本文選題：Hsp90抑制劑 + Reblastatin��； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年碩士論文

【摘要】：Hsp90是一類能夠促進蛋白質(zhì)正確折疊,并在應(yīng)激條件下防止蛋白質(zhì)變性以及細胞凋亡的分子伴侶,它在癌細胞中高度表達,促進癌癥的發(fā)生與發(fā)展。抑制Hsp90的功能,可促使癌基因泛素化并降解,達到治療癌癥的目的。 Geldanamycin和Reblastatin等苯安莎霉素類天然產(chǎn)物及其結(jié)構(gòu)修飾物能夠競爭性抑制Hsp90的N端ATP結(jié)合位點,表現(xiàn)出良好的Hsp90抑制活性。本論文總結(jié)前人的研究基礎(chǔ),設(shè)計了一條經(jīng)濟高效的路線完成了對Reblastatin的全合成,并對Geldanamycin的合成進行了探索。具體分為以下幾點：1.Geldanamycin的合成探索 嘗試通過Evans輔基誘導(dǎo)的烷基化反應(yīng)構(gòu)建C11-C20片段以及經(jīng)Julia烯化和環(huán)氧開環(huán)引入C8-C10片段失敗,最終探索了一條以Y-丁內(nèi)酯誘導(dǎo)的不對稱烷基化、將酯基徹底還原為甲基以及手性丙二烯誘導(dǎo)的不對稱炔丙基化等為關(guān)鍵反應(yīng)的路線完成了Geldanamycin的C8-C20片段的克級制備。雖在片段連接中出現(xiàn)了脫溴還原的現(xiàn)象以及關(guān)環(huán)反應(yīng)中出現(xiàn)了脫MOM的情況,但提出了此問題的解決方法,為后續(xù)的全合成工作打下了基礎(chǔ)。 2.Iteblastatin的全合成45mg first batch 經(jīng)γ-丁內(nèi)酯誘導(dǎo)的不對稱烷基化、將酯基徹底還原為甲基、手性丙二烯誘導(dǎo)的不對稱炔丙基化以及Zr/Zn介導(dǎo)的還原偶聯(lián)等關(guān)鍵反應(yīng)完成Reblastatin的全合成,優(yōu)化了手性丙二烯的合成方法及Panek的組裝策略。3.經(jīng)HWE、Sharpless不對稱雙羥化以及Pd/C氫化的方法完成了Herbimycin A全合成中關(guān)鍵中間體γ-丁內(nèi)酯的制備。
[Abstract]:Hsp90 is a kind of molecular chaperones which can promote the correct folding of proteins and prevent protein degeneration and apoptosis under stress. Hsp90 is highly expressed in cancer cells and promotes the occurrence and development of cancer. Inhibiting the function of Hsp90 can promote the Ubiquification and degradation of oncogene and achieve the purpose of cancer treatment. The natural products of benzamicin such as Geldanamycin and Reblastatin and their structural modifiers can competitively inhibit the N-terminal ATP binding sites of Hsp90. It showed good inhibitory activity of Hsp90. In this paper, we summarized the previous research basis, designed an economical and efficient route to complete the total synthesis of Reblastatin, and explored the synthesis of Geldanamycin. Geldanamycin synthesis attempts to construct C11-C20 fragment by Evans cogroup induced alkylation reaction, and failed to introduce C8-C10 fragment through Julia alkenation and epoxide ring opening. Finally, a key reaction route of asymmetric alkylation induced by Y- butyrolactone, complete reduction of ester group to methyl and asymmetric allylation induced by chiral allene was explored to prepare the C8-C20 fragment of Geldanamycin. Although the debromination reduction occurred in the fragment connection and the de-MOM occurred in the closed ring reaction, the solution to this problem was put forward. 2. The complete synthesis of Iteblastatin was induced by asymmetric alkylation of 緯 -butyrolactone, and the ester group was completely reduced to methyl. The synthesis of Reblastatin was completed by asymmetric allylation induced by chiral allylene and reduction coupling mediated by Zr / Zn. The synthesis method of chiral allylene and the assembly strategy of Panek were optimized. The synthesis of the key intermediate 緯 -butyrolactone in the total synthesis of Herbimycin A was completed by using the method of asymmetric double hydroxylation and PD / C hydrogenation.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914.5

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