Expanding the Repertoire of Heterocycle Ring Pairs for Programmable Minor Groove DNA Recognition

Abstract

The discrimination of the four Watson-Crick base pairs by minor groove DNA-binding polyamides have been attributed to the specificity of three five-membered aromatic amino acid subunits, 1-methyl-1H-imidazole (Im), 1-methyl-1H-pyrrole (Py), and 3-hydroxy-1H-pyrrole (Hp) paired four different ways. The search for additional ring pairs that demonstrate DNA-sequence specificity has led us to a new class of 6-5 fused bicycle rings as minor groove recognition elements. The affinities and specificities of the hydroxybenzimidazole/pyrrole (Hz/Py) and hydroxybenzimidazole/benzimidazole (Hz/Bi) pairs for each of the respective Watson-Crick base pairs within the sequence context 5'-TGGXCA-3' (X = A, T, G, C) were measured by quantitative DNaseI footprinting titrations. The Hz/Py and Hz/Bi distinguish T.A from A.T. Hairpin polyamides containing multiple Hz/Py pairs were examined and were shown to mimic the Hp/Py pair with regard to affinity and specificity. Therefore, the Hz/Py pair may be considered a second-generation replacement for the Hp/Py pair.

Sequence-Specific Conjugates of Oligo(2′-O-methylribonucleotides) and Hairpin Oligocarboxamide Minor-Groove Binders: Design, Synthesis, and Binding Studies with Double-Stranded DNA

“…Use of N-methylimidazole and other carboxamides [12] could extend their applications to any dsDNA sequence. In this case, an interesting question of disposition and orientation of this −bis-MGB× in the dsDNA minor groove arises.…”

“…Oligocarboxamide MGBs with hairpin structures (two oligocarboxamide blocks separated by a flexible linker) [9] [10] recognize quite short DNA sequences according to a discovered code [7] [11] [12], and need insertion of nonspecific amino acids for their structural adaptation to the DNA minor groove [13]. Triplex-forming oligonucleotides recognize longer sequences, but specifically interact only with polypurine/ polypyrimidine dsDNA fragments.…”

VUV photophysics and dissociative photoionization of pyrimidine, purine, imidazole and benzimidazole in the 7–18eV photon energy range

“…In this paper, we report results from a photoionization mass spectrometry (PIMS) study of pyrimidine and purine, and of the chemically related molecules imidazole and benzimidazole. Besides their astrobiological interest, we note that the imidazole ring can accept a hydrogen bond from the exocyclic amine of guanine [31], and that benzimidazole is known to be an important structural component in drug design [32], in particular it is an essential part of many antineoplastic derivatives [33]. Histidine, which is an amino acid involved 0301-0104/$ -see front matter Ó 2008 Elsevier B.V. All rights reserved.…”

Functionalized head-to-head hairpin polyamides: Synthesis, double-stranded DNA-binding activity and affinity

“…2 Many modifications of MGB have been already done to expand the range of recognizing units and to increase their DNA affinity, sequence specificity, and gene regulation properties. [3][4][5][6] Recently, we synthesized conjugates of minor groove binders and oligonucleotides having two head-to-head polycarboxamides attached to the same terminal phosphate (Fig. 1).…”