Synthesis and biological evaluation of some phosphate triester derivatives of the anti-viral drug AraA.
A number of novel phosphate triester derivatives of the anti-viral nucleoside analogue araA have been prepared by a rapid 2-step procedure, not necessitating prior sugar protection. Spectroscopic and lipophilicity data have been collected on these compounds, and they have been assayed with a range of hydrolytic enzymes. The compounds have been found to be highly resistant to hydrolysis at physiological pH, enzymatic or otherwise. An in vitro assay indicated inhibition of DNA synthesis by mammalian cells, by each of these compounds, in the range 3-300 microM. Moreover, the degree of inhibition showed a close correlation to chemical structure; in particular, there was a direct relationship between inhibition of thymidine incorporation and lipophilicity. These results suggest cellular penetration by the phosphate triesters and intracellular hydrolysis, by an unspecified mechanism, to the free nucleotide or nucleoside.
McGuigan
C
C
Department of Chemistry, University College London, UK.
Tollerfield
S M
SM
Riley
P A
PA
D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004952:Esters; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D004952:Esters; D004247:DNA; D000243:Adenosine Deaminase; D014740:Vidarabine; D013936:Thymidine