開發新型抗病毒前驅化合物暨發展新穎碳-碳鍵合成方法

Development of New Anti-Viral Lead Compounds and Novel Method of CC Bond Formation in Organic Syntheses

卡莫漢(Mohit Kapoor)

指導教授 ： 胡紀如

國立清華大學/理學院/化學系/博士(2014年)

摘要

有機化學是化學的主要領域 , 哪個環節眾多學科 , 並允許在研發 , 新方法 , 並開發新的藥物其他科學家合作。碳 - 碳鍵的形成是有機合成的本質。這些反應是用於構建結構複雜的有機結構單元 , 特別是在天然產物 , 藥物化學 , 農業化學和合成領域根本轉變。為碳 - 碳和碳 - 氧鍵形成開發新的和有效的方法 , 已在有機化學解決根本問題。Na@SiO2被開發作為一種強大的試劑的溶液 , 以中最重要的主題之一在有機合成 , 碳碳鍵形成。在Na@SiO2有機鹵化物的存在給予良好的醇以良好的收益率。廣闊的選擇羰基衍生物經過有效的CC和CO鍵的形成。不太活潑的格氏試劑經過光滑CC鍵的形成。Na@SiO2還協助α-鹵代化合物通過一個前所未有自由基通路與在地層中的環氧化物的醛反應。
替代Darzen的方法帶來的時間的經濟 , 產量高 , 傳輸選擇性環氧化物。在無數的可用的方法相比 , 採用新開發的方法相關的優點包括：（1）所需的加合物通常是非常良好的產率獲得 ,（2）反應是完全在環境溫度下2.0小時內 ,（3）要求的無水溶劑是沒有必要的 , 以及（4）操縱均相反應的很簡單。Na@SiO2在有機合成中的應用程序安裝到12五個綠色化學的指導方針。我們的方法提供了一個很好的替代品達參反應。達參反應一般需要17天用低屈服diastereoslective產物，這是由於鹼催化外消旋化。但在我們的情況下 , 各方反應2.0小時內完成 , 我們得到了獨家的反式環氧化物。不可能達參反應 , 反應時間延長並沒有異構化產品在我們的方法論。
在過去幾年中已經觀察到了一些新的病毒（“RNA病毒和新出現的病毒”）和其他的病原體已蔓延全球 , 從此不明疾病到先前未受影響的地區推行。因此 , 對於新的抗病毒動態發展 , 合成了新開發的方法 , 新的香豆素環氧化物偶聯物具有很好的抗丙型肝炎病毒的效力和選擇性。這些結合物中哈5-2細胞的最低EC50測試抗HCV 0.9μM和102的最大的SI值此外 , 雙和三重共軛化合物兩個庫的設計和用抗CHIKV活性合成。建立的結構 - 活性關係做的化學合成的60個新的化合物的基礎上 , 在其中尿嘧啶 , 香豆素 , 和芳烴被允許具有各種取代基上。尿嘧啶部分可以是5-甲基-2-硫尿嘧啶 , 2- thiobenzouracil , 和4-苯胺基-2- thiobenzouracil。 4-氯香豆素被允許具有在其上不同的取代基。芳烴部分可以經由-OSO2- , -OCH2- , 和-NH關節被鏈接到香豆素或嘧啶。所有化學合成的化合物的結構通過光譜法（NMR , 質譜 , 和IR）, 並通過X-射線晶體學確認。
在這個新的庫 , 其抗CHIKV測定中 , 抑制細胞生長的測定測定法和構效關係成立。幾種新的化合物被發現抑制CHIKV（899株）在Vero細胞亞型A的最吸引人的結果與結合物87 , 88 , 89相關聯 , 且102 , 其抑制CHIKV（899株）, 在EC50 1.96最小μM和最大37.4-苯胺喹唑啉的SI值被證明是有效的嘧啶核。此外 , 4- anilinoquinazolinone與香豆素偶聯提供了高選擇性CHIKV抑制。芳烴磺關節benzouracil - 香豆素綴合物被證明是有效的抗CHIKV引線。此外 , 14準則推斷其結構 , 親油性和抗CHIKV活性的分析。
兩個主要問題進行了討論 , 並解決了本文 , 其中包括新的CC鍵的形成和有效的抗CHIKV引線方法的發展。Na@SiO2介導的CC和CO鍵的形成提供了很好的選擇 , 以格利雅和達參反應 , 這是在實驗室中的突出和最有用的反應。抗CHIKV導致在我們的複合圖書館 , 這是最好的中報CHIKV抑製劑獲得的1.96μM最低EC50值。通過開發新的CC鍵形成方法和新穎的抗CHIKV線索 , 顯著的貢獻已取得有機和藥物化學領域 , 這可能為全球各地的研究人員進行的新方法和新藥物的開發有所幫助。

