Design, synthesis and pharmacological screening of novel renoprotective methionine-based peptidomimetics: Amelioration of cisplatin-induced nephrotoxicity
| Autor: | Nader E. Abo-Dya, Eatedal H. Abdel-Aal, Tarek S. Ibrahim, Zakaria K. Abdel-Samii, Khalid A. Agha, Nehal M. Elsherbiny, Mohamed El-Sherbiny |
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| Rok vydání: | 2021 |
| Předmět: |
Antioxidant
Side effect medicine.medical_treatment Antineoplastic Agents Pharmacology Protective Agents 01 natural sciences Biochemistry Nephrotoxicity Cell Line chemistry.chemical_compound Structure-Activity Relationship Methionine In vivo Drug Discovery medicine Humans Molecular Biology IC50 Cisplatin Cell Death Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Glutathione In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Oxidative Stress chemistry Drug Design Peptidomimetics medicine.drug |
| Zdroj: | Bioorganic chemistry. 114 |
| ISSN: | 1090-2120 |
| Popis: | Cisplatin (CP) is an effective chemotherapeutic agent for treatment of various types of cancer, however efforts are needed to reduce its toxic side effect. Previous studies revealed promising effect of peptides in decreasing CP induced nephrotoxicity. Herein, novel Met-based peptidomimetics were synthesized using N-acylbenzotriazole as acylating agent in high yield. Evaluation of renoprotective effect of the synthesized targets on CP treated kidney cell line (LLC-PK1) revealed that pretreatment with 1/3 IC50 of targets II, IIIa-g attenuated CP induced cell death where the IC50 of CP was raised from 3.28 µM to 9.25-41.1 µM. The most potent compounds IIIg, II and IIIb exhibited antioxidative stress in CP-treated LLC-PK1 cells as confirmed by raising GSH/GSSG ratio and SOD concentration as well as decreasing ROS and MDA. Additionally, in vivo experiments using Sprague Dawley rats showed renoprotective effect of IIIg against CP-induced nephrotoxicity as evidenced by improved results of renal function tests and attenuated CP-induced renal structural injury. Moreover, antioxidant activity of IIIg was demonstrated via its ability to reduce renal MDA level and up-regulate renal antioxidant element GSH level. Further, immunohistochemistry of renal specimens showed the ability of IIIg to restore CP-induced suppression of Nrf2. Interestingly, in vivo and in vitro studies demonstrated that IIIg had no effect on CP antiproliferative activity. An assessment of the ADMET properties revealed that targets IIIg, II and IIIb showed good drug-likeness in terms of their physicochemical, pharmacokinetic properties. The findings presented here showcase that IIIg is a promising renoprotective candidate with antioxidative stress potential. |
| Databáze: | OpenAIRE |
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