Design, synthesis, DNA sequence preferential alkylation and biological evaluation of N-mustard derivatives of Hoechst 33258 analogues.
The design, synthesis and biological evaluation of a series of bis-benzimidazole analogues of Hoechst 33258 bearing nitrogen mustard moieties is described. The novel compounds show clear evidence of interstrand cross-linking of linear lambda DNA, in contrast to their distamycin nitrogen mustard counterparts. Interference of the cross-linking reaction by the minor groove-selective distamycin suggests that this process takes place in the minor groove of DNA. Sequence preferential alkylation is revealed by high-resolution polyacrylamide gel electrophoresis and autoradiography. Alkylation occurs predominantly at the 5'-A or 5'-G termini of mixed sequences, determined largely by the sequence-recognizing properties of the bis-benzimidazole carrier moiety. An analysis of the frequency of bases around the alkylation sites reveals marked individual base preferences, especially for A at -3 and +3 positions. All of the compounds tested showed cytotoxic properties against the human tumor cell line KB in culture.
Gupta
R
R
Department of Chemistry, University of Alberta, Edmonton, Canada.
Wang
H
H
Huang
L
L
Lown
J W
JW
D000478:Alkylation; D000998:Antiviral Agents / Q000737:chemistry; D001345:Autoradiography; D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry; D006690:Bisbenzimidazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004270:DNA, Circular / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D007364:Intercalating Agents / Q000737:chemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000998:Antiviral Agents; D001562:Benzimidazoles; D004270:DNA, Circular; D004278:DNA, Superhelical; D004214:Distamycins; D007364:Intercalating Agents; D009588:Nitrogen Mustard Compounds; C009712:bis-benzimidazole; C030000:stallimycin; D004247:DNA; D006690:Bisbenzimidazole