Design, synthesis and pharmacological screening of novel renoprotective methionine-based peptidomimetics: Amelioration of cisplatin-induced nephrotoxicity

• Published in: Bioorganic chemistry Vol. 114; pp. 105100 - 105110
• Main Authors: Agha, Khalid A., Ibrahim, Tarek S., Elsherbiny, Nehal M., El-Sherbiny, Mohamed, Abdel-Aal, Eatedal H., Abdel-Samii, Zakaria K., Abo-Dya, Nader E.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.09.2021; Elsevier
• Subjects: Antineoplastic Agents - pharmacology; Antioxidative stress potential; Benzotriazole; Biochemistry & Molecular Biology; Cell Death - drug effects; Cell Line; Chemistry; Chemistry, Organic; Cisplatin; Cisplatin - antagonists & inhibitors; Cisplatin - pharmacology; Dose-Response Relationship, Drug; Drug Design; Humans; Life Sciences & Biomedicine; Methionine; Methionine - chemical synthesis; Methionine - chemistry; Methionine - pharmacology; Molecular Structure; Nephrotoxicity; Oxidative Stress - drug effects; Peptidomimetics; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Physical Sciences; Protective Agents - chemical synthesis; Protective Agents - chemistry; Protective Agents - pharmacology; Science & Technology; Structure-Activity Relationship; Antioxidative stress potential; Peptidomimetics; Nephrotoxicity; Benzotriazole; Cisplatin; Methionine; OXIDATIVE STRESS; SULFOXIDE; DRUG DISCOVERY; ACYLBENZOTRIAZOLES; IN-VITRO; PHARMACOKINETICS; METABOLISM; GLUTATHIONE; AMINO-ACIDS; CYTOTOXICITY
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105100

[Display omitted] •Design and synthesis of novel Novel Renoprotective Methionine-based Peptidomimetics.•Attenuation of Cisplatin induced nephrotoxicity.•The most potent compounds IIIg, II and IIIb exhibited antioxidative stress in CP-treated LLC-PK1 cells.•In vivo experiments using Sprague Dawley rats showed renoprotective effect of IIIg against cisplatin-induced nephrotoxicity.•Amongst the analogues Compounds II, IIIb IIIe and IIIg, possess favorable physicochemical and pharmacokinetic properties. 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.