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標題: | 設計與合成嶄新克流感生物等配體作為有效抗流感試劑 Design and Synthesis of Novel Oseltamivir Bioisosteres as Effective Anti-Influenza Agents |
作者: | Bei-Tao Hong 洪北濤 |
指導教授: | 方俊民 |
關鍵字: | 流感,克流感,生物等配體, influenza,oseltamivir,bioisostere, |
出版年 : | 2015 |
學位: | 博士 |
摘要: | 流行性感冒在近百年來是個常見且對人類健康有著重大威脅的疾病;目前抗流感病毒的藥物主要有兩種:針對M2 離子通道以及神經胺酸酶(NA);然而,因為有嚴重副作用以及病毒抗藥性的緣故,amantadine與rimantadine 這兩種針對M2 離子通道的藥物已經很少被用來治療流感;相較之下,被設計用來防止病毒離開宿主細胞醣蛋白的NA抑制劑,則是廣泛地運用在治療流感。
身為前驅藥物,且會被水解酶轉換成有作用力的酸基的克流感oseltamivir phosphate,則被用來作為第一線的治療選擇;oseltamivir carboxylic acid (OC)的酸基會與流感病毒的NA的S1部位上三個arginine的鹼基(Arg118, Arg292 and Arg371)之間有很強的靜電吸引力;不過流感病毒的突變相當迅速,最常見的抗藥性突變株病毒是最先在2007年於挪威被發現的H275Y病毒株,並在數年間就造成全球性地傳播;因此,開發嶄新的抗流感藥物是目前相當緊急的課題。 在過去幾年,本實驗室已開發出oseltamivir的磷酸等配體及其胍基衍生物;在本次研究中,我們則是利用醯胺鍵形成反應合成oseltamivir的醯基羥胺、醯基磺胺等配體與它們的胍基衍生物。在醯基羥胺衍生物中,我們發現增加此類衍生物官能基的疏水性時,會增加其抑制能力 (化合物25);但同時我們也觀察到另一不尋常的趨勢,醯基羥胺的胍基化合物29與33的抑制能力竟然比胺基化合物差,但是此二者對於突變株的抑制活性卻比OC還要來的好;與此相比,胍基化合物28反而這一系列中對野生型最有效,但對於突變株的抑制活性卻是遠不如另外兩個化合物。在醯基磺胺衍生物中,雖然觀察到具有長碳鏈以及苯環的化合物抑制能力相近,但卻比不上僅有甲基衍生的化合物35與40。 在另一方面,我們也利用了過渡金屬耦合反應合成oseltamivir與它們的胍基衍生物;在這些衍生物中,化合物64, 66, 71, 73, 86及87的抑制能力與OC不相上下,甚至還略高些許。 因此本研究可以提供相當多的資訊,有助於流感藥物之開發。 Influenza is a common disease and has been a threat to human health over centuries. There are two classes of anti-influenza drugs approved to target the virus M2 ion channel and neuraminidase (NA), respectively. Nevertheless, the M2 ion channel inhibitors amantadine and rimantadine are no longer recommended for treatment of influenza infection due to their severe side effects and drug resistance. Neuraminidase inhibitors, designed to prevent the cleavage of terminal sialic acid residue on the surface glycoprotein of host cells, are effectively used for the treatment of influenza infection. Oseltamivir, which is a prodrug and will be converted to the active acid by esterases, is taken as the front-line therapeutic option. The carboxylate group of oseltamivir carboxylic acid (OC) provides strong electrostatic interactions with the three arginine residues (Arg118, Arg292 and Arg371) in the S1 site of influenza NA. However, the drug-resistant influenza viruses have emerged. The most common and clinically relevant oseltamivir-resistant influenza virus is the H275Y strain, which was firstly found in Norway in 2007 and spread globally in a few years. Therefore, the development of novel anti-influenza agents is urgently needed. In the past years, our research team has developed some phosphonate congeners of oseltamivir and guanidino-oseltamivir. In this study, we synthesized the oseltamivir hydroxamates, acyl sulfonamides, and their guanidino derivatives via amide bond formation. We find that the inhibition abilities increase when the functional group of amino hydroxamate derivatives was replaced by more hydrophobic groups (compound 25). We also observed that guanidino hydroxamate compound 29 and 33 show better EC50 than OC against mutant H275Y influenza virus, though these two compounds have poorer inhibition efficiency than amino ones in the WSN assays. Interestingly, the guanidino hydroxamate compound 28 has the best EC50 in WSN assay with the poorest effect among the guanidino hydroxamate derivatives in H275Y assay. On the other hand, the n-butyl and phenyl acyl sulfonamides have similar inhibition abilities, but the methyl derivatives 35 and 40 achieve the best potency among the acyl sulfonamide derivatives. We also synthesized OC and GOC derivatives by transition-metal catalyzed coupling reactions. Some of these derivatives (64, 66, 71, 73, 86 and 87) demonstrate the inhibition efficiency similar to OC, or even better. In summry, this study provides useful information for development of novel anti-influenza drugs. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54727 |
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顯示於系所單位: | 化學系 |
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