Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells.
Antineoplastic Agents
/ chemistry
Apoptosis
/ drug effects
Benzamides
/ chemistry
Carcinoma, Non-Small-Cell Lung
/ pathology
Caspases
/ metabolism
Cell Line, Tumor
Colorectal Neoplasms
/ pathology
Cytoprotection
/ drug effects
Enzyme Activation
/ drug effects
ErbB Receptors
/ metabolism
Humans
Inhibitory Concentration 50
Lung Neoplasms
/ pathology
Mutation
Proteolysis
/ drug effects
Proto-Oncogene Proteins c-akt
/ metabolism
Colorectal cancer (CRC)
HSP90 inhibitors
Non-small cell lung cancer (NSCLC)
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 Oct 2020
01 Oct 2020
Historique:
received:
28
02
2020
revised:
26
05
2020
accepted:
04
06
2020
pubmed:
20
7
2020
medline:
23
4
2021
entrez:
20
7
2020
Statut:
ppublish
Résumé
A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC
Identifiants
pubmed: 32683166
pii: S0223-5234(20)30512-2
doi: 10.1016/j.ejmech.2020.112540
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Benzamides
0
ErbB Receptors
EC 2.7.10.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112540Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.