Recognition of the DNA minor groove by thiazotropsin analogues.

Hasan Y Alniss, Marie-Virginie Salvia, Mykhailo Sadikov, Igor Golovchenko, Nahoum G Anthony, Abedawn I Khalaf, Simon P MacKay, Colin J Suckling, John A Parkinson

Index: ChemBioChem. 15(13) , 1978-90, (2014)

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Abstract

Solution-phase self-association characteristics and DNA molecular-recognition properties are reported for three close analogues of minor-groove-binding ligands from the thiazotropsin class of lexitropsin molecules; they incorporate isopropyl thiazole as a lipophilic building block. Thiazotropsin B (AcImPy(iPr) ThDp) shows similar self-assembly characteristics to thiazotropsin A (FoPyPy(iPr) ThDp), although it is engineered, by incorporation of imidazole in place of N-methyl pyrrole, to swap its DNA recognition target from 5'-ACTAGT-3' to 5'-ACGCGT-3'. Replacement of the formamide head group in thiazotropsin A by nicotinamide in AIK-18/51 results in a measureable difference in solution-phase self-assembly character and substantially enhanced DNA association characteristics. The structures and associated thermodynamic parameters of self-assembled ligand aggregates and their complexes with their respective DNA targets are considered in the context of cluster targeting of DNA by minor-groove complexes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.