RT Journal Article
SR Electronic
T1 DNA-binding properties of a distamycin-ellipticine hybrid molecule.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 845
OP 855
VO 41
IS 5
A1 C Bailly
A1 C O'Huigin
A1 R Houssin
A1 P Colson
A1 C Houssier
A1 C Rivalle
A1 E Bisagni
A1 J P Henichart
A1 M J Waring
YR 1992
UL http://molpharm.aspetjournals.org/content/41/5/845.abstract
AB We have synthesized a distamycin-ellipticine hybrid compound and investigated its interaction with DNA, using various optical and gel electrophoresis techniques. Binding of the hybrid to DNA is evidenced by spectral shifts, fluorescence quenching, and induced linear dichroism. Absorbance measurements have been used to generate Scatchard plots, which reveal that the interaction cannot be described adequately in terms of a single binding mode, probably because of simultaneous intercalation and minor groove binding of the ligand. Competition with added distamycin has been used to verify involvement of the N-methyl-pyrrole portion of the hybrid molecule in the binding reaction. From electric linear dichroism experiments, it is estimated that the orientation of the DNA-bound ellipticine chromophore in the hybrid differs by about 10 degrees from the orientation of the equivalent chromophore lacking a distamycin tail. Topoisomerase assays establish that binding of the hybrid unwinds the DNA helix by a minimum of 11 degrees, which is consistent with intercalation but notably smaller than the unwinding angle of ellipticine. In footprinting experiments, it is found that the AT- and GC-specificity of distamycin and ellipticine, respectively, appear to be merged in the binding of the hybrid, which produces a pattern of protection distinct from the characteristic patterns for either of the parent compounds. The hybrid is an extremely effective inhibitor of cutting by DNase I.