Aryl-substituted and benzo-annulated cyc/osal-derivatives of 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate--correlation of structure, hydrolysis properties and anti-HIV activity.
The synthesis of phenyl-substituted and benzoannulated cycloSal phosphate triesters of the nucleoside analogue 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, Zerit) as lipophilic, membrane-soluble pronucleotides is described. The cycloSal moiety was introduced by using cyclic chlorophosphite agents prepared from phenyl-substituted saligenin derivatives and ortho-hydroxymethylated naphthols, respectively. Hydrolysis studies (HPLC analysis) of the triesters 2, 3 showed a range of hydrolytic stability from 1.4 h up to 5.1 h and the stability could be correlated with the substitution pattern in the cycloSal moiety. A slight decrease of their stability was observed, if phenyl-substituted derivatives were hydrolyzed in human CEM/O cell extracts. D4T and thymine, possible products of enzymatic cleavage of the pronucleotides, were not detected in the cell extracts. A further investigation of the hydrolysis process was performed by 31P-NMR spectroscopy. This technique allowed a precise monitoring of the degradation products and the exact determination of the product ratio. Finally, the newly synthesized compounds were tested concerning their antiviral activity against HIV in vitro. A strong correlation of the hydrolysis properties and the antiviral activity was found. 3-phenyl-cycloSal-d4TMP showed a threefold increase in its anti-HIV-1 activity and retained full activity in thymidine kinase (TK) deficient cells, indicative of a successful TK-bypass.
Ducho
Christian
C
Institut für Organische Chemie, Universität Hamburg, Germany.
Balzarini
Jan
J
Naesens
Lieve
L
De Clercq
Erik
E
Meier
Chris
C
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D054306:Dideoxynucleotides; D004355:Drug Stability; D004952:Esters; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D018119:Stavudine / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013937:Thymidine Kinase; D013942:Thymine Nucleotides; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; C415254:Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate; D054306:Dideoxynucleotides; D004952:Esters; D013942:Thymine Nucleotides; D018119:Stavudine; D013937:Thymidine Kinase; D013936:Thymidine