Thiophene-based diamidine forms a "super" at binding minor groove agent.

Mallena, S., Lee, M.P., Bailly, C., Neidle, S., Kumar, A., Boykin, D.W. and Wilson, W.D. (2004) Thiophene-based diamidine forms a "super" at binding minor groove agent. Journal of the American Chemical Society, 126 (42). pp. 13659-136569. 10.1021/ja048175m.

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DOI: 10.1021/ja048175m


The DNA minor groove is the interaction site for many enzymes and transcription control proteins and as a result, development of compounds that target the minor groove is an active research area. In an effort to develop biologically active minor groove agents, we are preparing and exploring the DNA interactions of a systematic set of diamidine derivatives with a powerful array of methods including DNase I footprinting, biosensor-SPR methods, and X-ray crystallography. Surprisingly, conversion of the parent phenyl-furan-phenyl diamidine to a phenyl-thiophene-benzimidazole derivative yields a compound with over 10-fold-increased affinity for the minor groove at AT sequences. Single conversion of the furan to a thiophene or a phenyl to benzimidazole does not cause a similar increase in affinity. X-ray results indicate a small bond angle difference between the C−S−C angle of thiophene and the C−O−C angle of furan that, when amplified out to the terminal amidines of the benzimidazole compounds, yields a very significant difference in the positions of the amidines and their DNA interaction strength.

Item Type:Article
Additional Information:Full text available in print and electronically from the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group
ID Code:1754
Journal or Publication Title:Journal of the American Chemical Society
Deposited By:Library Staff
Deposited On:13 Aug 2010 10:52
Last Modified:13 Aug 2010 10:52

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