關鍵字

抗病毒 ； 屈公熱病毒 ； 2,4-喹唑啉二酮 ； 二氧化矽基鈉 ； 碳碳建合成 ； 環氧化合物

並列摘要

Organic chemistry is the major field in chemistry, which links many scientific disciplines and allows for collaboration with other scientists in researching, new methodologies, and developing new drugs. Carbon–carbon bond formation is the essence of organic synthesis. These reactions are fundamental transformations for constructing structurally complex organic building blocks, especially in the realm of natural products, medicinal chemistry, and agrochemical synthesis. Developing new and efficient method for carbon–carbon and carbon–oxygen bond formation, have solved fundamental problem in organic chemistry. Na@SiO2 was developed as a powerful reagent for a solution to one of the most important themes in organic synthesis, carbon to carbon bond formation. In the presence of Na@SiO2 organohalides to give alcohols in good to excellent yield. A broad selection of carbonyl derivatives undergoes efficient CC and CO bond formation. Less reactive Grignard reagent undergoes smooth CC bond formation. Na@SiO2 also assisted
α-halocarbonyl compounds to react with aldehydes in the formation epoxides through an unprecedented radical pathway.
Alternative to Darzen’s method brings time economic, high yield and trans- selectivity in epoxides. In comparison with myriad available methods, advantages associated with the newly developed methods include: (1) the desired adducts were often obtained in very good yields, (2) reactions were complete at ambient temperature within 2.0 hours, (3) requirement for anhydrous solvent was not necessary, and (4) manipulation of the heterogeneous reaction was simple. Application of Na@SiO2 in organic synthesis fits into five of twelve guidelines of green chemistry. Our methodology offers a good alternative to Darzens reaction. Darzens reaction usually takes 1−7 days with low yield of diastereoselective product, which is due to base catalyzed racemization. But in our case, all of the reactions completed within 2.0 hours and we got exclusively trans-epoxides. Unlikely to Darzens reaction, prolonged reaction time didn't isomerize the product in our methodology.
Over the past years it has been observed that a number of new viruses ("RNA viruses and emerging viruses") and other pathogens has spread worldwide, introducing since then unknown diseases into previously unaffected regions. So, for the development of new anti-viral leads, novel coumarin-epoxide conjugates with high anti-HCV potency and selectivity were synthesized by newly developed method. These conjugates were tested against HCV in huh 5-2 cells with minimum EC50 of
0.9 μM and maximum SI value of 102. Moreover, two libraries of doubly and triply conjugated compounds were designed and synthesized with anti-CHIKV activity. Establishment of structure-activity relationship was done on the basis of chemically synthesized 60 new compounds, in which uracil, coumarin, and arene was allowed to possess various substituents. The uracil moiety can be 5-methyl-2-thiouracil,
2-thiobenzouracil, and 4-anilino-2-thiobenzouracil. 4-Chloromethyl coumarin was allowed to possess different substituent on it. Arene moiety can be linked to coumarin or pyrimidine via –OSO2– , –OCH2–, and –NH joint. The structure of all chemically synthesized compounds were confirmed by spectroscopic methods (NMR, Mass, and IR) and by X-ray crystallography.
In this new library, their anti-CHIKV assay, cytostatic determination assays were performed and the structure−activity relationship was established. Several new compounds were found to inhibit CHIKV (899 strain) in Vero cells subtype A. The most appealing results were associated with conjugates 87, 88, 89, and 102, which inhibited CHIKV (899 strain) at minimum EC50 of 1.96 μM and maximum SI value of 37. 4-Anilinoquinazoline was proved to be potent pyrimidine nucleus. Furthermore, conjugation of 4-anilinoquinazolinone with coumarin offers high selectivity in CHIKV inhibition. Arene-sulfo joint with benzouracil-coumarin conjugate was proved to be potent in anti-CHIKV leads. Moreover, 14 guidelines were deduced from the analysis of their structures, lipophilicity, and anti-CHIKV activity.
Two major issues has been discussed and solved in this dissertation, which includes the development of new method of CC bond formation and potent anti- CHIKV leads. Na@SiO2 mediated CC and CO bond formation offers good alternative to Grignard and Darzens reaction, which are the prominent and most useful reaction in laboratory. Anti-CHIKV leads with minimum EC50 value of
1.96 μM was obtained in our compound library, which is best among reported CHIKV inhibitor. By developing new CC bond formation method and novel anti-CHIKV leads, significant contribution has been made in organic and medicinal chemistry field, which may helpful for the researchers around the globe for the development of new methodologies and new drugs.

並列關鍵字

Antiviral ； Chikungrnya ； Benzouracil ； Na@SiO2 ； C-C bond formation ； Epoxide

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