本文關(guān)鍵詞： 苦參堿 柯薩奇病毒 構(gòu)效關(guān)系 類藥五原則 病毒性心肌炎　出處：《青島科技大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：柯薩奇病毒是一類傳播途徑較廣,且致病性極強(qiáng)的腸道病毒,其中又以B3型(CVB3)亞種致病性最強(qiáng),危害性最大。CVB3病毒的感染會導(dǎo)致心肌細(xì)胞的凋亡,進(jìn)而導(dǎo)致病毒性心肌炎的發(fā)作。根據(jù)數(shù)據(jù)顯示,約有50%的病毒性心肌炎(VMC)的發(fā)病與CVB3病毒的感染相關(guān)。此外CVB3病毒還可以引起心包炎、流行性胸痛、胰腺炎、腦膜炎甚至手足口病等多種極其嚴(yán)重的疾病。苦參提取物(槐果堿注射液)是已經(jīng)被應(yīng)用于治療由柯薩奇病毒B3引起的病毒性心肌炎等疾病的藥物,其安全性與療效得到了普遍認(rèn)可。但是由于其對CVB3病毒的抑制活性有限,導(dǎo)致其在臨床應(yīng)用劑量較大,且治療周期較長,因此對苦參類藥物的結(jié)構(gòu)進(jìn)行修飾以提高其病毒的活性具有重要的意義。本課題組對此類化合物抗CVB3病毒的活性有了初步的構(gòu)效關(guān)系總結(jié)：頭期構(gòu)效關(guān)系表明12-N-苯磺�；〈腔钚员匦杌鶊F(tuán),當(dāng)苯磺�；谋交巧线B有吸電子基團(tuán)時,化合物活性較好；C11側(cè)鏈為非活性必需基團(tuán),但可以通過改變其脂溶性等參數(shù)來調(diào)節(jié)目標(biāo)化合物的溶解度以及藥代參數(shù)來提高化合物的成藥性。為了進(jìn)一步提高藥物的活性以及成藥性,并降低研發(fā)成本及時間。本課題以其構(gòu)效關(guān)系為基礎(chǔ),參照類藥五原則,并采用計算機(jī)對預(yù)合成化合物的C1ogP以及tPSA等藥代參數(shù)進(jìn)行了計算以使其符合高成藥性的標(biāo)準(zhǔn),進(jìn)而指導(dǎo)后續(xù)的合成工作。本課題以苦參堿為原料,經(jīng)過開環(huán),酯化,水解,還原胺化,斯文氧化,四氫鋁鋰還原,成醚,酸胺縮合等一系列化學(xué)合成手段,累計合成了34個未見文獻(xiàn)報道的目標(biāo)化合物,結(jié)果均經(jīng)1H-NMR, 13C-NMR, MS和HRMS確證。其中的苦參酰胺類,苦參丁烷類以及苦參醚類化合物都取得了較好的活性數(shù)據(jù)。此外還對以前的構(gòu)效關(guān)系進(jìn)行了進(jìn)一步驗證及修改。其中進(jìn)一步驗證了12-N上的苯磺�；现挥羞B有強(qiáng)吸電子基團(tuán)時才具有最良好的活性與治療窗口。另外,本文通過大量的實驗數(shù)據(jù),認(rèn)為11位側(cè)鏈基團(tuán)也是活性必需基團(tuán),側(cè)鏈的PKa值會直接影響化合物的抗CVB活性�？鄥Ⅴ０坊衔�21c-d,21j以及苦參丁烷類化合物ks-dw-1,ks-dw-3都體現(xiàn)出了非常好的抗CVB3活性以及治療窗口指數(shù),已經(jīng)被用來做下一步的研究。
[Abstract]:Coxsackie virus (Coxsackie virus) is a kind of enteroviruses with wide transmission route and strong pathogenicity, among which B3 type CVB3 subspecies are the most pathogenic. The most harmful. CVB3 virus infection will lead to cardiomyocyte apoptosis, and then lead to the outbreak of viral myocarditis. According to the data show. About 50% of viral myocarditis (VMC) is associated with the infection of CVB3 virus. In addition, CVB3 virus can also cause pericarditis, epidemic chest pain, pancreatitis. The extract of Sophora flavescens (Sophora flavescens injection) has been used in the treatment of viral myocarditis caused by Coxsackie virus B3 and other diseases. Its safety and efficacy have been generally accepted, but because of its limited inhibitory activity against CVB3 virus, it has a large dose in clinical use and a long treatment period. Therefore, it is of great significance to modify the structure of Sophora flavescens to improve their viral activity. The preliminary structure-activity relationship of these compounds against CVB3 virus is summarized. The first phase structure-activity relationship indicated that 12-N- benzene sulfonyl group was the necessary active group. When the benzenesulfonyl group is attached to the benzenesulfonyl group, the activity of the compound is better. The side chain of C11 is an inactive essential group. However, the solubility and pharmacological parameters of the target compounds can be adjusted by changing their liposolubility and other parameters to improve the drug formation, in order to further improve the drug activity and drug formation. And reduce the cost and time of research and development. This subject is based on its structure-activity relationship, referring to the five principles of drugs. The pharmacological parameters such as C1ogP and tPSA of presynthetic compounds were calculated by computer to make them meet the standard of Gao Cheng. In this paper, matrine was used as raw material through a series of chemical synthesis methods, such as ring opening, esterification, hydrolysis, reductive amination, Sven oxidation, lithium tetrahydroaluminate reduction, ether formation, acid amine condensation and so on. A total of 34 target compounds were synthesized and confirmed by 1H-NMRs, 13C-NMRs, MS and HRMS. Good activity data were obtained for both Sophora flavescens butane and Sophora flavescens. In addition, the former structure-activity relationships were further verified and modified. It was further verified that only the benzenesulfonyl group on 12-N was found. Even if there is a strong electron group, it has the best activity and therapeutic window. In addition. Based on a large amount of experimental data, it is considered that the 11 side chain group is also a necessary active group, and the PKa value of the side chain will directly affect the anti CVB activity of the compound. 21j and ks-dw-1ks-dw-3 have shown very good anti- CVB3 activity and therapeutic window index, which have been used for further research.
【學(xué)位授予單位】：青島科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R914.5;R96

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