Antitumour polycyclic acridines. Part 4. Physico-chemical studies on the interactions between DNA and novel tetracyclic acridine derivatives.
The non-covalent interactions between a series of new tetracyclic acridine derivatives (5-11) and DNA have been studied by spectrophotometric analysis, fluorescences quenching, thermal denaturation, and circular and linear dichroism. In order to compare the extent of the DNA binding by compounds 5-11 in their neutral and cationic forms, all experiments were conducted at pH 7.4 (physiological pH) and 5.0. The results indicated that compounds 5-11 are strong DNA-binding ligands with DNA affinities comparable to that of m-AMSA (1) or even higher. They showed a stronger DNA binding activity at pH 5.0 as a result of the N-protonation of the pyridoacridine aromatic chromophore. Ethidium-DNA fluorescence assays showed an A-T base pair preference of the binding distinguishing these novel compounds from simple acridines which show a slight G-C base pair preference. Circular and linear dichroism studies indicated that the drugs bind to DNA by undergoing intercalation inside the duplex macromolecule at high DNA:drug ratios and revealed alternative binding modes at low DNA:drug ratios.
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, UK.
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Giménez-Arnau
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Missailidis
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Stevens
D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D004996:Ethidium / Q000737:chemistry; D006358:Hot Temperature; D007700:Kinetics; D009691:Nucleic Acid Denaturation; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
D000166:Acridines; D000970:Antineoplastic Agents; D002021:Buffers; D004247:DNA; D004996:Ethidium