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Discovery of tofacitinib derivatives as orally active antitumor agents based on the scaffold hybridization strategy
- Source :
- European Journal of Medicinal Chemistry. 203:112601
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity.
- Subjects :
- p38 mitogen-activated protein kinases
Administration, Oral
Antineoplastic Agents
Apoptosis
01 natural sciences
Mice
03 medical and health sciences
Piperidines
Cell Movement
Cell Line, Tumor
Drug Discovery
medicine
Animals
Humans
IC50
Cell Proliferation
030304 developmental biology
Pharmacology
0303 health sciences
Tofacitinib
010405 organic chemistry
Chemistry
Organic Chemistry
food and beverages
Cancer
Cell migration
General Medicine
Cell cycle
medicine.disease
Xenograft Model Antitumor Assays
Mitochondria
0104 chemical sciences
Pyrimidines
Drug Design
Cancer research
lipids (amino acids, peptides, and proteins)
Signal transduction
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 203
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....4c4a233f363d53e0b9fb025ed121fda2