环巴胺类似物的合成及体外抗肿瘤活性评价

发布时间：2018-06-12 07:02

本文选题：Hedgehog信号通路 + 环巴胺　；参考：《大连理工大学》2014年硕士论文

【摘要】：Hedgehog (Hh)信号通路在成人细胞中的异常激活与许多恶性肿瘤有密切联系,因此成为靶向抗肿瘤药物的新靶点。以环巴胺为代表的甾体生物碱是最早发现作用于开关蛋白Smoothened (SMO)的Hh通路抑制剂。在肿瘤治疗方面显示了良好的前景,但存在酸稳定性差、溶解度低、活性不高及来源困难的缺陷,限制了临床应用。本文以来源丰富的甾体生物碱介芬胺和藜芦胺为原料,采用构象限制和类似物设计原理,设计合成两个系列的环巴胺类似物。首先以介芬胺为原料,采用选择性还原、甲基化、氧化反应及缩合反应合成了环巴胺及其9个类似物,其中化合物4、9、10的结构未见文献报道。其次以藜芦胺为原料,经过氧化、甲基化、酰化反应得到了5个化合物,其中化合物14、15、16和17的结构未见文献报道。此外,将伪介芬胺进行酸催化水解得到了新化合物18。运用MS、 NMR对合成的化合物进行了结构表征。在体外抗肿瘤活性筛选实验中,选用人胃癌细胞SGC-7901和人胰腺癌细胞Aspc-1,以MTT法研究所合成化合物对肿瘤细胞体外增殖的抑制作用,以环巴胺为阳性对照；设置100、80、50、30、10、1μmol·L-1六个浓度分别培养48h和72h,考察目标产物抑制肿瘤细胞增殖的抑制作用。结果显示化合物11抑制SGC-7901细胞的IC50达到46.33(48h)和43.18μmol/L(72h),而对Aspc-1细胞的IC50达到19.65(48h)和13.32μmol/L (72h),均优于环巴胺；且对Aspc-1选择性更高。化合物16、17的抑制活性也优于环巴胺。初步构效关系表明,介芬胺的11位为亚甲基时活性最优,无论是羰基还是羟基取代活性均降低；藜芦胺的哌啶环接入大小合适的基团时会有助于活性提升。该结果为环巴胺类Hh通路抑制剂的结构优化提供了依据。
[Abstract]:The abnormal activation of Hedgehog) signaling pathway in adult cells is closely related to many malignant tumors, so it has become a new target of anti-tumor drugs. The steroidal alkaloids, represented by cyclobaramine, are the first Hh pathway inhibitors found to act on the switch protein Smoothened SMOs. It has shown a good prospect in the treatment of cancer, but it has the defects of poor acid stability, low solubility, low activity and difficult source, which limits the clinical application. In this paper, the steroidal alkaloids such as mesophenamine and veratramine were used as raw materials. Two series of cyclobaramine analogues were designed and synthesized by conformational confinement and analogous design. At first, cyclobarylamine and its nine analogues were synthesized by selective reduction, methylation, oxidation and condensation using mesophenamine as raw material. Secondly, five compounds were obtained from the oxidation, methylation and acylation of veratramine, and the structures of compounds 1415, 1516 and 17 were not reported in the literature. In addition, a new compound 18. 3 was obtained by acid catalytic hydrolysis of pseudo-mesophenamine. The synthetic compounds were characterized by MS and NMR. In vitro screening experiments, SGC-7901 and Aspc-1cells were used to study the inhibitory effect of the synthesized compounds on the proliferation of tumor cells in vitro. Cyclophosphamide was used as positive control. The inhibitory effects of the target product on the proliferation of SGC-7901 cells were investigated at six concentrations of 100,80,80,30c30c10U 1 渭 mol L-1 for 48h and 72h, respectively. The results showed that the IC50 of compound 11 against SGC-7901 cells reached 46.33 h / L and 43.18 渭 mol / L ~ (72) h, while the IC50 of Aspc-1 cells was 19.65 ~ 48h) and 13.32 渭 mol / L ~ (72) h ~ (-1) was superior to cyclophosphamide. And the selectivity to Aspc-1 is higher. The inhibitory activity of compound 16C17 was also superior to that of cyclopramine. The preliminary structure-activity relationship showed that the activity of mesophenamine was optimal when the 11 position was methylene and the activity of carbonyl or hydroxyl group was decreased, and the pethidine ring of veratramine could improve the activity when it was connected with the group of appropriate size. The results provide a basis for structural optimization of cyclobaramine Hh pathway inhibitors.
【学位授予单位】：大连理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96

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