Pyrazole analogues of the bispyrrolecarboxamide anti-tumour antibiotics: synthesis, DNA binding and anti-tumour properties.
Four bispyrazole compounds have been prepared as potentially more stable analogues of the DNA minor groove binding polypyrrole compounds netropsin and distamycin, which are susceptible to oxidative breakdown. These compounds bind less strongly to DNA, and show much lower specificity for binding to AT-rich DNA sequences in comparison with distamycin. N.m.r. studies show that two of these compounds cause a downfield shift of the DNA imino proton resonances on interaction with the oligonucleotide d(ATATATATAT)2, suggesting that these isomers can adopt low-energy conformations similar to that shown by distamycin in its DNA minor groove binding site. The benzoic acid mustard analogue of one of the minor groove binding bispyrazoles was prepared, and showed in vitro cytotoxicity comparable with that of the previously-reported distamycin mustard, but only a low level of activity in vivo.
Lee
H H
HH
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Boyd
M
M
Gravatt
G L
GL
Denny
W A
WA
D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000378:metabolism*; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives; D009841:Oligonucleotides / Q000378:metabolism; D011067:Poly dA-dT / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000577:Amides; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D009841:Oligonucleotides; D011089:Polydeoxyribonucleotides; D011758:Pyrroles; D011067:Poly dA-dT; C019530:poly(dC-dG); D009429:Netropsin