DNA binding by antitumor anthracene derivatives.
The relative DNA binding strengths of bisantrene and nine new analogues were measured by spectrophotometric titration and melt transition temperature (Tm) techniques. Data from the spectrophotometric titrations could not be fit by simple Scatchard plots. However, they were fit by a McGhee-von Hippel equation over part of the binding range. The entire range of data was fit by a smoothing cubic spline function. The first derivative of this function gave, for each compound, a curve whose intercept provided a measure of relative binding strength. The delta Tm values agreed qualitatively with the spectrophotometric titration results, although there was not a precise linear relationship. Determinations of macroscopic pKas revealed that most of the compounds were dications at pH 7.0, but a few were mixtures of monocations and dications. No correlation was found between these binding studies and antitumor potencies in a clonogenic assay, which suggests that factors other than DNA binding can determine cytotoxicity for some of the analogues.
Wunz
T P
TP
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson 85721.
Craven
M T
MT
Karol
M D
MD
Hill
G C
GC
Remers
W A
WA
D000818:Animals; D000873:Anthracenes / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D013329:Structure-Activity Relationship
D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; C031404:bisantrene; D004247:DNA