cycloSal-d4TMPs) 4) as the first pronucleotides with a mask-to-drug ratio of 1:2 that is still a novelty in the field of pronucleotides. Here, we report on a new set of compounds of these unique type of cycloSaligenyl prodrugs 5 that bear a biaryl axis at the 5-position of the cycloSal residue. All compounds 5 showed pronounced in vitro activity against HIV-1 and HIV-2 in wild-type CEM cell cultures and better retained their antiviral activities in thymidine kinase-deficient CEM cells than the compound 4 series. Moreover, compound 5b is the first bis-(cycloSal-d4TMP) that even showed complete retention of antiviral activity in TK-deficient CEM cells. The complex hydrolysis behavior of 5 was investigated, and the proposed hydrolysis mechanism was proven by means of (31)P NMR spectroscopy and HPLC analysis.
Gisch
Nicolas
N
Organic Chemistry, Department of Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, Hamburg, Germany.
Balzarini
Jan
J
Meier
Chris
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054306:Dideoxynucleotides / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D019906:Nuclear Magnetic Resonance, Biomolecular; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013942:Thymine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology*
D019380:Anti-HIV Agents; C415254:Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate; D054306:Dideoxynucleotides; D013942:Thymine Nucleotides; D018119:Stavudine