DNA-binding studies of a series of novel water-soluble derivatives of 1,4-dihydropyridine

Abstract

Aim. To the determine DNA interaction modes for a series of 1,4-dihydropyridines with different biological activities synthesized in the Latvian Institute of Organic Synthesis. Methods. Affinity of the compounds to DNA was detected by UV/VIS spectrometry and re-proofed by means of spectrofluorimetry, EBr extrusion assay, cyclic voltammetry and DNA melting. Radical scavenging was tested by electron paramagnetic resonance spectroscopy, peroxynitrite binding was monitored spectrophotometrically, protection of DNA against hydroxyl radical was determined by gel electrophoresis. Results. In a series of water-soluble monocyclic derivatives of 1,4-dihydropyridine with carboxylate groups in position-4 the different affinity to DNA was determined mainly by substituents in positions 3 and 5. 1,4-DHP with ethoxycarbonyl groups in positions 3 and 5 (AV-153) manifested high affinity to DNA. Strong effects were observed in the spectra of tricyclic fused derivatives (PP-150-Na and PP-544-NH4). Unlike AV-153, J-4-96 did not extrude EtBr from the complex with DNA, this indicates binding to minor groove. Ability of PP-544-NH4 to intercalate DNA molecule was proved electro-chemically and by DNA melting. No correlation between affinity of a 1,4-DHP to DNA and capabilities of the compound to bind peroxynitrite, to scavenge hydroxyl radical or to protect DNA against the above radical were observed. Conclusions. DNA-binding activities of 1,4-DHP are evidently determined by groups in positions 3 and 5. Tricyclic fused 1,4-DHP derivatives are also good DNA binders. Ability to interact with DNA does not correlate with other effects produced by the compounds.