Structure-activity relationships for the inhibition of DNA polymerase alpha by aphidicolin derivatives.
Aphidicolin and 17 derivatives that have been structurally modified in the A- and D-rings were assessed for their ability to inhibit DNA polymerase alpha. No derivative surpassed the activity of aphidicolin; derivatives with structural alterations in the A-ring exhibited significantly greater loss of activity relative to derivatives with structural alterations in the D-ring. The conclusions of these studies indicate a critical role for the C-18 function in the interaction of aphidicolin with polymerase alpha. Molecular modelling studies could not identify structural features of the aphidicolin-dCTP "overlap" that is unique to dCTP, relative to the remaining dNTPs, and that is consistent with the extant structure-activity data.
Prasad
G
G
Department of Chemistry, University of Virginia, Charlottesville 22901.
Edelson
R A
RA
Gorycki
P D
PD
Macdonald
T L
TL
D016590:Aphidicolin; D001665:Binding Sites; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D004224:Diterpenes / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004224:Diterpenes; D016590:Aphidicolin; D004257:DNA Polymerase II