【摘要】：鉍、銻具有悠久的藥用歷史。近期研究表明鉍、銻配合物具有良好的抑菌和抗腫瘤等生物活性。但由于常規(guī)的有機(jī)鉍(銻)配合物對(duì)水和空氣較為敏感，穩(wěn)定性差，其應(yīng)用受到限制。因此，設(shè)計(jì)開(kāi)發(fā)具有較高穩(wěn)定性的有機(jī)鉍(銻)配合物，并探索其在生命科學(xué)中的應(yīng)用，具有重要的學(xué)術(shù)意義和應(yīng)用價(jià)值。 本文以配合物與DNA分子的作用方式為依據(jù)，選取具有共軛芳香環(huán)的有機(jī)鉍(銻)配合進(jìn)行研究。利用紫外-可見(jiàn)吸收光譜譜學(xué)手段，證實(shí)環(huán)狀有機(jī)鉍(銻)配合物與小牛胸腺DNA (CT-DNA)以插入方式相互作用。以人肺腺癌細(xì)胞A549、肝癌細(xì)胞HepG2、食管癌Ec109等細(xì)胞為模型，采用CCK-8法從配合物中篩選出能有效抑制腫瘤細(xì)胞增殖的C3([t-BuN(CH2C6H4)2]BiCl)、C4([O(CH2C6H4)2]BiCl)、C5([O(CH2C6H4)2]BiNO3)、 C9([t-BuN(CH2C6H4)2]SbCl)和C12([{t-BuN(CH2C6H4)2}Sb]2O)。構(gòu)效關(guān)系研究結(jié)果表明配合物的抗增殖活性可能與鉍、銻和配位原子之間的配位作用有關(guān)。為了進(jìn)一步研究配合物的抗增殖機(jī)制，本文采用了流式細(xì)胞術(shù)檢測(cè)配合物對(duì)細(xì)胞周期和細(xì)胞凋亡的影響，使用激光共聚焦顯微鏡觀察配合物作用下A549細(xì)胞的形態(tài)學(xué)變化及凋亡現(xiàn)象，利用realtime PCR及Western Blot分析凋亡相關(guān)基因和蛋白的表達(dá)。一系列的實(shí)驗(yàn)結(jié)果表明，，環(huán)狀有機(jī)鉍配合物C3、C4、C5和環(huán)狀有機(jī)銻配合物C9、C12對(duì)細(xì)胞周期的阻滯作用可能與其抗腫瘤細(xì)胞增殖效應(yīng)有關(guān)，另一方面，配合物可能通過(guò)Bcl-2表達(dá)的下調(diào)及Bax的過(guò)表達(dá)誘導(dǎo)的細(xì)胞凋亡。 本文采用試管法和瓊脂擴(kuò)散法考察環(huán)狀有機(jī)鉍(銻)配合物的抑菌作用，研究表明與鉍、銻配位基團(tuán)具有較小位阻和較強(qiáng)供電能力的環(huán)狀有機(jī)鉍配合物(C3([t-BuN(CH2C6H4)2]BiCl)、C4([O(CH2C6H4)2]BiCl)、C5([O(CH2C6H4)2]BiNO3))和環(huán)狀有機(jī)銻配合物(C9([t-BuN(CH2C6H4)2]SbCl)和C12([{t-BuN(CH2C6H4)2}Sb]2O)同樣具有較好抑菌活性，尤其是對(duì)革蘭氏陽(yáng)性菌的抑菌作用呈劑量依賴性。 本研究成果為深入探究環(huán)狀有機(jī)鉍(銻)的抗腫瘤及抑菌作用機(jī)制，為生物活性分子的合理設(shè)計(jì)、活性化合物的篩選以及藥物的研制提供理論及實(shí)驗(yàn)依據(jù)。
[Abstract]:Bismuth and antimony have a long medicinal history. Recent studies have shown that bismuth and antimony complexes have good bacteriostatic and antitumor activities. However, due to the sensitivity and poor stability of conventional organic bismuth (antimony) complexes to water and air, their application is limited. Therefore, it is of great academic significance and application value to design and develop organic bismuth (antimony) complexes with high stability and to explore their application in life science. Based on the interaction of complexes with DNA molecules, the coordination of organic bismuth (antimony) with conjugated aromatic rings was studied in this paper. The interaction between cyclic organic bismuth (antimony) complex and calf thymic DNA (CT-DNA) was confirmed by UV-vis absorption spectroscopy. C3 ([t-BuN (CH2C6H4) 2] BiCl), C 4 ([O (CH2C6H4) 2] BiCl), C 5 (O (CH2C6H4) 2] BiNO3), C9 ([t-BuN (CH2C6H4) 2] SbCl) and C12 ([{t-BuN (CH2C6H4) 2} Sb] 2O) were screened from human lung adeno cell line A549 and hepatocellular carcinoma cell line HepG2, esophageal carcinoma Ec109 by CCK- 8 method. The results of structure-activity relationship show that the anti-proliferation activity of the complex may be related to the coordination between bismuth, antimony and coordination atoms. In order to further study the anti-proliferation mechanism of the complex, the effects of the complex on cell cycle and apoptosis were detected by flow cytometry. The morphological changes and apoptosis of A549 cells under the action of the complex were observed by laser confocal microscope, and the expression of apoptosis-related genes and proteins was analyzed by realtime PCR and Western Blot. A series of experimental results show that the blocking effects of cyclic organic bismuth complexes C _ 3, C _ 4, C _ 5 and cyclic organic antimony complexes C _ 9 and C _ 12 on cell cycle may be related to their anti-tumor cell proliferation effects. on the other hand, the complexes may induce apoptosis through down-regulation of Bcl-2 expression and overexpression of Bax. The bacteriostatic effect of cyclic organic bismuth (antimony) complex with bismuth and antimony was investigated by tube test method and Agar diffusion method. The results showed that cyclic organic bismuth complex (C3 ([t-BuN (CH2C6H4) 2] BiCl), C 4 ([O (CH2C6H4) 2] BiCl),) with bismuth and antimony coordination group had small steric hindrance and strong power supply ability. C5 ([O (CH2C6H4) 2] BiNO3) and cyclic organic antimony complexes (C9 ([t-BuN (CH2C6H4) 2] SbCl) and C12 ([{t-BuN (CH2C6H4) 2} Sb] 2O) also have good bacteriostatic activity, especially against Gram-positive bacteria in a dose-dependent manner. The results of this study provide theoretical and experimental basis for the anti-tumor and bacteriostatic mechanism of cyclic organic bismuth (antimony), and for the rational design of bioactive molecules, the screening of active compounds and the development of drugs.
【學(xué)位授予單位】：湖南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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