Human DNA topoisomerase I inhibitory activities of synthetic polyamines: relation to DNA aggregation.
Fiche publication
Date publication
mai 2001
Journal
Bioorganic & medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DEVY Jérôme, Pr LEHN Jean-Marie, Pr NABIEV Igor
Tous les auteurs :
Sukhanova A, Dêvy J, Pluot M, Bradley JC, Vigneron JP, Jardillier JC, Lehn JM, Nabiev I
Lien Pubmed
Résumé
DNA aggregation by polyamines has acquired importance as a prerequisite for the cellular uptake of DNA for gene therapy. Intracellular polyamines are constitutive components of mammalian cells and their availability is critical for cell proliferation. Interference of polyamine biosynthesis by synthetic polyamines leads to cytotoxicity. Optimization of the polyamine structural parameters is necessary to control their DNA aggregation, cytotoxic or enzyme inhibitory activities. We designed two series of tetra- and hexamines and compared their human DNA topoisomerase I (top1) inhibitory effects with the DNA aggregation properties. We show that hexamines are more efficient inhibitors of DNA relaxation by top1 than tetramines and that they suppress the top1-mediated DNA cleavage while tetramines do not. The DNA aggregation abilities within two series of polyamines correlate with the length of their central methylene chain. By contrast, the top1 inhibition within two series does not show the same correlation but demonstrates a threshold inhibitory effect on going from the (CH(2))(12) to the (CH(2))(14) central chain. We show further that the structures of DNA aggregates formed by polyamines with the (CH(2))(10-12) or with the (CH(2))(14-16) chains are very different. The first are a fluid cholesteric-type phases, whereas the second are well-structured aggregates similar to columnar liquid crystals with high packing density of DNA duplexes. The structures of polyamines-induced DNA aggregates are proposed to be crucial for top1 catalysis. The structure-function correlation described here may serve as a guide for rational design of polyamines with desired DNA-aggregation or anti-top1 activities.
Mots clés
Base Sequence, physiology, Biogenic Polyamines, metabolism, Chemical Precipitation, DNA, drug effects, DNA Fragmentation, drug effects, DNA Topoisomerases, Type I, metabolism, Humans, Microscopy, Polarization, Molecular Sequence Data, Plasmids, genetics, Polyamines, chemical synthesis, Topoisomerase I Inhibitors
Référence
Bioorg. Med. Chem.. 2001 May;9(5):1255-68