Targeting multiple G-quadruplex-forming DNA sequences: Design, biophysical and biological evaluations of indolo-naphthyridine scaffold derivatives.
Antineoplastic Agents
/ chemical synthesis
Base Sequence
Cell Proliferation
/ drug effects
DNA, Neoplasm
/ drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
G-Quadruplexes
/ drug effects
Humans
Indoles
/ chemical synthesis
Ligands
Models, Molecular
Molecular Structure
Naphthyridines
/ chemical synthesis
Structure-Activity Relationship
Tumor Cells, Cultured
Biophysical characterization
G-quadruplex DNA
Ligands
Molecular modelling
Multi-target
Oncogene promoters
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Nov 2019
15 Nov 2019
Historique:
received:
24
06
2019
revised:
02
08
2019
accepted:
14
08
2019
pubmed:
26
8
2019
medline:
3
1
2020
entrez:
26
8
2019
Statut:
ppublish
Résumé
It is well recognized that the non-canonical DNA structures known as G-quadruplexes (G4s) have a potential anticancer significance and several compounds have been discovered and evaluated as promising G4 binders with anticancer activity. Here, starting from a promising hit with an indolo-naphthyridine scaffold, a small series of five indolo-naphthyridine based derivatives have been designed and evaluated as G4-targeting compounds. FRET biophysical studies were performed on multiple DNA G4 structures, leading to the identification of a multi-target G4 stabilizer with a slight preference for the c-KIT1 and a good G4 over duplex selectivity. The good affinity of this compound against c-KIT1 G4 was also confirmed by SPR and MST experiments, while biological assays revealed its cytotoxic activity on tumour cells. Finally, Molecular Dynamics simulations helped to elucidate the stabilization effect of the selected compound against the c-KIT1 G4.
Identifiants
pubmed: 31446246
pii: S0223-5234(19)30761-5
doi: 10.1016/j.ejmech.2019.111627
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
DNA, Neoplasm
0
Indoles
0
Ligands
0
Naphthyridines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
111627Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.