The Bioreductive Alkylation of DNA by Kalafungin: A Theoretical Investigation
Paul A. Hume A , Margaret A. Brimble A and Jóhannes Reynisson A B
+ Author Affiliations
- Author Affiliations
A School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
B Corresponding author. Email: j.reynisson@auckland.ac.nz
Australian Journal of Chemistry 65(4) 402-408 https://doi.org/10.1071/CH12018
Submitted: 17 January 2012 Accepted: 20 February 2012 Published: 30 March 2012
Abstract
The thermochemical cascades for the bioreductive alkylation of DNA by kalafungin were calculated using density functional theory (DFT). Guanine (G) was used as a model nucleotide. According to the calculations both one- and two-electron reduction of kalafungin is possible in vivo. Furthermore, a clear pathway was found for both mono- and bis-alkylations of G with the former favoured. Alkylation at C-8 position of G is considerably more exothermic than on the N2-exocyclic amine. In the absence of experimentally identified adduct structures of kalafungin, the results presented here support the idea that this compound readily forms covalent bonds with DNA resulting in pro-mutagenic lesions.
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