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 have synthesized two types of hybrid groove binders composed of an isoalloxazine (flavin) chromophore linked through a polymethylenic chain to either a bis- or a tris(pyrrolecarboxamide) moiety related to netropsin and distamycin, respectively. In both types of molecules, the polymethylenic chain is linked to the alloxazine ring either in the N10 position 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 moiety undergoes a redox cycling process generating superoxide anion and hydroxyl radical. Generation of oxy radicals appears to be more efficient with the hybrids in which the polymethylenic chain is linked at the N10 position. The generation of oxy radicals results in the occurrence of single strand break in supercoiled DNA. Breaks preferentially occur in the vicinity of A + T-rich sequences. The advantage of flavin 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.
Herfeld
P
P
Laboratoire de Chimie Thérapeutique, CNRS URA 1310, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Helissey
P
P
Giorgi-Renault
S
S
Goulaouic
H
H
Pager
J
J
Auclair
C
C
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D016172:DNA Fingerprinting; D004270:DNA, Circular / Q000187:drug effects / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D004214:Distamycins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D005415:Flavins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009429:Netropsin / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010777:Photochemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014783:Viscosity
D000577:Amides; D003432:Cross-Linking Reagents; D004270:DNA, Circular; D004278:DNA, Superhelical; D004214:Distamycins; D005415:Flavins; D011758:Pyrroles; D017382:Reactive Oxygen Species; C008173:isoalloxazine; D009429:Netropsin; D004247:DNA