Aniline mustard analogues of the DNA-intercalating agent amsacrine: DNA interaction and biological activity.
Two series of analogues of the clinical antileukemic drug and DNA-intercalating ligand amsacrine have been prepared, containing aniline mustard sidechains of varying reactivity, linked either at the 4-position of the intercalating acridine chromophore (type A) or at the 1'-position of the 9-anilino group (type B). DNase I footprinting assays showed that compounds of type B had stronger reversible binding to DNA than did compounds of type A. Compounds of each type showed similar patterns of alkylation-induced cleavage of DNA, and alkylate at the N7 of guanines in runs of guanines (similar to the pattern for untargeted mustards) as well as some adenines. Both classes of compounds crosslinked DNA, although those bearing relatively inactive mustards did so only at high drug/base pair ratios. However, while the patterns of DNA alkylation were broadly similar, the compounds were considerably more cytotoxic than analogous untargeted mustards. Comparison of their cytotoxicities in wild-type and DNA repair-deficient lines indicated this toxicity was due to DNA crosslinks (except for the least reactive SO2-linked mustards). The 4-linked analogues showed slightly higher in vivo antileukemic activity than the corresponding 1'-linked analogues.
Fan
J Y
JY
Cancer Society Research Laboratory, Faculty of Medicine and Health Science, University of Auckland, New Zealand.
Valu
K K
KK
Woodgate
P D
PD
Baguley
B C
BC
Denny
W A
WA
D000677:Amsacrine / Q000737:chemistry / Q000494:pharmacology*; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004274:DNA, Recombinant / Q000737:chemistry / Q000187:drug effects*; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D014407:Tumor Cells, Cultured
D004274:DNA, Recombinant; D007364:Intercalating Agents; D000677:Amsacrine; D000816:Aniline Mustard