Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells
Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells
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优化二亚硝基铁配合物作为平滑肌细胞的治疗方法
DOI：
10.1021/acs.molpharmaceut.9b00389
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发表时间：
2019
影响因子：
4.9
通讯作者：
Lim, Soon-Mi
中科院分区：
文献类型：
--
作者：
Pectol, D. Chase;Khan, Sarosh;Chupik, Rachel B.;Elsabahy, Mahmoud;Wooley, Karen L.;Darensbourg, Marcetta Y.;Lim, Soon-Mi
在这项研究中，二亚硝酰铁络合物（DNIC）被证明可以将一氧化氮（NO）输送到血管平滑肌细胞（SMC）的胞质溶胶中，这在血管舒张和收缩中起着重要作用。SMC的功能障碍可导致高血压、哮喘和勃起功能障碍等疾病。为了比较五种DNIC衍生物，检查了以下方案：（a）检测亚硝酸盐的Griess测定（来源于NO转化）;（B）3-（4，5-二甲基噻唑-2-基）-5- 2-（3-羧基甲氧基苯基）（c）免疫毒性测定，以确定DNIC是否刺激免疫应答;和（d）荧光测定以检测来自DNIC处理的细胞内NO。发现含有苯基硫醇盐桥的二聚体黄曲霉素红酯（RRE）型{Fe（NO）2} 9络合物[（μ-SPh）Fe（NO）2] 2或SPhRRE以对细胞毒性的最低影响递送NO（即，最高IC 50）。相反，具有生物相容性硫代葡萄糖部分[（μ-SGlu）Fe（NO）2]2（SGlu = 1-硫代-β-d-葡萄糖四乙酸酯）或SGluRRE的RRE-DNIC向SMC的胞质溶胶递送更高浓度的NO，IC 50降低10倍。此外，还合成了由大体积N-杂环卡宾（NHC），即1，3-双（2，4，6-三甲基苯基）咪唑叉（IMes）稳定的单体DNIC，得到了DNIC配合物SGluNHC，[IMes（SGlu）Fe（NO）2]和SPhNHC，[IMes（SPh）Fe（NO）2]。这些氧化的{Fe（NO）2} 9 NHC DNIC的IC 50为1.77 μM;然而，基于NHC的络合物不能将NO转移到SMC中。与此相反，减少，单核{Fe（NO）2} 10 neocuproine为基础的DNIC，neoDNIC，压抑的SMCs的活力，以及产生的细胞内NO的增加。无论配位环境或氧化态，所有DNIC表现出二亚硝酰铁单位（DNIU）依赖性的活力增加。本研究证明了DNIU协调环境与DNIC治疗功效之间的结构-功能关系。
In this study, dinitrosyl iron complexes (DNICs) are shown to deliver nitric oxide (NO) into the cytosol of vascular smooth muscle cells (SMCs), which play a major role in vascular relaxation and contraction. Malfunction of SMCs can lead to hypertension, asthma, and erectile dysfunction, among other disorders. For comparison of the five DNIC derivatives, the following protocols were examined: (a) the Griess assay to detect nitrite (derived from NO conversion) in the absence and presence of SMCs; (b) the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay for cell viability; (c) an immunotoxicity assay to establish if DNICs stimulate immune response; and (d) a fluorometric assay to detect intracellular NO from treatment with DNICs. Dimeric Roussin’s red ester (RRE)-type {Fe(NO)2}9complexes containing phenylthiolate bridges, [(μ-SPh)Fe(NO)2]2orSPhRRE, were found to deliver NO with the lowest effect on cell toxicity (i.e., highest IC50). In contrast, the RRE-DNIC with the biocompatible thioglucose moiety, [(μ-SGlu)Fe(NO)2]2(SGlu = 1-thio-β-d-glucose tetraacetate) orSGluRRE, delivered a higher concentration of NO to the cytosol of SMCs with a 10-fold decrease in IC50. Additionally, monomeric DNICs stabilized by a bulky N-heterocyclic carbene (NHC), namely, 1,3-bis(2,4,6-trimethylphenyl)imidazolidene (IMes), were synthesized and yielded the DNIC complexesSGluNHC, [IMes(SGlu)Fe(NO)2], andSPhNHC, [IMes(SPh)Fe(NO)2]. These oxidized {Fe(NO)2}9NHC DNICs have an IC50of ∼7 μM; however, the NHC-based complexes did not transfer NO into the SMC. Per contra, the reduced, mononuclear {Fe(NO)2}10neocuproine-based DNIC,neoDNIC, depressed the viability of the SMCs, as well as generated an increase of intracellular NO. Regardless of the coordination environment or oxidation state, all DNICs showed a dinitrosyl iron unit (DNIU)-dependent increase in viability. This study demonstrates a structure–function relationship between the DNIU coordination environment and the efficacy of the DNIC treatments.