Title
Intercalator induced DNA superstructure formation: doxorubicin and a synthetic quinoxaline derivative
Author
Tridib Mahata, Jeet Chakraborty, Ajay Kanungo, Dipendu Patra, Gautam Basu, Sanjay Dutta
Year
2018
Journal
Biochemistry
Abstract
Small molecules that intercalate DNA have tremendous therapeutic potential. Typically, DNA intercalators do not alter the overall DNA double helical structure, except locally at the intercalation sites. In a previous report we had shown that a quinoxaline-based intercalator with a mandatory benzyl substitution (1d), induced unusually large CD signal upon DNA binding, suggesting the formation of intercalated-DNA superstructures. However, no detailed structural studies were reported. Using AFM we have probed the nature of the superstructure and report the formation of a plectonemically oversupercoiled structure of pBR322 plasmid DNA by 1d, where close association of distant DNA double helical stretches is the predominant motif. Without the benzyl moiety (1a), no such DNA superstructure was observed. Similar superstructures were also observed with doxorubicin (dox), a therapeutically important DNA intercalator, suggesting that the superstructure is common to some intercalators. The superstructure formation, for both the intercalators, was observed to be GC-specific. Interestingly, at higher concentrations (1d and dox) the DNA superstructure led to DNA condensation – a phenomenon typically associated with polyamines but not intercalators. The superstructure may have important biological relevance in connection to a recent study where dox was shown to evict histone at micromolar concentrations.
Instrument
J-815
Keywords
Circular dichroism, Induced circular dichroism, DNA structure, Ligand binding, Chemical stability, Biochemistry