開發雙亞硝基鐵錯合物作為一氧化氮供體及其於生物體中效果之探討

一氧化氮在生物體內具有重要的功能性，包含:血管舒張、神經傳導、血壓調控、殺死外來病原體等。然而，其本身的不穩定性，使一氧化氮在生物及藥物學方面之相關研究與應用更為複雜。因此，開發能夠穩定控制釋放NO•的化合物，成為目前一氧化氮相關研究及應用重要的課題之一。在本研究中以雙亞硝基鐵錯合物(Dinitrosyl iron complex, DNIC)，[Fe2(μ-SR)2(NO)4]，做為一氧化氮提供試劑。首先發現 [Fe2(μ-SR)2(NO)4] 在有氧的條件下可開始釋放一氧化氮，即其具有一個氧氣觸發釋放的機制。除此之外，利用硫醇配位基的不同，可進一步調控其釋放一氧化氮的半衰期自 0.5 小時至 27.4 小時。本研究進一步利用線蟲(C. elegans)做為動物模型，利用NO•的螢光探針分子搭配共軛焦顯微鏡，確認DNIC-1 可於線蟲中釋放NO•。除此之外，我們發現，[Fe2(μ-SEtOH)2(NO)4] (DNIC-1a)的 NO•釋放反應能夠將線蟲的壽命自 16.9±0.5 天延長至 18.7±0.4 天，並且延遲衰老細胞(cell senescence)的積累，以達到延緩老化的效果。此外，藉由次世代定序的結果得知，此延緩線蟲老化的路徑與 AMPK、IIS、粒線體功能訊息傳遞鏈有關，對於老化過程的探索，進一步提供相關的了解與證據。研究發現[Fe2(μ-SEtCOOH)2(NO)4] (DNIC-1b)在酸性有氧環境下會快速瓦解釋放一氧化氮，本研究將[Fe2(μ-SEtCOOH)2(NO)4] (DNIC-1b)利用其上-COOH官能基修飾在MIL-88B(Fe)上合成出DNIC@MOF，研究DNIC@MOF在不同pH值穩定性，利用IR、UV、XRD鑑定，發現DNIC@MOF能在pH5以下酸性環境中穩定存在。近一步將DNIC@MOF管餵具高血壓的SHR大鼠，量測老鼠24小時血壓變化，探討DNIC@MOF在生物體內是否能穩定釋放一氧化氮來降低血壓。本研究證實，DNIC 可以作為很好的一氧化氮提供試劑，並且可進一步應用於一氧化氮相關生物學和藥理學，配合有機金屬骨架作為藥物載體或者是應用於發現更多一氧化氮未知的生理作用。

關鍵字

雙亞硝基鐵錯合物；一氧化氮；有機金屬骨架

並列摘要

Nitric oxide has important functions in the body, including: vasodilation, nerve conduction, blood pressure regulation, and other pathogens. However, instability of nitric oxide makes the research and application of nitric oxide more complicated in biology and pharmacology. Therefore, the development of compounds capable of stably releasing NO• has become one of the important topics in the current research and application of nitric oxide. In this study, dinitrosyl iron complex (DNIC) and [Fe2(μ-SR)2(NO)4] were used as nitric oxide delivery reagents. It was first discovered that [Fe2(μ-SR)2(NO)4] can triggered to release nitric oxide under aerobic conditions. In addition, the half-life for the release of nitric oxide, ranging from 0.5 hours to 27.4 hours, can be controlled by using different thiol ligands. Moreover, C. elegans was used as a biological model, and NO•-fluorescent probe was used in combination with a Confocal Microscope to confirm that DNIC-1 can release NO in C. elegans. In addition, we have found that the NO •-release [Fe2(μ-SEtOH)2(NO)4] (DNIC-1a) can extend the lifespan of C. elegans from 16.9±0.5 days to 18.7±0.4 days and delay accumulation of cell senescence to achieve the effect of delaying aging. The study found that [Fe2(μ-SEtCOOH)2(NO)4] (DNIC-1b) will rapidly decay and release nitric oxide in an acidic aerobic environment. In this study, we used [Fe2(μ-SEtCOOH)2(NO)4] (DNIC-1b) to modify MIL-88B(Fe) to synthesize DNIC@MOF through -COOH functional group. To study the stability of DNIC@MOF at different pH values, using IR, UV, XRD identification, found that DNIC@MOF can be stable in the acidic environment below pH5. In the next step, DNIC@MOF was fed to hypertensive SHR rats to measure blood pressure changes in mice for 24 hours to investigate whether DNIC@MOF can stably release nitric oxide in vivo to lower blood pressure.