Báo cáo khoa học: A novel dicyclodextrinyl diselenide compound with glutathione peroxidase activity

A Novel Dicyclodextrinyl Diselenide Compound With Glutathione Peroxidase Activity

Tác giả: Shao-Wu Lv, Xiao-Guang Wang, Ying Mu, Tian-Zhu Zang, Yue-Tong Ji, Jun-Qiu Liu, Jia-Cong Shen, and Gui-Min Luo

Lĩnh vực: Hóa học, Sinh hóa

Nội dung tài liệu: Nghiên cứu này trình bày việc thiết kế và tổng hợp hợp chất 6A,6A’-dicyclohexylamine-6B,6B′-diselenide-bis-β-cyclodextrin (6-CySeCD) như một mô hình bắt chước hoạt động của enzyme chống oxy hóa glutathione peroxidase (GPX). Hợp chất mới này sử dụng β-cyclodextrin để tạo môi trường kỵ nước cho việc gắn kết cơ chất và nhóm cyclohexylamine được tích hợp gần nguyên tử selen để tăng cường độ ổn định của trung gian selenolat. 6-CySeCD cho thấy hoạt tính GPX cao hơn so với các hợp chất tương tự khác như 6-SeCD và Ebselen trong việc khử hydroperoxide. Các nghiên cứu động học cho thấy cơ chế phản ứng kiểu ping-pong, tương tự như GPX tự nhiên. Nghiên cứu cũng đánh giá khả năng bảo vệ chống lại tổn thương oxy hóa trên ty thể, cho thấy 6-CySeCD có hiệu quả bảo vệ tốt hơn các hợp chất so sánh. Kết quả nghiên cứu nhấn mạnh tầm quan trọng của việc khớp hình dạng vị trí gắn kết cơ chất và sự ổn định của trung gian selenolat trong việc cải thiện hiệu quả xúc tác của các mô hình GPX.

Mục lục chi tiết:

• Keywords
• Correspondence
• A novel dicyclodextrinyl diselenide compound with glutathione peroxidase activity
• Glutathione peroxidase (GPX; EC 1.11.1.9) is a well-known selenoenzyme that catalyzes the reduction of harmful hydroperoxides by glutathione (GSH) and protects lipid membranes and other cellular components against oxidative damage.
• Abbreviations
• 6-CySeCD displays GPX activity
• Scheme 1. Catalytic cycle for GPX.
• Approach seems to help stabilize the selenolate and enhance the GPX-like activity of diselenides.
• In this study we designed and synthesized a new GPX mimic, 6A,6A’-dicyclohexylamine-6B,6B′-diselenide-bis-β-cyclodextrin (6-CySeCD), in which the cyclohexylamine group was incorporated in the proximity of the selenium atom and the β-CD cavity provided a hydrophobic environment for substrate binding.
• 6-CySeCD showed higher GPX activity than 6-SeCD for the reduction of H2O2, tert-butyl hydroperoxide (t-BuOOH) and cumenyl hydroperoxide (CumOOH) by GSH, indicating that incorporation of the imido-group in the proximity of the selenium atom may increase the stability of the nucleophilic intermediate selenolate and enhance GPX-like activity in selenium-containing GPX mimics.
• Results and Discussion
• Synthesis and characterization of 6-CySeCD
• Scheme 2. Synthetic route of 6-CySeCD.
• The content and valence of selenium in 6-CySeCD were measured by X-ray photoelectron spectroscopy.
• GPX activity of 6-CySeCD
• Scheme 3. Structures of 6-CySeCD.
• The GPX activities of 6-CySeCD and other GPX mimics catalyzed the reduction of hydroperoxides by GSH are listed in Table 1.
• Scheme 4. Catalytic mechanism proposed by Wilson et al. [11].
• In the investigation of GPX mimics, Wilson’s diselenides are successful [11].
• Kinetics of 6-CySeCD
• Table 1. Comparison between GPX activities of the 6-CySeCD-catalyzed reduction of hydroperoxides by GSH and other species.
• Fig. 1. Double-reciprocal plots for the reduction of H2O2 by GSH catalyzed by 5 μμ 6-CySeCD.
• Table 2. Kinetic parameters of the 6-CySeCD.
• Protection of mitochondria against oxidative damage by 6-CySeCD
• Fig. 2. Plots of vo versus [H2O2] for 1 mм GSH in 50 мм potassium phosphate buffer, pH 7.4, and 37 °C, at [BHT] = 0 μμ (a) and 50 μμ (b).
• Fig. 3. (A) Effect of concentration of 6-CySeCD on the swelling of mitochondria. (B) Effect of different GPX mimics on mitochondrial swelling.
• Exposing mitochondria in vitro to redox active xenobiotics may simulate oxidative damage of mitochondria in vivo.
• Fig. 4. (A) Dependence of extent of TBARS accumulation on the concentration of 6-CySeCD. (B) Effect of different GPX mimics on TBARS accumulated during mitochondrial damage.
• Conclusion
• We developed a novel GPX mimic, 6-CySeCD.
• Experimental procedures
• Apparatus and materials
• Synthesis of 6-CySeCD
• Determination of GPX-like activity and kinetics
• Preparation of mitochondria
• Ferrous sulfate/ascorbate-induced mitochondrial damage
• Biological analysis of mimics against mitochondrial damage
• Acknowledgements
• References