Toward an Understanding of the Chemical Etiology for DNA Minor‐Groove Recognition by Polyamides

Abstract

Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday Crescent-shaped polyamides composed of aromatic amino acids, i.e., 1-methyl-1H-imidazole Im, 1-methyl-1H-pyrrole Py, and 3-hydroxy-1H-pyrrole Hp, bind in the minor groove of DNA as 2 : 1 and 1 : 1 ligand/DNA complexes. DNA-Sequence specificity can be attributed to shape-selective recognition and the unique corners or pairs of corners presented by each heterocycle(s) to the edges of the base pairs on the floor of the minor groove. Here we examine the relationship between heterocycle structure and DNA-sequence specificity for a family of five-membered aromatic amino acids. By means of quantitative DNase-I footprinting, the recognition behavior of polyamides containing eight different aromatic amino acids, i.e., 1-methyl-1H-pyrazole Pz, 1H-pyrrole Nh, 5-methylthiazole Nt, 4-methylthiazole Th, 3-methylthiophene Tn, thiophene Tp, 3-hydroxythiophene Ht, and furan Fr, were compared with the polyamides containing the parent-ring amino acids Py, Im, and Hp for their ability to discriminate between the four WatsonÀCrick base pairs in the DNA minor groove. Analysis of the data and molecular modeling showed that the geometry inherent to each heterocycle plays a significant role in the ability of polyamides to differentiate between DNA sequences. Binding appears sensitive to changes in curvature complementarity between the polyamide and DNA. The Tn/Py pair affords a modest 3-fold discrimination of T ¥ A vs. A ¥ T and suggests that an S-atom in the thiophene ring prefers to lie opposite T not A.

Rationalising sequence selection by ligand assemblies in the DNA minor groove: the case for thiazotropsin A

“…When a steric clash occurs between a guanine amino group and ligand (as for CCTAGG 8 when ligand Dp tail encounters G 8 -NH 2 , Figs S8 and S9 in the Supporting Information †) binding is opposed and affinity is reduced. The resulting substantial loss in enthalpy decreases binding affinity despite the favourable entropy contribution to DG.…”

“…In recent years elegant solutions to DNA sequence targeting have emerged through the design of residue specific hairpin and cyclic polyamides containing N-methylpyrrole, N-methylimidazole 4-7 and other heterocyclic building blocks. 8 The longterm goal of controlling gene expression with small molecules is therefore on the horizon.…”

Synthesis of G-quadruplex-targeting flexible macrocyclic molecules via click reaction

“…The triazo-alkynyl-containing precursors were readily cyclized by the formation of two triazoles with high yields at the concentration of 2 mM in the optimized click reaction condition. In addition, our starting material 12 for cPT (3) and cPTN (4) was obtained from pyrrole via five steps according to the procedures reported 25,26 . cPT (3) and cPTN (4) were also synthesized from triazole derivative 7 by the similar method (Scheme 2).…”

Minimization of a Protein−DNA Dimerizer

“…Thus, the presence of dimerizer 1 enhances Exd's DNA affinity by 1000-fold. 4 In controls, experiments with 50 nM of the parent polyamide 2, which contains no peptide but has been shown previously by DNase footprinting experiments to bind specifically to the DNA-binding domain match site, 16 appears to enhance Exd's DNA affinity for DNA, as evidenced by the partial band shift (i.e., Θ app = 0.5 ± 0.2). 17 The mismatch polyamide 3, which is not expected to bind the polyamide match site, 18 does not lead to any measurable enhancement of Exd's DNA affinity.…”