Compounds that cause DNA and RNA damage via radicals are of utility for treating disease as well as for studying polynucleotide structures in footprintng experiments that probe solvent accessible areas for damage by radicals. Of particular interest are light-responsive compounds that generate radicals due to the ability to spatiotemporally control reactivity, which is advantageous in treating disease and in studying polynucleotide structure. Alkylcobalamins generate carbon-centered radicals which are capable of causing DNA strand scission when exposed to visible light wavelengths (400 – 600 nm). The majority of reported compounds that cause radical mediated DNA cleavage in a light-dependent manner require illumination with ultraviolet light, which is readily absorbed by polynucleotide bases causing damage. This damage resulting from direct light exposure interferes with studying polynucleotide structure by radical footprinting experiments. Methylcobalamin effectively causes DNA strand scission with light wavelengths (&gt;500 nm) that are not absorbed by polynucleotide bases demonstrating the potential utility for using alkylcobalamins in radical footprinting experiments of polynucleotide structure. DNA cleavage efficacy improved by an order of magnitude by appending the DNA binding moiety spermine to an alkylcobalamin. Agents that cause double-strand DNA scission, which are used as chemotherapeutics as well as antibiotics, are of considerable interest due to these lesions being more difficult for the cellular machinery to repair than single-strand DNA scission. Covalently linking two cobalamins together with a propyl chain results in a complex that causes double-strand DNA events in a visible-light mediated manner due to two radicals being generated temporally and spatially close to each other. Due to the exceptionally high quantum yields of alkylcobalamins, photolysis of the covalently connected cobalamin moieties occurs nearly simultaneously generating a diradical propyl chain that is capable of cleaving opposite strands proximally at the same time leading to double-strand scission events.

Light-mediated DNA cleavage by alkylcobalamins

2019 Spring National Meeting

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