The 5H-pyrido[4,3-b]indole, 11H-indolo[3,2-c]quinoline, 5H-benzo[f]pyrido[4,3-b]indole, and 13H-benz[5,6]indolo[3,2-c]quinoline heteroaromatic nuclei have been synthesized by the Graebe−Ullmann method by classical heating or under microwave irradiation. These tri-, tetra-, and pentacyclic compounds were transformed into the corresponding cationic derivatives by N-alkylation, and the DNA-binding properties of the resulting cationic systems were examined using UV−vis spectroscopy, viscometric determinations, and molecular modeling techniques. The tetracyclic cations were transformed into bis-salts by means of a diethyl bispiperidine rigid chain and a more flexible polyamide linker, but the low solubility of these bis-salts made the study of their bisintercalating properties difficult.
A new class of DNA intercalators based on the 8H-pyridazino[1‘,6‘:1,2]pyrido[4,3-b]indol-5-inium system in which the cationic nature of the chromophore is provided by a brigdehead quaternary nitrogen has been obtained. These cations along with 10H-indolo[3,2-c]pyridazino[1,6-a]quinolin-5-inium, 13H-dibenz[f,h]indolo[3‘,2‘:3,4]pyrido[1,2-b]cinnolin-10-inium, and 5H-acenaphtho[1‘,2‘:3‘,4‘]pyridazino[1‘,6‘:1,2]pyrido[4,3-b]indol-8-inium were synthesized by the Westphal reaction of carbolinium derivatives with various 1,2-dicarbonyl compounds. When these tetra-, penta-, and heptacyclic heteroaromatic nuclei were evaluated as DNA intercalators using UV−vis spectroscopy, viscometric determinations, and unwinding angle determinations, we found that only the 8H-pyridazino[1‘,6‘:1,2]pyrido[4,3-b]indol-5-inium cations behaved as DNA intercalators. Molecular modeling studies allowed the preferred orientation of the intercalating chromophore within a CpG intercalation site to be explored and will provide help in the rational design of novel bis-intercalators based on these chromophores.
1-Methyl-y-carboline derivatives were transformed into the corresponding N-aminoazinium salts, which were condensed with 1,2-dicarbonyl compounds (Westphal reaction) to afford azonia derivatives with a bridgehead quaternary nitrogen atom. Some of them show DNA intercalating properties. Copyright © 1996 Elsevier Science Ltd Since DNA is an important cellular receptor, most anticancer agents exert their effects trough binding to it.Intercalation is one of these modes of interaction, in which a molecule is inserted between two adjacent base pairs causing lengthening, stiffening and unwinding of the helix. ~ Planar polyheteroaromatic cations are particularly well adapted for intercalation between nucleic acid base pairs. While the positive charge in the chromophore seems to be essential for increasing their DNA affinity, 2 their orientation in the intercalative proccess is highly dependent on the electrostatic component of the stacking interaction. Favourable dipolar interactions between the chromophore .and the base pairs contribute to explain the observed selectivity for CpG or TpA steps. 3 For these reasons, alterations of the dipole moment of the chromophore is an important element to be considered when DNA bisintercalators are being designed. H N NN2 HO i ]Ethldlum Bromide C611ptiu~The above considerations led us to explore the DNA binding properties of type 1 azonia derivatives, incorporating as chromophore a polyheteroaromatic cation, in which the positive charge is not introduced by Nalkylation of the azaheterocycle, such is the case of well known DNA intercalators, such as ethidium bromide and some antitumour compounds of the ellipticine group (e. g. Crliptium®),. but by the presence of a quaternary bridgehead nitrogen. 4 In this communication we wish to report our initial results on the transformation of the "ycarboline system into tetracyclic and beptacyclic azonia derivatives, along with the DNA binding properties and charge distribution of a representative compound.The 1-methylcarbolines were prepared by thermal or microwave decomposition of the corresponding pyridylbenzotriazoles 2 (Graebe-Ullmann reaction) 5 as previously described. 6 These derivatives were easily transformed into the salts 3 by amination with (O-mesitylenesulfonyl)hydroxylamine (MSH) in CH2C12 at room 1453
The structures of complexes obtained by reacting acyl N-aminides and ZnCI: were ascertained by Xray analysis and were show to incorporate one Zn atom and two molecules of the N-aminide in a distorted tetrahedral geometry. Bis-aminides act as bidentate tigands forming ZnI,C12 complexes.
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