Extending the σ-Hole Motif for Sequence-Specific Recognition of the DNA Minor Groove.
Biochemistry
; 59(18): 1756-1768, 2020 05 12.
Article
em En
| MEDLINE
| ID: mdl-32293884
ABSTRACT
The majority of current drugs against diseases, such as cancer, can bind to one or more sites in a protein and inhibit its activity. There are, however, well-known limits on the number of druggable proteins, and complementary current drugs with compounds that could selectively target DNA or RNA would greatly enhance the availability of cellular probes and therapeutic progress. We are focusing on the design of sequence-specific DNA minor groove binders that, for example, target the promoter sites of transcription factors involved in a disease. We have started with AT-specific minor groove binders that are known to enter human cells and have entered clinical trials. To broaden the sequence-specific recognition of these compounds, several modules that have H-bond acceptors that strongly and specifically recognize G·C base pairs were identified. A lead module is a thiophene-N-alkyl-benzimidazole σ-hole-based system with terminal phenyl-amidines that have excellent affinity and selectivity for a G·C base pair in the minor groove. Efforts are now focused on optimizing this module. In this work, we are evaluating modifications to the compound aromatic system with the goal of improving GC selectivity and affinity. The lead compounds retain the thiophene-N-alkyl-BI module but have halogen substituents adjacent to an amidine group on the terminal phenyl-amidine. The optimum compounds must have strong affinity and specificity with a residence time of at least 100 s.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiofenos
/
Benzimidazóis
/
DNA
/
Amidinas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos