Liu, B;
Pett, L;
Kiakos, K;
Patil, PC;
Satam, V;
Hartley, JA;
Lee, M;
(2018)
DNA-binding properties of new fluorescent AzaHx-amides: Methoxy-pyridyl-aza-benzimidazole-pyrrole-imidazole/pyrrole.
ChemBioChem
, 19
(18)
pp. 1979-1987.
10.1002/cbic.201800273.
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Abstract
DNA minor groove binding polyamides have been extensively developed to control abnormal gene expression. Establishment of the novel, inherently fluorescent Hx-amides has provided an alternative path for studying DNA binding in cells by direct observation of cell localization. Because of the 2:1 antiparallel stacking homodimer binding mode of these molecules to DNA, modification of Hx-amides to AzaHx-amides has successfully extended the DNA recognition repertoire, from central CG (recognized by Hx-I) to central GC (recognized by AzaHx-P) recognition. To potentially target two consecutive GG bases, new modifications from AzaHx moiety to 3-Pyr-AzaHx and 2-Pyr-AzaHx moieties were developed. The newly designed molecules are also small-sized, fluorescent amides with Pyr-AzaHx connected to two conventional five-membered heterocycles. Complementary biophysical methods were carried out to investigate DNA binding properties of these molecules. The results showed that neither 3-Pyr-AzaHx nor 2-Pyr-AzaHx was able to mimic I-I to specifically target GG dinucleotides. Rather, 3-Pyr-AzaHx functions like AzaHx or f-I or P-I as a antiparallel stacked dimer. 3-Pyr-AzaHx-PI (2) binds 5'-ACGCGT'-3' with improved binding affinity and high sequence specificity when compared to its parent molecule AzaHx-PI (1). However, 2-Pyr-AzaHx is detrimental to DNA binding because of an unfavorable steric clash upon stacking in the minor groove.
| Type: | Article |
|---|---|
| Title: | DNA-binding properties of new fluorescent AzaHx-amides: Methoxy-pyridyl-aza-benzimidazole-pyrrole-imidazole/pyrrole |
| Location: | Germany |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/cbic.201800273 |
| Publisher version: | https://doi.org/10.1002/cbic.201800273 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | 3-Pyr-AzaHx, AzaHx, DNA recognition, fluorescent, polyamides |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10054031 |
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