Recognition of the DNA Minor Groove by Thiazotropsin Analogues

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.

Imino proton NMR guides the reprogramming of A•T specific minor groove binders for mixed base pair recognition

“…A barrier to this approach for control of gene expression in cells is that only a limited variety of small molecules bind strongly and sequence-specifically to DNA ( 9 , 10 ). The modification of heterocycles in classical type minor groove binders is an approach to expand the applications of minor groove binders ( 11 , 12 ).…”

Structural and Kinetic Profiling of Allosteric Modulation of Duplex DNA Induced by DNA‐Binding Polyamide Analogues

“…The origins of these differences become apparent when comparing the extent of minor groove penetration of the three complexes (Figure ). NMR‐restrained molecular dynamics of the PA1⋅ODN4 complex reveal PA1 penetrating deep within the minor groove, exemplified by a hydrogen bond distance of 2.01 Å between Me‐Im N3 and the exocyclic amine G5N2 (Figure a) . In contrast, the PA3⋅ODN4 complex shows a reduced level of minor groove penetration with an average distance of 2.36 Å between the i Pr‐Nt N3 and the exocyclic amine G5N2 (Figure b) .…”

“…NMR‐restrained molecular dynamics of the PA1⋅ODN4 complex reveal PA1 penetrating deep within the minor groove, exemplified by a hydrogen bond distance of 2.01 Å between Me‐Im N3 and the exocyclic amine G5N2 (Figure a) . In contrast, the PA3⋅ODN4 complex shows a reduced level of minor groove penetration with an average distance of 2.36 Å between the i Pr‐Nt N3 and the exocyclic amine G5N2 (Figure b) . The PA4⋅ODN4 complex on the other hand shows a significant level of minor groove penetration (2.10 Å) relative to PA3⋅ODN4 but it is not as extensive as that observed for the PA1⋅ODN4 complex (2.01 Å) .…”

Four pyrrole derivatives used as building blocks in the synthesis of minor-groove binders

“…A large number of structural modifications have been carried out on the original, naturally occurring compounds distamycin and netropsin, in order to optimize their biological activities (Lang et al, 2014). In addition to modifying the biological activities, structural changes have been made to the head group, tail group and the heterocyclic moieties in order to modulate their solubility, selectivity and the degree of binding to the minor groove of DNA (Alniss et al, 2014). We have recently turned to developing MGB-biotin hybrid molecules to be used as novel biochemical probes in order to determine the mechanism of action of MGBs.…”