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Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2020 Aug 01; Vol. 199, pp. 112349. Date of Electronic Publication: 2020 May 11. - Publication Year :
- 2020
-
Abstract
- In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC <subscript>50</subscript> value of 0.031 μM, and better selectivity between cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other cancer cells but also different gastric cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial-mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric cancer.<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 :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Cell Cycle Checkpoints drug effects
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Epithelial-Mesenchymal Transition drug effects
Humans
Molecular Structure
Stomach Neoplasms pathology
Structure-Activity Relationship
Thiosemicarbazones chemical synthesis
Thiosemicarbazones chemistry
Tumor Cells, Cultured
Wound Healing drug effects
Antineoplastic Agents pharmacology
Drug Discovery
Stomach Neoplasms drug therapy
Thiosemicarbazones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 199
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32438199
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112349