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Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells
- Source :
- European journal of medicinal chemistry. 203
- Publication Year :
- 2020
-
Abstract
- 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 IC50 value of 27.8 ± 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BIIB021 whose IC50 values are 43.0 ± 0.9 nM and 56.8 ± 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment.
- Subjects :
- Lung Neoplasms
Colorectal cancer
Population
non-small cell lung cancer (NSCLC)
Antineoplastic Agents
Apoptosis
01 natural sciences
03 medical and health sciences
Inhibitory Concentration 50
Epidermal growth factor
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Drug Discovery
medicine
Humans
education
Protein kinase B
030304 developmental biology
Pharmacology
0303 health sciences
education.field_of_study
biology
010405 organic chemistry
Chemistry
Organic Chemistry
General Medicine
Prodrug
medicine.disease
Hsp90
0104 chemical sciences
Enzyme Activation
ErbB Receptors
Cytoprotection
Caspases
Cancer cell
Benzamides
Mutation
Proteolysis
Cancer research
biology.protein
Colorectal Neoplasms
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 203
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....4fa56aae4bd85030acdcf15cfd360186