本文選題：支氣管哮喘 + α-萜品烯醇�。� 參考：《浙江大學》2016年博士論文

【摘要】：支氣管哮喘是由氣道慢性炎癥病變引起的支氣管高反應性疾病,全球患者已達到3億,它不僅嚴重影響人們的正常生活,嚴重的哮喘甚至威脅生命。迄今為止,哮喘尚無根治手段,只能采用癥狀改善藥物進行治療和預防,臨床治療主要采用支氣管擴張藥(β2受體激動劑為主)和抗炎藥物(激素為主)的聯合用藥方案。β2受體激動劑對于危重哮喘患者存在一定程度的心功能損害,且與哮喘嚴重程度呈正相關,對于此類患者,聯合用藥方案會加大心衰的風險。因此,尋找和發(fā)現對心臟功能無影響、無激素類副作用的抗哮喘藥物,將為患者提供新的選擇,對于哮喘的臨床治療具有重要的價值。前期課題組發(fā)現天然產物單萜類化合物α-萜品烯醇對氣管平滑肌有直接松弛的作用,且具有祛痰、鎮(zhèn)咳、抗過敏等作用。但是α-萜品烯醇在艾葉中含量低,無法用水汽蒸餾法提取,藥用來源受到限制,亟需采用新方法解決。另外,雖然α-萜品烯醇解痙作用好、起效快,但是其有效作用時間短(僅半小時左右)。因此,限制了該藥物在臨床中治療哮喘的使用。針對藥用來源受限的問題,本論文對αα-萜品烯醇的提取、分離方法進行研究,采用超臨界CO2萃取與高速逆流色譜法分離相結合的方法,對艾葉中α-萜品烯醇進行分離純化,成功獲得90%以上含量的產物;另一方面,α-萜品烯醇的體內初步藥代動力學研究表明,其半衰期T1/2約為2.148h,清除率為1.544L/h/kg,證明其口服吸收迅速、作用時間短是由于其藥代動力學特性所致。針對α-萜品烯醇雖吸收速度快、但有效作用時間短的缺點,本文采用前藥策略,對其結構中的羥基進行酯化修飾,設計、合成17個α-萜品烯醇酯類前藥。另一方面,利用藥物駢合原理,將具舒張支氣管作用的NO供體片段亞硝酸酯(ONO2)引入α-萜品烯醇中,獲得2個含有亞硝酸酯片段的α-萜品烯醇衍生物。此外,還合成了 α-萜品烯醇雙鍵還原產物,初步探索烯烴片段對活性的影響。對上述合成的21個化合物進行豚鼠支氣管平滑肌舒張試驗。結果顯示,有8個化合物顯示出優(yōu)良的舒張支氣管平滑肌活性,優(yōu)于陽性對照氨茶堿(舒張率45%)。特別是化合物6a和6d,在1.25mmol/l的濃度下,舒張率分別達到83%和85%。作用機制研究表明,6a、6b、6c、6d、6f、6g、6i等化合物對平滑肌細胞內cAMP含量有顯著提升,提示該類化合物可能是通過增加細胞內cAMP含量來舒張支氣管平滑肌,且與β2受體無關。MTT試驗表明,在1.25mmol/L和0.625mmol/L濃度下,上述7個化合物對支氣管平滑肌細胞增殖無明顯影響。對高活性化合物6a,6d的體內初步藥代動力學研究表明,化合物6a和6d的半衰期分別為2.309h和3.386h,較α-萜品烯醇的T1/2=2.148h有所提升,證明論文前藥設計策略的合理性和可行性。進一步對化合物6a,6d開展整體動物平喘活性評價(大鼠哮喘模型),以肺功能、炎癥因子IL-4,IL-17A等作為評價指標。結果顯示,化合物6a,6d可通過提高哮喘鼠的氣道順應性和減少氣道阻力,達到改善肺功能的效果,同時,可降低血清中的IL-4、IL-17A含量,抑制炎癥,且對哮喘鼠的心率沒有明顯影響。因此,上述化合物顯示出舒張支氣管平滑肌和抗炎的雙重活性,具有代替臨床上β2受體激動劑和激素聯合用藥的潛力。
[Abstract]:Bronchial asthma is a bronchial hyperreactivity disease caused by chronic airway inflammation, and the global patient has reached 300 million. It not only seriously affects people's normal life, severe asthma and even life. So far, there is no radical cure for asthma. It can only be treated and prevented with symptoms modified by drugs. Clinical treatment is mainly used. A combined regimen of bronchiectasis (beta 2 receptor agonist) and anti inflammatory drugs (hormone based). Beta 2 receptor agonists have a certain degree of cardiac dysfunction in critical asthma patients and are positively related to the severity of asthma. For these patients, the combination regimen will increase the risk of heart failure. The antiasthmatic drug with no hormone side effects and no hormone side effects will provide a new choice for the patients. It is of great value for the clinical treatment of asthma. The previous research group found that the natural product monoterpenoid terpenoid enol has direct relaxation on the smooth muscle of the trachea, and it has the effect of expectorant, antitussive, and anti allergy. The content of alpha terpene enol in the leaf is low and can not be extracted by steam distillation. The source of medicine is limited and new methods need to be solved. In addition, although the effect of alpha terpenol enol is good and its effect is fast, its effective time is short (about half an hour). Therefore, it is limited to the use of the drug in the clinical treatment of asthma. In this paper, the extraction and separation of