SYNTHESIS, DNA-BINDING PROPERTIES AND CYTOTOXIC ACTIVITY OF FLAVIN-OLIGOPYRROLECARBOXAMIDE AND FLAVIN-OLIGOIMIDAZOLECARBOXAMIDE CONJUGATES

The aim of this study was to develop novel series of photosensitizer-D NA minor groove binder hybrids composed of a flavin (isoalloxazine) ch romophore linked to a moiety related to netropsin or distamycin. Three series (Fla-Pyr, Fla-Gly-Pyr and Fla-Gly-Im) were synthesized which d iffer by the number and the nature of the heterocyclic nuclei in the o ligopeptide units, the nature of the linker and its anchoring position on the flavin. In terms of DNA binding and DNA specificity, satisfact ory data are obtained in the ma-Pyr and Fla-Gly-Pyr series; in terms o f photo-induced cytotoxicity, the results are disappointing. The prese nt study allows us to draw the following structure-activity relationsh ips: (i) substitution of the flavin nucleus in either the N3 or the N1 0 position does not affect the activity; (ii) tris-pyrrolic hybrids ar e more efficient than bis- and tetra-pyrrolic analogs; (iii) the prese nce of a glycin in the linking chain does not suppress the DNA binding properties or the cytotoxic activities of the hybrids; and (iv) the r eplacement of the pyrrole nuclei by imidazols has a drastic effect sin ce it results in the loss of DNA affinity and cytotoxicity.