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Design, Synthesis and Pharmacological Screening of Novel Renoprotective Methionine-based Peptidomimetics: Amelioration of Cisplatin-induced nephrotoxicity
Faculty
Pharmacy
Year:
2021
Type of Publication:
ZU Hosted
Pages:
105100
Authors:
Zakareyah Kamel Abdelsamie
Staff Zu Site
Abstract In Staff Site
Journal:
Bioorganic Chemistry ELSEVIER
Volume:
114
Keywords :
Design, Synthesis , Pharmacological Screening , Novel Renoprotective
Abstract:
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.
Author Related Publications
Zakareyah Kamel Abdelsamie, "Regioselective hydroxysulphenylation of derivatives of allylic alcohols and amines.", Tetrahedron Letters, 1986
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Zakareyah Kamel Abdelsamie, "New routes to heterocycles via sulphenylation of unsaturated amides", Tetrahedron Letters, 1987
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Zakareyah Kamel Abdelsamie, "Trifluoroacetoxysulphenylation of unsaturated nitriles as a route to lactones", Tetrahedron Letters, 1986
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Zakareyah Kamel Abdelsamie, "Synthesis of certain s-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of pharmaceutical interest", Eygpt J. Pharm. Sci, 1987
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Zakareyah Kamel Abdelsamie, "Synthesis and biological activity of some novel triazolothiadiazines", Eygpt J. Pharm. Sci, 1988
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Department Related Publications
Etedaal Hassan Mohamed Abdulaal, "7. Reaction of 2-Amino-4,5,6,7-Tetrahydrobenzo (b) Thiophen-3-Carboxylic Acid with Substituted Ureas and Thioureas. ", لايوجد, 1900
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Etedaal Hassan Mohamed Abdulaal, "22. Synthesis of New Benzenesulfonamide and Benzisothiazolone Derivatives as Proteolytic Enzyme Inhibitors", لايوجد, 1900
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Etedaal Hassan Mohamed Abdulaal, "8. Synthesis and Antibacterial Activity of some 1,3,4- oxadiazolines", لايوجد, 1900
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Hanan Abdelraziek Abdelfattah Ali Hamied, "Synthesis of Fused Pyrrole Derivativies and other Heterocyclic Compounds of", لايوجد, 1900
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Hanan Abdelraziek Abdelfattah Ali Hamied, "Synthesis an antimicrobial activity of new 5-cyanopyrimidine derivatives containing 3, 4, 5- trimethoxyphenyl substituent", لايوجد, 1900
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