Recognition of the DNA minor groove by thiazotropsin analogues

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, which incorporate isopropyl thiazole as a lipophilic building block. Thiazotropsin B (AcImPy^iPrThDp) shows similar self-assembly characteristics to thiazotropsin A (FoPyPy^iPrThDp) although being 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 respective DNA targets are considered in the context of cluster targeting of DNA by minor groove complexes.