Binding to DNA, cellular uptake and biological activity of a distamycin-ellipticine hybrid molecule.
A hybrid molecule which conjugates the minor groove binding agent distamycin and an ellipticine derivative was synthesized and evaluated for cytostatic and cytotoxic activities against L1210 leukaemia cells in vitro. The binding of the hybrid molecule, named 'Distel', to a range of natural DNAs and synthetic polynucleotides with different base pair arrangements was studied by electric linear dichroism. The interaction with DNA simultaneously implicates binding of the distamycin part in the minor groove and intercalation of the ellipticine chromophore. The drug binds to DNA without any apparent preference for AT or GC polynucleotides, and can accommodate both homopolymeric and co-polymeric sequences as a binding site. However, the geometry of the drug-DNA complex varies depending on the targeted sequence. The lower activity of the hybrid as compared to the ellipticine derivative cannot be explained in terms of DNA binding. Taking advantage of the fluorescence of the pyridocarbazole chromophore, fluorescence microscopy was used to map cellular uptake of the hybrid molecule compared to the ellipticine derivative. Both the conjugate and the ellipticine derivative preferentially accumulate in the nuclei of HeLa cells rather than in the cytoplasm. Nuclei of ellipticine derivative-treated cells appear markedly more fluorescent than those of cells treated with the hybrid, which seems to be preferentially located in the nucleoli. Therefore, we consider the possibility that the difference in cytotoxicity between the two ellipticine-containing drugs is due to different intranuclear concentrations of these two compounds.
Bailly
C
C
INSERM Unité 124, Institut de Recherches sur le Cancer, Lille, France.
Leclere
V
V
Pommery
N
N
Colson
P
P
Houssier
C
C
Rivalle
C
C
Bisagni
E
E
Hénichart
J P
JP
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003016:Clostridium perfringens / Q000235:genetics; D004247:DNA / Q000187:drug effects*; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology*; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007939:Leukemia L1210; D051379:Mice; D008837:Micrococcus / Q000235:genetics; D008856:Microscopy, Fluorescence; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured
D004214:Distamycins; D004611:Ellipticines; C078726:Distel; D004247:DNA