I. 雙萜類衍生物的合成及其活性的探討 II. 開發含有三環雜環之羥基醯胺作為選擇性第二類 組蛋白去乙醯酶抑制劑

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題名:	I. 雙萜類衍生物的合成及其活性的探討 II. 開發含有三環雜環之羥基醯胺作為選擇性第二類組蛋白去乙醯酶抑制劑 I. Study on the synthesis and activity of diterpenoid derivatives II. Development of tricyclic heterocycles containing hydroxamates as selective class II histone deacetylase inhibitors
作者:	呂宛珣 Huang, Wei-Jan
貢獻者:	生藥學研究所碩士班黃偉展
關鍵詞:	雙萜類衍生物;組蛋白去乙醯酶抑制劑 Diterpenoid derivatives;Histone deacetylase inhibitors
日期:	2022-01-12
上傳時間:	2022-08-05 09:33:14 (UTC+8)
摘要:	I.雙萜類衍生物的合成及其活性的探討甜菊因為它的甜度高於蔗糖，所以在南美洲被當作天然甜味劑使用。甜菊葉中含量最豐富的成分是甜菊糖苷，它被發現具有抗發炎作用。異甜菊醇是一種由甜菊糖苷水解產生的二萜類化合物，該化合物也具有抗發炎活性。發炎是身體的防禦機制，可分為急性發炎和慢性發炎，其中慢性發炎與癌症和糖尿病有關，而抑制環加氧酶-2（COX-2）的表現被發現具有抗發炎活性。本研究旨在對異甜菊醇進行化學修飾，包括對 A 環上的 C-19 酸基和 D 環上的 C-16 酮基的修飾。最後我們總共獲得了 11 種具有不同胺的二萜類化合物。測試了這些化合物對 RAW264.7 巨噬細胞中 LPS 誘導的 COX-2 過表達的抑制作用，以評估它們的抗發炎活性。結果表明，化合物 4a，一個在 C-16 上含有芐胺的二萜類化合物，比甜菊苷具有更強的抗發炎活性。目前正在進一步研究甜菊醇衍生物治療炎症相關疾病的潛力。 II.開發含有三環雜環之羥基醯胺作為選擇性第二類組蛋白去乙醯酶抑制劑組蛋白去乙醯酶（HDAC）是一種能催化組蛋白使其去乙醯化的酵素，總共有 18 種亞型。這些亞型可以根據它們的同源性、分佈位置和生物學功能分為四大類。在這些酵素中，第二類組蛋白去乙醯酶可以促進癌細胞的轉移，除了對癌症的抑制活性外，還發現它們可作為治療神經系統疾病的潛在靶點。數據顯示只有四種組蛋白去乙醯酶抑制劑被 FDA 批准用於治療癌症，並且它們有些是廣泛型組蛋白去乙醯酶抑制劑，有些是第一類組蛋白去乙醯酶抑制劑。本次研究中，我們使用先前合成具有強效第二類組蛋白去乙醯酶抑制活性的化合物 4a作為先導化合物進行結構優化。基於環狀生物等效性的概念而將化合物4a的cap基團吩噻嗪被吩惡嗪所取代，獲得的一些含有吩惡嗪的異羥肟酸衍生物表現出比化合物 4a 更高的第二類組蛋白去乙醯酶抑制活性。將這些化合物其中之一命名為化合物 21，它在吩惡嗪環上具有 C-3 修飾，顯示出最強的第二類組蛋白去乙醯酶抑制活性，在細胞毒性試驗中，與化合物4a和SAHA相比，化合物21的細胞毒性最低。綜合以上結果，化合物21有潛力被開發為治療神經退化性疾病的藥物。 I. Study on the synthesis and activity of diterpenoid derivatives Stevia Rebaudiana is used as a natural sweetener in South America because its sweetness higher than sucrose. The most abundant ingredient in stevia leaves is stevioside, which is found to have anti-inflammatory effect. Isosteviol is a diterpene produced from the hydrolysis of stevioside and this compound also has anti-inflammatory activity. Inflammation is the body’s defense mechanism. It can be divided into acute and chronic inflammation. Chronic inflammation is associated with cancer and diabetes. Inhibition of cyclooxygenase-2（COX-2） is found to induce anti-inflammatory activity. This study is aimed to perform the chemical modification of the isosteviol. It included modification for C-19 acid group on A-ring and C-16 ketone group on the D ring. In total, we obtained 11 diterpenoids with varied amines. These compounds were tested for their inhibition against COX-2 over expression induced by LPS in RAW264.7 macrophages to evaluate their anti-inflammatory activities. The result showed that compound 4a, a C-16 benzylamine containing diterpene has more potent anti-inflammatory activity than stevioside. Further studies on investigating the potential of steviol derivatives to treat inflammation-related diseases are being undertaken. II.Development of tricyclic heterocycles containing hydroxamates as selective class II histone deacetylase inhibitors Histone deacetylases (HDAC), the enzymes that catalyze deacetylation of histone have 18 isoforms. These isoform enzymes can be divided into four classes based on their homology, distribution and biological function. Of these enzymes, class II HDAC can promote the metastasis of cancer cells. In addition to their inhibiting activity against cancers, class II HDACs are found to act as the potential targets to treat neurological diseases. The data show, only four HDAC inhibitors are approved by FDA for treating cancers and they are pan- or class I-HDAC inhibitors. In this study, we use previously synthesized compound 4a with potent class II HDAC inhibitory activity as a lead compound to perform structure optimization. Based on the ring bioisostere concept, the cap group-phenothiazine of compound 4a was replaced by phenoxazine. Some resulting phenoxazine-containing hydroxamic acids exhibited higher class II HDAC inhibition than compound 4a. One of these compounds, designated compound 21, with C-3 modification on phenoxazine ring displayed the strongest class II HDAC inhibition. In the cytotoxicity test, compared with compound 4a and SAHA, compound 21 had the lowest cytotoxicity. Overall, these results showed compound 21 has the potential to be developed as a drug for the treatment of neurodegenerative diseases.
描述:	碩士指導教授:黃偉展委員:許凱程委員:楊瀅臻委員:黃偉展
資料類型:	thesis
顯示於類別:	[生藥學研究所] 博碩士論文

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