alpha terpene enol was studied in this paper. The method of supercritical CO2 extraction and high speed counter current chromatography was used to separate and purify the alpha terpene enol in the leaf. The product was more than 90%. On the other hand, the primary pharmacokinetics of alpha terpene enol in the body. The study shows that the half-life of T1/2 is about 2.148h and the clearance rate is 1.544L/h/kg. It is proved that its oral absorption is rapid and its action time is due to its pharmacokinetic characteristics. Although the absorption rate of alpha terpene enol is fast, but the effective time is short, this paper uses the prodrug strategy to modify the hydroxyl group in its structure. To synthesize 17 alpha terpene enol esters prodrugs. On the other hand, using the NO donor fragment nitrite (ONO2) with diastolic bronchodilation into alpha terpene enol, 2 nitrite enol derivatives containing nitrite fragments were obtained by the use of the principle of antipyrexia, in addition to the synthesis of alpha terpene enol double bond reduction products and preliminary exploration of alkenes. The effects of hydrocarbon fragments on the activity of the 21 compounds were conducted in guinea pig bronchi smooth muscle relaxation tests. The results showed that 8 compounds showed excellent diastolic bronchial smooth muscle activity, superior to positive control aminophylline (diastolic rate 45%), especially compound 6a and 6D, and the diastolic rate reached 83% at 1.25mmol/l concentration, respectively. 6a, 6b, 6C, 6D, 6F, 6G, 6I and other compounds have a significant increase in the content of cAMP in smooth muscle cells, suggesting that the compounds may be dilatation of the bronchial smooth muscle by increasing the intracellular cAMP content, and the.MTT test is not related to the beta 2 receptor. The preliminary pharmacokinetic study of high active compound 6a, 6D in vivo showed that the half-life of 6a and 6D compounds were 2.309h and 3.386h respectively, and the T1/2=2.148h of alpha terpene enol was improved, which proved the rationality and feasibility of the design strategy of the pre thesis. Further, 6D opened to compound 6A. The evaluation of the antiasthmatic activity of the whole animal (rat asthma model), with lung function, inflammatory factor IL-4, and IL-17A as evaluation indicators. The results show that compound 6a, 6D can improve the effect of lung function by improving airway compliance and reducing airway resistance in asthmatic rats. At the same time, it can reduce the serum IL-4, IL-17A content, and inhibit inflammation. The heart rate of the asthmatic mice is not significantly affected. Therefore, these compounds show the double activity of dilatation of bronchial smooth muscle and anti inflammation, which has the potential to replace the combination of clinical beta 2 receptor agonists and hormones.
【學位授予單位】：浙江大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R914;R96

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