Synthesis, DNA binding and cytotoxicity of 1-[[omega-(9-acridinyl)amino]alkyl]carbonyl -3-(chloromethyl)-6-hydroxyindolines, a new class of DNA-targeted alkylating agents.
We report the first synthesis of examples of the seco-CI DNA alkylating moiety 3-(chloromethyl)-6-hydroxyindoline linked to a 9-aminoacridine DNA-intercalating unit (compounds 1a-1c). The sequence-specificity of DNA alkylation by these compounds was studied by the gel electrophoresis cleavage assay. In contrast to the known trimethoxyindole-linked compound (1d), which alkylates exclusively at N3 of adenines in the minor groove, the acridine-linked analogues (1a-1c) alkylate predominantly at the N7 of guanines in the major groove (the first CI analogues reported to do so), although DNase I footprinting experiments show that the initial non-covalent binding of 1a-1c is not base sequence selective. DNA unwinding experiments show that the acridine moiety of 1a-1c remains intercalated after alkylation.
Fan
J Y
JY
Cancer Society Research Laboratory, Faculty of Medicine and Health Sciences, University of Auckland, New Zealand.
Tercel
M
M
Denny
W A
WA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D018736:DNA Adducts; D018983:DNA Footprinting; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004273:DNA, Neoplasm; D007364:Intercalating Agents