雙亞硝基鐵錯合物轉換成亞硝硫醇以及單電子氧化之雙亞硝基鐵錯合物電子結構之研究與探討

Study on DNIC-mediated S-nitrosylation (DNIC = Dinitrosyl Iron Complex) and the Electronic Structure of One-Electron Oxidation of {Fe(NO)2}9 DNIC

鄒智欽(Chih-Chin Tsou)

指導教授 ： 廖文峯

國立清華大學/理學院/化學系/博士(2012年)

https://doi.org/10.6843/NTHU.2012.00219

摘要

硫醇亞硝化是一種蛋白質後轉譯修飾，其可傳遞由一氧化氮(NO)所產生之各式各樣的細胞訊息。蛋白質鍵結的雙亞硝基鐵核錯合物(DNIC)已被證實是一種最主要產生蛋白質亞硝硫醇(RSNO)的物質，其中半胱胺酸(cysteine)附近的含正負電荷之胺基酸也被推測會與DNIC作用來產生RSNO。為了更加了解DNIC到RSNO的反應過程，使用雙核雙亞硝基鐵核錯合物(RRE)做為起始物，並且合成了布忍斯特酸穩定的S,N-DNIC與S,O-DNIC。在沒有布忍斯特酸的情況下，將DNIC與(DTC)2 (DTC = S2CNMe2)反應會得到單亞硝基鐵核錯合物(MNIC) [(NO)Fe(DTC)2] (3)、(NO)以及RSSR；然而，DNIC在布忍斯特酸的催化下與(DTC)2反應則可以順利轉換成亞硝硫醇(RSNO)以及MNIC 3，此證明了布忍斯特酸可以促進單硫配位的DNIC之硫基亞硝化，並生成RSNO。使用動力學方法來研究[(NO)2Fe(SPh)(Me4Im)] (2-PhS)在含有過量的布忍斯特酸與過量的(DTC)2反應如何轉換成MNIC 3，其反應機制最好描述成一個兩步驟的分子內反應。此結果不只解釋了為何生物體中RSNO附近總存在著許多含正負電荷之胺基酸，也提供了蛋白質亞硝硫醇可能的生化合成機制。
雙亞硝基鐵核錯合物(DNIC)的電子結構可被分類成高自旋FeIII (S=5/2)與兩個NO– (S=2)經由反鐵磁作用而產生Stotal=1/2的{Fe(NO)2}9，以及高自旋FeII (S=2)與兩個NO– (S=2)經由反鐵磁作用而產生Stotal=0的{Fe(NO)2}10。單電子氧化{Fe(NO)2}9 [(NO)2Fe(N(mesityl)(TMS))2]– (9)可形成[(NO)2Fe(N(mesityl)(TMS))2] (10)，在經由紅外光譜儀、可見光紫外光光譜儀、15N核磁共振儀、超導量磁干涉儀、X光吸收光譜儀以及X-光單晶繞射儀的鑑定後，其電子結構最好描述成[{FeIII(NO–)2}9-配位基之含氮自由基]，而非以往認為的{Fe(NO)2}8。
[(NO)2Fe(μ-NR2)]2 (NR2 = NPh2 (12), N(TMS)2 (13), N=CtBu2 (14))顯示了其雙核DNIC存在著很短的Fe-Fe鍵長(2.43~2.58 Å)，在藉由一系列的光譜量測與結構鑑定，其電子結構最好描述成{FeIII(NO–)2}9與另一個{FeIII(NO–)2}9藉由Fe-Fe鍵進行反鐵磁作用，最後成為一個Stotal=0的錯合物。

