本文關(guān)鍵詞： 優(yōu)勢結(jié)構(gòu) 茚并吡唑 微管蛋白 微管蛋白抑制劑 抗腫瘤　出處：《山東大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：優(yōu)勢結(jié)構(gòu)是指能與多種生物受體進(jìn)行有力結(jié)合或者作用的分子結(jié)構(gòu),具有"類藥"、"類先導(dǎo)化合物"等特性。茚并吡唑是三環(huán)雜環(huán)結(jié)構(gòu),由苯環(huán),中心5元環(huán)和吡唑環(huán)組成。作為"優(yōu)勢結(jié)構(gòu)",茚并吡唑近年來已經(jīng)廣泛用于具有多種靶點(diǎn)的抗腫瘤藥物設(shè)計(jì),如作為檢查點(diǎn)激酶-1,表皮生長因子受體,血管內(nèi)皮生長因子,血小板衍生生長因子受體,細(xì)胞周期蛋白依賴性激酶和微管蛋白聚合的抑制劑等。在前期研究中,我們實(shí)驗(yàn)室發(fā)現(xiàn)了一個(gè)新型茚并吡唑類衍生物L(fēng)L-01。LL-01作用于微管蛋白秋水仙堿結(jié)合位點(diǎn),能夠抑制微管蛋白的聚合,在體外對多種腫瘤細(xì)胞,包括多藥耐藥腫瘤細(xì)胞具有非常好的抑制活性。LL-01能使腫瘤細(xì)胞有絲分裂停滯于G2/M期,能誘導(dǎo)細(xì)胞凋亡,在體內(nèi)具有良好的抗腫瘤活性。為進(jìn)一步探討該類化合物的構(gòu)效關(guān)系,發(fā)現(xiàn)了活性更高的茚并吡唑衍生物,本研究擬在茚并吡唑的6位、7位進(jìn)行結(jié)構(gòu)修飾,并在3位苯胺取代基上引入乙胺基、乙氧基、氰基、酯基和酰胺基等,設(shè)計(jì)合成了 15個(gè)茚并吡唑類衍生物。以5,6-二甲氧基-1-茚酮為起始原料,經(jīng)脫甲基反應(yīng)后,乙基選擇性地5位酚羥基反應(yīng),6位酚羥基經(jīng)TBS保護(hù),合成茚酮中間體,再與異硫氰酸酯衍生物親核加成,經(jīng)水合肼環(huán)合后,N原子甲基化,脫去6位羥基保護(hù)后,與氯乙酸甲酯經(jīng)威廉姆遜成醚反應(yīng)成醚,再進(jìn)行氨解,制備了 10個(gè)化合物(A1-A10)。用MOM選擇性保護(hù)5,6-二羥基-1-茚酮的5位酚羥基,6位羥基與3-氯-1-丙醇反應(yīng)成醚,引入3-羥基丙基,再用MOM保護(hù)其伯羥基,制備茚酮中間體。與異硫氰酸酯衍生物經(jīng)親核加成,水合肼環(huán)合后,N原子甲基化,用樟腦磺酸脫去MOM保護(hù)基,合成了 6位酚羥基取代的茚并吡唑衍生物B1、B2和B3。將B1、B2 7位側(cè)鏈上的伯羥基用TBS保護(hù)后,6位酚羥基與對甲氧基氯芐經(jīng)威廉姆遜成醚,脫去TBS保護(hù)基后,合成了茚并吡唑衍生物B4和B5。對合成的化合物經(jīng)1HNMR,13CNMR,ESI-Ms等進(jìn)行了結(jié)構(gòu)確證,并且進(jìn)行了抗腫瘤細(xì)胞(K562,MCF-7,A549)增殖活性測試。初步地抗腫瘤活性篩選實(shí)驗(yàn)表明,大多數(shù)化合物對該三種腫瘤細(xì)胞的抑制活性顯著優(yōu)于ABT-751。在3-苯胺基的間位引入酯基,化合物A1的活性優(yōu)于先導(dǎo)化合物L(fēng)L-01。在化合物A1的7位側(cè)鏈酰胺的氮原子上引入甲基或乙基,導(dǎo)致活性降低,而引入羥基,化合物A2的活性與LL-01相當(dāng)。在3-苯胺基的間位引入氰基、甲酰胺基,活性降低。在茚并吡唑的6位引入對甲氧基芐氧基或羥基,化合物的活性大幅降低。通過本研究,發(fā)現(xiàn)了比LL-01活性更高的茚并吡唑衍生物,進(jìn)一步的抗腫瘤藥理學(xué)研究有待進(jìn)行。
[Abstract]:The dominant structure refers to the molecular structure which can bind or interact with various biological receptors, and has the characteristics of "medicine-like" and "lead-like compounds". Ninopyrazole is a tricyclic heterocyclic structure consisting of benzene ring. As a "dominant structure", indenopyrazole has been widely used in the design of anti-tumor drugs with multiple targets, such as kinase-1 as a checkpoint, epidermal growth factor receptor. Vascular endothelial growth factor, platelet-derived growth factor receptor, cyclin dependent kinase and inhibitor of tubulin polymerization. We have found a novel indenopyrazole derivative LL-01.LL-01 acting on the tubulin colchicine binding site, which can inhibit tubulin polymerization in vitro for a variety of tumor cells. Including multidrug resistant tumor cells with very good inhibitory activity. LL-01 can make tumor cells mitosis arrest at G 2 / M phase, can induce cell apoptosis. In order to further study the structure-activity relationship of these compounds, a more active indenopyrazole derivative was found. In this study, the structure of ninopyrazole was modified at the 6 ~ 7 position. Fifteen derivatives of indenopyrazole were designed and synthesized by introducing