Design, synthesis, DNA sequence preferential alkylation and biological evaluation of N-mustard derivatives of distamycin and netropsin analogues.
The design and synthesis of certain oligopeptides structurally related to distamycin and netropsin, but bearing mixed heterocyclic moieties capable of recognizing alternative base sites and nitrogen mustard moieties capable of covalent binding to DNA, are described. The binding and thermally induced DNA cleavage, covalent interstrand cross-linking, DNA preferential alkylation and anticancer cytotoxicities of the new agents are described. In contrast to the mustard derivative derived directly from distamycin, the new agents give evidence of extensive DNA alkylation and interstrand cross-linking. In general, strong alkylation is observed at A residues for this class of agents, while the G residues that are alkylated appear to be more characteristic of individual compounds. Densitometric analysis of the frequency of bases adjacent to the alkylation sites (-3 to +3) revealed that the preferred bases are exclusively A/T with little preference shown for G bases and none for C sites. Further insight into the DNA alkylation processes afforded by the drugs was provided by an independent assay whereby heating the drug-DNA adduct with 10% aqueous piperidine only yielded strand breaks specifically at G-N7 sites in the major groove.
Xie
G
G
Department of Chemistry, University of Alberta, Edmonton, Canada.
Gupta
R
R
Lown
J W
JW
D000478:Alkylation; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004214:Distamycins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004586:Electrophoresis; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007624:KB Cells; D007700:Kinetics; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D004214:Distamycins; D007364:Intercalating Agents; D009588:Nitrogen Mustard Compounds; D009842:Oligopeptides; D009429:Netropsin; C030000:stallimycin; D004247:DNA