本文選題：Hedgehog信號(hào)通路 + 環(huán)巴胺　； 參考：《大連理工大學(xué)》2014年碩士論文

【摘要】：Hedgehog (Hh)信號(hào)通路在成人細(xì)胞中的異常激活與許多惡性腫瘤有密切聯(lián)系,因此成為靶向抗腫瘤藥物的新靶點(diǎn)。以環(huán)巴胺為代表的甾體生物堿是最早發(fā)現(xiàn)作用于開關(guān)蛋白Smoothened (SMO)的Hh通路抑制劑。在腫瘤治療方面顯示了良好的前景,但存在酸穩(wěn)定性差、溶解度低、活性不高及來(lái)源困難的缺陷,限制了臨床應(yīng)用。 本文以來(lái)源豐富的甾體生物堿介芬胺和藜蘆胺為原料,采用構(gòu)象限制和類似物設(shè)計(jì)原理,設(shè)計(jì)合成兩個(gè)系列的環(huán)巴胺類似物。首先以介芬胺為原料,采用選擇性還原、甲基化、氧化反應(yīng)及縮合反應(yīng)合成了環(huán)巴胺及其9個(gè)類似物,其中化合物4、9、10的結(jié)構(gòu)未見文獻(xiàn)報(bào)道。其次以藜蘆胺為原料,經(jīng)過(guò)氧化、甲基化、�；磻�(yīng)得到了5個(gè)化合物,其中化合物14、15、16和17的結(jié)構(gòu)未見文獻(xiàn)報(bào)道。此外,將偽介芬胺進(jìn)行酸催化水解得到了新化合物18。運(yùn)用MS、 NMR對(duì)合成的化合物進(jìn)行了結(jié)構(gòu)表征。 在體外抗腫瘤活性篩選實(shí)驗(yàn)中,選用人胃癌細(xì)胞SGC-7901和人胰腺癌細(xì)胞Aspc-1,以MTT法研究所合成化合物對(duì)腫瘤細(xì)胞體外增殖的抑制作用,以環(huán)巴胺為陽(yáng)性對(duì)照；設(shè)置100、80、50、30、10、1μmol·L-1六個(gè)濃度分別培養(yǎng)48h和72h,考察目標(biāo)產(chǎn)物抑制腫瘤細(xì)胞增殖的抑制作用。 結(jié)果顯示化合物11抑制SGC-7901細(xì)胞的IC50達(dá)到46.33(48h)和43.18μmol/L(72h),而對(duì)Aspc-1細(xì)胞的IC50達(dá)到19.65(48h)和13.32μmol/L (72h),均優(yōu)于環(huán)巴胺；且對(duì)Aspc-1選擇性更高�；衔�16、17的抑制活性也優(yōu)于環(huán)巴胺。初步構(gòu)效關(guān)系表明,介芬胺的11位為亞甲基時(shí)活性最優(yōu),無(wú)論是羰基還是羥基取代活性均降低；藜蘆胺的哌啶環(huán)接入大小合適的基團(tuán)時(shí)會(huì)有助于活性提升。該結(jié)果為環(huán)巴胺類Hh通路抑制劑的結(jié)構(gòu)優(yōu)化提供了依據(jù)。
[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.
【學(xué)位授予單位】：大連理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5;R96

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本文編號(hào)：2008808