ethylamino, ethoxy, cyanyl, ester and amideyl groups on the 3-position substituted aniline group. After demethylation reaction, ethyl-5-phenolic hydroxyl group was selectively reacted with 6-phenolic hydroxyl group, protected by TBS, the intermediate of indenone was synthesized, then nucleophilic addition of indenone with isothiocyanate derivative was carried out, and cyclized by hydrazine hydrate. The N atom was methylated, 6 hydroxyl groups were removed and then reacted with methyl chloroacetate to form ethers by Williamson and then ammoniated. Ten compounds, A1-A10, were prepared and reacted with 3-chloro-1-propanol to form ethers, which were selectively protected by MOM in the presence of 5-phenolic hydroxyl group and 6-position phenolic hydroxyl group. Indanone intermediate was prepared by introducing 3-hydroxypropyl group and protecting its primary hydroxyl group with MOM. The N atom methylated by cyclization of hydrazine hydrate was synthesized by nucleophilic addition with isothiocyanate derivative. The six phenolic hydroxyl substituted indenopyrazole derivatives B _ 1C _ 2 and B _ 3 were synthesized by removing MOM protection group from camphor sulfonic acid. The primary hydroxyl groups on B _ 1 / B _ 2 _ 7 side chain were protected by TBS. The 6-position phenolic hydroxyl group and p-methoxybenzyl chloride were synthesized by the synthesis of indolopyrazole derivatives B _ 4 and B _ 5. the synthesized compounds were synthesized by 1HNMR-13CNMR after the removal of the TBS protection group from the 6-position phenolic hydroxyl group and p-methoxybenzyl chloride (p-methoxybenzyl). ESI-Ms et al were used to confirm the structure and to test the proliferative activity of K562MCF-7A549. The results showed that the anti-tumor activity was screened. The inhibitory activity of most compounds on these three tumor cells was significantly better than that on ABT-751.Ester groups were introduced into the 3-aniline group. The activity of compound A1 is superior to that of lead compound LL-01.Introduction of methyl or ethyl to the nitrogen atom of the 7-position side chain amide of compound A1 leads to the decrease of activity and the introduction of hydroxyl. The activity of compound A2 was similar to that of LL-01. The activity of compound A2 was decreased by introducing cyanide and formamide at the m-site of 3-aniline group, and p-methoxy benzoxy group or hydroxyl group at the sixth position of indenopyrazole. The activity of the compounds was significantly reduced. In this study, ninhydropyrazole derivatives with higher activity than LL-01 were found, and further antitumor pharmacological studies were needed.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96

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相關(guān)碩士學(xué)位論文 前2條

1 紀(jì)婭婷;茚并吡唑類微管蛋白抑制劑的結(jié)構(gòu)修飾及活性測定[D];山東大學(xué);2016年

2 劉晏娜;新型茚并吡唑類微管蛋白抑制劑的設(shè)計(jì)、合成及活性研究[D];山東大學(xué);2015年

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本文編號：1478613