抗病毒青蒿素核苷类轭合物的设计与合成研究
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摘要
艾滋病(AIDS)和病毒性乙型肝炎(Type B hepatisis)已成为严重威胁人类健康的两种重大传染性疾病,它们分别由艾滋病毒(HIV)和乙型肝炎病毒(HBV)所引起。HIV是一种能够攻击人体细胞免疫系统的病毒,它能大量吞噬、破坏T4淋巴细胞,从而使机体抵抗力和免疫功能严重损伤,最终使免疫系统崩溃,使人体因丧失对各种疾病的抵抗力而继发多种机会性感染和肿瘤并死亡。HBV是一种以感染肝脏细胞,诱发炎症和坏死病变为主的一种病毒,其传染性极强。迄今为止,对于艾滋病和乙型肝炎尚没有很好的药物和治疗方法,因此,对治疗艾滋病和乙型肝炎药物的研究极为重要。开发新型高效抗病毒药物已成为当今治疗艾滋病和乙型肝炎的重要研究方向。
青蒿素类具有独特的过氧桥键结构及特有的抗疟疾、抗癌作用机制。诸多研究表明,青蒿素类除具有抗疟疾、抗癌等作用之外,还有广泛的抗病毒作用,如艾滋病病毒、肝炎病毒、抗人细胞巨化病毒及抗柯萨奇B组病毒等。
本论文根据前体药物原理和药物拼合原理,以双氢青蒿素为先导化合物,以脂肪二元酸为连接基,经两次酯化反应,与具有抗病毒作用的核苷类等药物连接起来,形成青蒿素类轭合物,共合成了16个目标化合物,其中14个未见文献报道。它们在不破坏活性基团的前提下,将两者连接起来,很有可能得到抗病毒能力更强的新化合物。以期望将药物的有效基团顺利引向作用靶点,达到单分子多靶点、多疗效的作用以及相互协同作用,从而显著提高药物的作用。所有目标化合物的结构经1H-NMR、FAB-MS、元素分析确证。
所有目标化合物的抗HIV和抗HBV活性待测。
Acquired immune deficiency syndrome (AIDS) and type B viral hepatitis, which were caused by human immunodeficiency viruses (HIV) and hepatitis B viruses (HBV) respectively, are two types of severe infective diseases which seriously threaten the health of human being. HIV can attack the cell immune system in human body, destroy T4 Lymphocytes, weaken the resistance of organism, ruin the immune system, and eventually cause many opportunistic infections and tumors to make people death. HBV, with strong communicability, is a type of viruses which can infect hepatic cells and induce inflammation and necrosis. Heretofore, there are no good therapies to cure both two diseases. Thus, developing new potent anti-virus drugs is very important and become the main ways to cure AIDS and type B viral hepatitis.
Artemisinin derivatives contain unique structure of peroxide bridge and have special mechanisms of anti-malaria and anti-tumor activity. A lot of reports present that besides their anti-malaria and anti-tumor activity, artemisinin derivatives had anti-virus activity against HIV, hepatitis virus, cytomegalovirus, coxsackie b virus, and so on.
Based on principle of prodrug and hybridization, the lead compound dihydroartemisinine were linked to anti-virus drugs of nucleosides to form conjugates via different type of binary acids by twice of esterification. Sixteen compounds were synthesized and not been report in literature. Linking the compound with undestroyed active group to another may produce a more potent anti-virus drug. This conjugate may be led to action targets, acts as a multi-target and multi-effect anti-virus drug, makes synergistic effect and improves its anti-virus activity significantly. The structures of target compounds were confirmed by 1H-NMR, FAB-MS and elemental analysis.
The anti-HIV and anti-HBV activity of target compounds will be assayed.
青蒿素类具有独特的过氧桥键结构及特有的抗疟疾、抗癌作用机制。诸多研究表明,青蒿素类除具有抗疟疾、抗癌等作用之外,还有广泛的抗病毒作用,如艾滋病病毒、肝炎病毒、抗人细胞巨化病毒及抗柯萨奇B组病毒等。
本论文根据前体药物原理和药物拼合原理,以双氢青蒿素为先导化合物,以脂肪二元酸为连接基,经两次酯化反应,与具有抗病毒作用的核苷类等药物连接起来,形成青蒿素类轭合物,共合成了16个目标化合物,其中14个未见文献报道。它们在不破坏活性基团的前提下,将两者连接起来,很有可能得到抗病毒能力更强的新化合物。以期望将药物的有效基团顺利引向作用靶点,达到单分子多靶点、多疗效的作用以及相互协同作用,从而显著提高药物的作用。所有目标化合物的结构经1H-NMR、FAB-MS、元素分析确证。
所有目标化合物的抗HIV和抗HBV活性待测。
Acquired immune deficiency syndrome (AIDS) and type B viral hepatitis, which were caused by human immunodeficiency viruses (HIV) and hepatitis B viruses (HBV) respectively, are two types of severe infective diseases which seriously threaten the health of human being. HIV can attack the cell immune system in human body, destroy T4 Lymphocytes, weaken the resistance of organism, ruin the immune system, and eventually cause many opportunistic infections and tumors to make people death. HBV, with strong communicability, is a type of viruses which can infect hepatic cells and induce inflammation and necrosis. Heretofore, there are no good therapies to cure both two diseases. Thus, developing new potent anti-virus drugs is very important and become the main ways to cure AIDS and type B viral hepatitis.
Artemisinin derivatives contain unique structure of peroxide bridge and have special mechanisms of anti-malaria and anti-tumor activity. A lot of reports present that besides their anti-malaria and anti-tumor activity, artemisinin derivatives had anti-virus activity against HIV, hepatitis virus, cytomegalovirus, coxsackie b virus, and so on.
Based on principle of prodrug and hybridization, the lead compound dihydroartemisinine were linked to anti-virus drugs of nucleosides to form conjugates via different type of binary acids by twice of esterification. Sixteen compounds were synthesized and not been report in literature. Linking the compound with undestroyed active group to another may produce a more potent anti-virus drug. This conjugate may be led to action targets, acts as a multi-target and multi-effect anti-virus drug, makes synergistic effect and improves its anti-virus activity significantly. The structures of target compounds were confirmed by 1H-NMR, FAB-MS and elemental analysis.
The anti-HIV and anti-HBV activity of target compounds will be assayed.
引文
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