關鍵字

一氧化氮 ； 鐵 ； 電子結構 ； 雙亞硝基鐵錯合物

並列摘要

S-nitrosation, coupling of NO and a cysteine-sulfur, has been identified as a post-translational modification of proteins to convey part of the ubiquitous influence of nitric oxide on thiol-dependent cellular-signaling transduction. Protein-bound dinitrosyl iron complexes (DNICs) were demonstrated to be a dominant species for producing cellular protein RSNOs. In order to uncover the DNIC-to-RSNO pathway, this biomimetic investigation on S-nitrosation of the coordinated thiolate in DNICs generating RSNOs was demonstrated. Consistent with the transformation of [(NO)2Fe(μ-StBu)]2 (1-tBuS) into the {Fe(NO)2}9 DNIC [(NO)2Fe(StBu)(MeIm)] (2-MeIm) upon addition of 1-methylimidazole (MeIm) into the THF solution of 1-tBuS, the dynamic interconversion between the {Fe(NO)2}9 [(NO)2Fe(S-NAP)(DMSO)] (2-DMSO) (NAP = N-acetyl-D-penicillamine) and [(NO)2Fe(μ-S-NAP)]2 (1-NAP) occurred in the DMSO solution of complex 1-NAP. In contrast to the reaction of 2-MeIm and bis(dimethylthiocarbamoyl) disulfide ((DTC)2) yielding the {Fe(NO)}7 [(NO)Fe(DTC)2] (3) (DTC = S2CNMe2), (tBuS)2 and NO(g), transformation of the {Fe(NO)2}9 2-MeIm (2-DMSO) into RSNOs (RS = tBuS, NAP-S) along with MNIC 3 facilitated by (DTC)2 and Brønsted acid demonstrates that Brønsted acid may play a critical role in triggering S-nitrosation from DNICs 2-MeIm and 2-DMSO to produce RSNOs. Transformation of DNICs into RSNOs may only occur on the one-thiolate-containing {Fe(NO)2}9 DNICs, in contrast to the protonation of the two-thiolate-containing DNICs [(NO)2Fe(SR)2]- by Brønsted acid yielding [(NO)2Fe(μ-SR)]2. Kinetic strudy on the transformation of [(NO)2Fe(SPh)(Me4Im)] (2-PhS) into MNIC 3 in the presence of Brønsted acid suggests a two-step intramolecular mechanism for the DNIC-mediated S-nitrosation. Conclusively, DNIC-to-RSNO requires a Brønsted acid and Lewis base pair to trigger the formation of RSNO. These results may rationalize that the known protein-Cys-SNO sites derived from DNIC were located adjacent to acid and base motifs, and no protein-bound-SNO characterized nowadays was directly derived from [protein-(cysteine)2Fe(NO)2] in biology.
DNICs can be classified into the EPR-active {Fe(NO)2}9 DNICs with a high-spin FeIII (S = 5/2) antiferromagnetically coupled to two triplet NO– (S = 2) as well as the EPR-silent {Fe(NO)2}10 DNICs with a high-spin FeII (S = 2) antiferromagnetically coupled to two triplet NO– (S = 2). Complexes {Fe(NO)2}9 [(NO)2Fe(N(mesityl)(TMS))2]– (9) and [(NO)2Fe(N(mesityl)(TMS))2] (10) are redox reversible interconversion. The electronic structure of the one-electron oxidized form, DNIC 10, was characterized by a detailed analysis of IR, 15N NMR, SQUID, XAS and X-ray structure, and is best described as [{FeIII(NO–)2}9- (L•)(L–)], instead of [{Fe(NO)2}8-(L–)2] (L = [N(mesityl)(TMS)]). That is, an aminyl radical can be stabilized by an electron-deficient {Fe(NO)2}9 fragment to yield the isolated complex 10. Our results bridging XAS study of the electronic richness of the {Fe(NO)2}9/10 core and the study of the electronic structures of the redox forms DNIC 9 DNIC 10 may point the way to understanding that all of tetrahedral DNICs isolated and characterized nowadays are confined in the {Fe(NO)2}9 and {Fe(NO)2}10 DNICs in chemistry and in biological system.
Dinuclear dinitrosyl iron complexes [(NO)2Fe(μ-NR2)]2 (NR2 = NPh2 (12), N(TMS)2 (13), N=CtBu2 (14)) display the shortest Fe-Fe bond distances of 2.43~2.58 Å, compared to the known terminal-nitrosyl diiron complexes containing thiolate-bridged ligands showing Fe…Fe distance of 2.62~2.79 Å. The electronic structure of complexes 12, 13 and 14, characterized by IR, UV-vis, Fe K-edge XAS, single-crystal X-ray structure and DFT calculation, is best described as S = 1/2 {FeIII(NO–)2}9 antiferromagnetically coupled with another S =1/2 {FeIII(NO–)2}9 via direct interaction of Fe-Fe bond in combination with indirect coupling through bridged ligands. Reduction on complexes 12, 13 and 14 may result in adding an electron on the dx2-y2-dx2-y2 antibonding, breaking metal-metal bond, and finally leading to degradation, compared to the reduction of [(NO)2Fe(μ-SR)]2 yielding [(NO)2Fe(μ-SR)]2–. Not only does development of the chemistry of NR2-RREs give a way for the new type of NO-donor drugs, but it may also provide another possible form for NO storage and transport in biological system.

並列關鍵字

Nitric oxide ； Iron ； Electronic structure ； Dinitrosyl iron complex

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