Stamellou E, Storz D, Botov S, Ntasis E, Wedel J, Sollazzo S, Krämer B K, van Son W, Seelen M, Schmalz H G, Schmidt A, Hafner M, Yard B A
Institute for Molecular and Cellular Biology, Mannheim University of Applied Sciences, Mannheim, Germany ; Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University, Heidelberg Mannheim, Germany.
Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University, Heidelberg Mannheim, Germany.
Redox Biol. 2014 Jun 5;2:739-48. doi: 10.1016/j.redox.2014.06.002. eCollection 2014.
Acyloxydiene-Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further provides a rational framework for designing acyloxydiene-Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms.
酰氧基二烯 - Fe(CO)₃ 配合物可作为酶触发的一氧化碳释放分子（ET - CORMs）。它们的生物活性强烈依赖于其衍生的母体化合物，即环己烯酮或环己二酮，以及它们所具有的酯官能团的位置。本研究探讨了后者的特性是否会影响一氧化碳的释放，ET - CORMs 的细胞毒性是否通过铁释放或细胞呼吸抑制介导，以及环己烯酮和环己二酮衍生的 ET - CORMs 在对抗肿瘤坏死因子 -α 介导的炎症方面的能力差异程度如何。无论配方是（二甲基亚砜或环糊精），与环己烯酮部分内部（rac - 1）位置相比，在外部（rac - 4）带有酯官能团的 ET - CORMs 对人脐静脉内皮细胞（HUVEC）的毒性显著更高。这与前一种 ET - CORM 释放一氧化碳的增加相平行。毒性并非通过铁介导，因为 rac - 4 的半数有效浓度（EC50）值显著低于氯化亚铁或氯化铁，并且不受铁螯合的影响。ATP 耗竭先于毒性出现，提示细胞呼吸受损是细胞死亡的假定原因。在长期的 HUVEC 培养中，rac - 1 对血管细胞黏附分子 -1（VCAM - 1）表达的抑制随时间减弱，而对于环己二酮衍生的 rac - 8，抑制作用似乎增强。核因子κB（NFκB）被 rac - 1 和 rac - 8 抑制，与核因子κB 抑制蛋白α（IκBα）降解无关。两种 ET - CORMs 均激活核因子E2相关因子2（Nrf - 2），并因此诱导血红素加氧酶 -1（HO - 1）的表达。本研究进一步为设计具有不同一氧化碳释放和生物活性的酰氧基二烯 - Fe(CO)₃ 配合物作为 ET - CORMs 提供了一个合理的框架。我们还从机制角度更好地理解了这些配合物如何影响细胞生物学。
