Sequence selectivity, cross-linking efficiency and cytotoxicity of DNA-targeted 4-anilinoquinoline aniline mustards.
We have investigated the sequence selectivity, DNA binding site characteristics, interstrand cross-linking ability and cytotoxicity of four 4-anilinoquinoline aniline mustards related to the AT-selective minor groove-binding bisquaternary ammonium heterocycles. The compounds studied include two full mustards that differ in alkylating power, a half mustard and a quaternary anilinoquinolinium bismustard. We have also compared their cytotoxicity with their precursor diols and their toxicity and cross-linking ability with the classical alkylating agents melphalan and chlorambucil. We find that the anilinoquinoline aniline mustards weakly and non-specifically alkylate guanines in the major groove and that they bind strongly to AT-rich sequences in the minor groove, where they alkylate both adenines and guanines at the N3 position. The most preferred sites are classical minor groove binder AT-tracts to which all four ligands bind equally well. The remaining sites are AT-rich, but include GC base pairs, to which the ligands bind with preferences depending on their structure. The full mustards alkylate at the 3' ends of the binding site in an orientation that depends on the spatial disposition of the purines within the two strands. Generally speaking guanines are found to be much less reactive than adenines. The anilinoquinoline aniline mustards are interstrand cross-linking agents that are 60- to 100-fold more effective than melphalan, with the quaternary compound being the most efficacious. However, the type of binding site at which the cross-links occur is not clear, since distamycin challenge fails to antagonize them fully. The full mustards are 20- to 50-fold more cytotoxic than their diol precursors, are more cytotoxic than the half mustard and are 20- to 30-fold more active than melphalan and chlorambucil. The quaternary ligand is the most potent. Given the evidence to hand, it appears that antitumour activity correlates with capacity to cause interstrand cross-links at classical or near-classical AT-minor groove binder sites, rather than with ability to discriminate between the subsets of potential anilinoquinoline aniline mustard binding sites.
McClean
S
S
Chemistry Department, University College Dublin, Belfield, Ireland.
Costelloe
C
C
Denny
W A
WA
Searcey
M
M
Wakelin
L P
LP
D000478:Alkylation; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000633:toxicity*; D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D003432:Cross-Linking Reagents / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004214:Distamycins / Q000378:metabolism / Q000633:toxicity; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000235:genetics; D011804:Quinolines / Q000378:metabolism / Q000633:toxicity; D013379:Substrate Specificity
D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D003432:Cross-Linking Reagents; D004214:Distamycins; D011804:Quinolines; C030000:stallimycin; D004247:DNA; D000816:Aniline Mustard