POLY(PYRROLECARBOXAMIDES) LINKED TO PHOTOACTIVABLE CHROMOPHORE ISOALLOXAZINE - SYNTHESIS, SELECTIVE BINDING, AND DNA-CLEAVING PROPERTIES

In an attempt to obtain DNA sequence-specific cleaving molecules, we h ave synthesized two types of hybrid groove binders composed of an isoa lloxazine (flavin) chromophore linked through a polymethylenic chain t o either a bis- or a tris(pyrrolecarboxamide) moiety related to netrop sin and distamycin, respectively. In both types of molecules, the poly methylenic chain is linked to the alloxazine ring either in the N-10 p osition or in the N3 position. As netropsin and distamycin,the hybrid derivatives preferentially bind to A + T-rich sequences and recognize sequences such as 5'-ATTT. Upon visible light irradiation the flavin m oiety undergoes a redox cycling process generating superoxide anion an d hydroxyl radical. Generation of oxy radicals appears to be more effi cient with the hybrids in which the polymethylenic chain is linked at the N-10 position. The generation of oxy radicals results in the occur rence of single strand break in supercoiled DNA. Breaks preferentially occur in the vicinity of A + T-rich sequences. The advantage of flavi n relative to other oxy radicals generating compounds such as ferrous- EDTA is that it does not require chemical reduction but can be reduced either by visible light or by cellular enzymes, both conditions being compatible with pharmacological constraints.