Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency.
Antineoplastic Agents
/ chemical synthesis
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Flavonoids
/ chemical synthesis
Humans
Molecular Docking Simulation
Molecular Structure
Piperidines
/ chemical synthesis
Protein Kinase Inhibitors
/ chemical synthesis
Protein Kinases
/ metabolism
Structure-Activity Relationship
Tumor Cells, Cultured
CDK10
CDK9
Cytotoxicity
Kinase inhibitors
Kinases
Structure-activity relationship
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:
01 Aug 2020
01 Aug 2020
Historique:
received:
10
03
2020
revised:
02
04
2020
accepted:
16
04
2020
pubmed:
14
5
2020
medline:
2
2
2021
entrez:
14
5
2020
Statut:
ppublish
Résumé
In this work, unique flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9, CDK10, and GSK3β protein kinases.
Identifiants
pubmed: 32402934
pii: S0223-5234(20)30325-1
doi: 10.1016/j.ejmech.2020.112355
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Flavonoids
0
Piperidines
0
Protein Kinase Inhibitors
0
alvocidib
45AD6X575G
Protein Kinases
EC 2.7.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112355Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest Stéphane Bach is a founder and member of the scientific advisory board of SeaBeLife Biotech, which is developing novel therapies for treating liver and kidney acute disorders. This work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.