褪黑激素及血清激素的7-氮雜吲哚類似物之合成與光物理性質探討

Synthesis and Photophysical Properties of 7-Azaserotonin and 7-Azamelatonin

吳珮雯(Pei-Wen Wu)

指導教授 ： 周必泰

國立臺灣大學/理學院/化學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.00216

摘要

二十一世紀生物學的重點學門之一，為腦神經生理學。從複雜的腦部構造，到神經傳導的分子機制，還有很大的研究空間空間。至今，許多神經類疾症的病因仍是個謎，但已有越來越多的研究指出血清激素(serotonin)或褪黑激素(melatonin)的異常表現似乎是神經類疾病的關鍵所在。因此，此兩種激素或許可稱為體內最為重要的神經傳導物質。有鑒於其在病理上的重要性，許多科學家致力於合成這類結構簡單,卻對腦部功能具極大影響的小分子。其中，許多血清激素及褪黑激素的類似物仍以吲哚環作為主要架構。不同於此，本論文則嘗試以7-氮雜吲哚環(7-azaindole)作為衍生物之主體，並成功合成出7-azaserotonin(產率~10 %)及7-azamelatonin(產率~6 %)。此外，本論文更進一步探討7-azaserotonin及7-azamelatonin在水及醇溶液中的光物理現象---激態雙質子轉移反應，並推想或許7-azaserotonin及7-azamelatonin在疏水的介質中，可經由水的催化進行質子轉移反應，以作為極具應用價值的分子感測器。而經由理論計算，初步資料顯示7-azaserotonin與5-HT1B的結合力較serotonin強，可作為有效的拮抗劑或激動劑以應用於抑鬱症或攻擊行為的治療。而7-azamelatonin則可藉由與calmodulin的強結合力來治療與雌激素相關的癌症(如:乳癌)。因此，我們相信7-azaserotonin及7-azamelatonin在醫藥及光物理領域具有極重要的應用價值。

關鍵字

褪黑激素 ； 血清激素

並列摘要

Perhaps, the most prominent neurotransmitters can be ascribed to serotonin and melatonin. In many neuropsychiatric disorders, the serotonin or melatonin system may play a key modulatory role. Although the pathophysiology of many neuropsychiatric disorders remains enigmatic, the abnormalities in serotonin or melatonin signaling have been strongly implicated.
Such a small molecule like serotonin or melatonin acting as a vital element in brain function has attracted much attention in the synthetic chemistry. Focus on derivatization of serotonin or melatonin has been one of the intensive areas in the medicinal chemistry. While most of the approaches lie in the substitution effect on the parent serotonin or melatonin, we have long been interested in replacing the parent indole moiety by the 7-azaindole chromophore, forming 7-azaserotonin, 7-azamelatonin.
Herein, we elaborated first synthesis of 7-azaserotonion in ~10 % total yield and rose up the yield of 7-azamelatonin by the synthetic route different from the synthetic pathway of Guillaumet in ~6 % total yield. Subsequently, we further investigated the photophysical properties of 7-azaserotonin and 7-azamelatonin, namely the excited state proton transfer reaction. Differentiation of photophysics between alcohol and water are intriguing. In view of bio-application, we suspect that once 7-azaserotonin and 7-azamelatonin are in the hydrophobic medium, water catalyzed proton transfer reaction may take place, serving as suitable molecular probes. We also performed the molecular dynamic approaches for 7-azaserotonin (and 7-azamelatonin) to investigate the difference of interaction to the 5-HT1B receptor (and calmodulin) between serotonin (melatonin) and 7-azaserotonin (7-azamelatonin). Our preliminary data indicate that 7-azaserotonin (7-azamelatonin) has larger association strength than that of serotonin (melatonin). Thus, 7-azaserotonin may serve as a powerful 5-HT1B agonist or antagonist to treat aggression or depression, respectively. 7-azamelatonin could be taken to treat estrogen responsive cancers more efficiently. We believe that exploration of 7-azaserotonin and 7-azamelatonin may spark a broad spectrum of interest in the fields of medicinal chemistry and biophysics.

並列關鍵字

melatonin ； serotonin

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