新型三氮唑核苷类化合物的合成、表征及生物活性测试

发布时间：2018-11-06 20:51

【摘要】：目前临床上用于抗HIV、HBV、HCV三种病毒的药物很多是核苷类化合物。核苷在生物体内参与遗传信息的保留、复制、转录等过程。核苷类似物与天然核苷结构很相似,病毒难以识别。许多核苷类似物是通过抑制病毒DNA聚合酶和逆转录酶的活性同时与天然核苷竞争性地插入病毒DNA链中从而抑制或阻断病毒的复制繁衍。然而,核苷类药物长期服用会产生毒性而且容易使病毒产生耐药性。因此,对核苷类化合物进行结构优化尤为重要。核苷类化合物是在天然核苷结构的基础上对糖环或碱基进行修饰改造或同时修饰改造得到的。索菲布韦是2013年被FDA批准用于治疗HCV四种基因型的核苷类药物。由索菲布韦的构效分析,其最突出的特点就是2'-β-甲基-2'-α-氟的存在。利巴韦林是用于抑制HCV复制的核苷类药物,它的新颖之处在于其结构中存在三氮唑碱基。三氮唑由于其无毒、水溶性好、稳定性好、具有广谱生物活性等优点而被许多科研者引进到核苷的结构修饰中。我们实验室长期致力于核苷类化合物的合成。本文在保留2'-β-甲基-2'-α-氟呋喃糖基骨架结构的基础上,通过对核苷的碱基进行改造,得到了1,2,3-三氮唑基团作为碱基的一系列新的核苷类似物。同时在糖基4'-位分别引入叠氮和氟两种基团,最终合成了两种新型核苷类似物。对这些核苷类似物进行抗病毒活性测试,以期得到比较好的抗病毒活性。(1)以2'-β-甲基-2'-α-氟修饰的糖环内酯为原料,运用SN2、click、脱保护等反应合成了核苷类似物5-7(α和β两种构型)、11、12这8个1,2,3-三氮唑核苷类似物。我们又进一步合成了7-β的单磷酸酯化合物14。这些化合物的结构均通过~1H NMR、~(13)C NMR和HRMS进行了确认,其中5-β和7-β两种化合物用X-单晶衍射仪对其分子结构进一步确认;(2)对合成的9个化合物进行抗HIV、HCV初步活性筛选,结果显示,这些化合物并没有表现出明显优异的抑制病毒复制的活性;(3)通过对7-β化合物进行进一步修饰,在4'位引入叠氮基和氟,最终得到了4'-叠氮和4'-氟取代的三氮唑核苷类似物20和24,以期得到较好的抗病毒活性。
[Abstract]:At present, many of the drugs used to fight HIV,HBV,HCV virus are nucleoside compounds. Nucleosides are involved in the preservation, replication and transcription of genetic information in organisms. Nucleoside analogs are very similar to natural nucleoside structures and the virus is difficult to recognize. Many nucleoside analogues can inhibit or block the replication of virus by inhibiting the activity of virus DNA polymerase and reverse transcriptase and inserting the nucleoside into the DNA chain of virus competitively with the natural nucleoside. However, long-term use of nucleoside drugs can be toxic and susceptible to virus resistance. Therefore, it is very important to optimize the structure of nucleoside compounds. Nucleoside compounds are obtained by modifying or modifying sugar ring or base on the basis of natural nucleoside structure. Sofibuvir is a nucleoside drug approved by FDA in 2013 for the treatment of four genotypes of HCV. According to the structure activity analysis of sofebuvir, the most prominent characteristic is the existence of 2- 尾 -methyl-2- 伪 -fluorine. Ribavirin is a nucleoside drug used to inhibit the replication of HCV. Its novel feature lies in the existence of triazole bases in its structure. Because of its nontoxic, water-soluble, stable and broad-spectrum biological activity, triazole has been introduced into the structural modification of nucleoside by many researchers. Our laboratory has been devoted to the synthesis of nucleoside compounds for a long time. A series of new nucleoside analogues have been obtained by modifying the base of nucleoside on the basis of retaining the skeleton structure of 2O- 尾 -methyl-2n- 伪 -fluorofuran glycosyl group. At the same time, two new nucleoside analogues were synthesized by introducing azide and fluorine groups into the 4 ~ (-) -glycosyl group. The antiviral activity of these nucleoside analogues was tested in order to obtain better antiviral activity. (1) SN2,click, was used as the raw material of glycosylcyclolactone modified with 2n- 尾 -methyl-2keto- 伪 -fluorine. The nucleoside analogues 5-7 (伪 and 尾) and 11 / 12 were synthesized by deprotection reaction. We further synthesized 7-尾 monophosphate compounds. The structures of these compounds were confirmed by ~ 1H NMR,~ (13) C NMR and HRMS), and the molecular structures of 5- 尾 and 7- 尾 were further confirmed by X-ray single crystal diffractometer. (2) the 9 compounds were screened against HIV,HCV. The results showed that these compounds did not exhibit remarkable inhibition activity against virus replication. (3) through the further modification of 7- 尾 compounds and the introduction of azide and fluorine at the 4'site, the nucleoside analogues 20 and 24 of 4- azido and 4- fluorine substituted triazoside were obtained in order to obtain better antiviral activity.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.1

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