Ugi efficient synthesis, biological evaluation and molecular docking of coumarin-quinoline hybrids as apoptotic agents through mitochondria-related pathways
Autor: | Leila Hosseinzadeh, Yalda Shokoohinia, Maryam Nazifi, Mahboubeh Mansourian, Salman Taheri |
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Rok vydání: | 2019 |
Předmět: |
Caspase 3
Antineoplastic Agents Apoptosis Mitochondrion 01 natural sciences Biochemistry Western blot Coumarins Drug Discovery Survivin medicine Tumor Cells Cultured Humans Benzopyrans Molecular Biology Caspase-9 Membrane Potential Mitochondrial Ovarian Neoplasms medicine.diagnostic_test biology 010405 organic chemistry Chemistry Organic Chemistry 0104 chemical sciences Mitochondria Molecular Docking Simulation 010404 medicinal & biomolecular chemistry biology.protein Quinolines Ugi reaction Female Signal transduction Reactive Oxygen Species |
Zdroj: | Bioorganic chemistry. 91 |
ISSN: | 1090-2120 |
Popis: | Ugi reaction was a reliable procedure for the synthesis of new coumarin-quinoline frameworks. Excellent yields, mild reaction conditions and easily available and inexpensive starting materials are advantages of this protocol. Cytotoxic effects of fourteen products were investigated in A2780 human ovarian cancer cells. Two synthesized compounds (L11 and L12) exhibited more anti-cancer activity than other derivatives with IC50 values of 0.042 mmol/L and 0.102 mmol/L, respectively and were thus selected for further studies. Apoptosis was induced through the intrinsic pathway by activating caspase 9 and ended at the executioner pathway of caspase 3. Measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were also carried out for both of them. Further studies on a mechanism by Real Time-PCR and Western blot analysis were performed for anti-apoptotic proteins Bcl-2 and survivin both in mRNA and protein level relating to the untreated A2780 cells. The treatment of A2780 cells with compound L11 significantly (P-value ≤ 0.05) induced apoptosis by down-regulation of Bcl-2 and survivin both in mRNA and protein level via a single dose (0.042 mmol/L), as well as activation of caspase 9 and 3, loss of MMP, and high ROS. Accordingly, findings supported the first report under which the pro-apoptotic activity of compound L11 as an apoptosis-inducing agent was related to mitochondrial-mediated dysfunction signaling pathways. Molecular docking supports experimental outcomes. Evidently, coumarin-quinoline scaffolds are potentially favorable options for further assessment as influential chemotherapeutic agents for the future. |
Databáze: | OpenAIRE |
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