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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 [Eur J Med Chem] 2020 Oct 01; Vol. 203, pp. 112601. Date of Electronic Publication: 2020 Jul 12. - Publication Year :
- 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 IC <subscript>50</subscript> 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.<br />Competing Interests: 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.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Apoptosis drug effects
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Humans
Mice
Mitochondria drug effects
Mitochondria pathology
Xenograft Model Antitumor Assays
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Drug Design
Piperidines chemistry
Piperidines pharmacology
Pyrimidines chemistry
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 203
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32682202
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112601