Synthesis, DNA-binding properties and cytotoxic activity of flavin-oligopyrrolecarboxamide and...

The aim of this study was to develop novel series of photosensitizer-DNA minor groove binder hybrids composed of a flavin (isoalloxazine) chromophore linked to a moiety related to netropsin or distamycin. Three series (Fla-Pyr, Fla-Gly-Pyr and Fla-Gly-Im) were synthesized which differ by the number and the nature of the heterocyclic nuclei in the oligopeptide units, the nature of the linker and its anchoring position on the flavin. In terms of DNA binding and DNA specificity, satisfactory data are obtained in the Fla-Pyr and Fla-Gly-Pyr series; in terms of photo-induced cytotoxicity, the results are disappointing. The present study allows us to draw the following structure-activity relationships: (i) substitution of the flavin nucleus in either the N3 or the N10 position does not affect the activity; (ii) tris-pyrrolic hybrids are more efficient than bis- and tetra-pyrrolic analogs; (iii) the presence of a glycin in the linking chain does not suppress the DNA binding properties or the cytotoxic activities of the hybrids; and (iv) the replacement of the pyrrole nuclei by imidazoles has a drastic effect since it results in the loss of DNA affinity and cytotoxicity.