本文選題：微管蛋白抑制劑　切入點(diǎn)：苯并咪唑　出處：《吉林大學(xué)》2014年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：微管是細(xì)胞骨架的基本組成部分，參與維持細(xì)胞形態(tài)、細(xì)胞內(nèi)物質(zhì)輸送、信號(hào)傳導(dǎo)、細(xì)胞分裂等重要過(guò)程。微管蛋白作為微管的基本單位，是抗腫瘤藥物研究的重要靶點(diǎn)之一。目前有多種微管蛋白抑制劑作為一線抗腫瘤藥物應(yīng)用于臨床，在延長(zhǎng)患者生存時(shí)間和提高生活質(zhì)量方面發(fā)揮重要作用。然而，現(xiàn)有的微管蛋白抑制劑普遍存在結(jié)構(gòu)復(fù)雜難于合成、容易產(chǎn)生獲得性耐藥、毒副作用大等缺陷。因此，尋找作用機(jī)制新穎、高效低毒的小分子微管蛋白抑制劑已成為當(dāng)今社會(huì)研究的熱點(diǎn)之一。 苯并咪唑類(lèi)抗寄生蟲(chóng)藥物廣泛應(yīng)用于臨床，作用機(jī)制是與寄生蟲(chóng)的微管蛋白結(jié)合，對(duì)哺乳動(dòng)物宿主幾乎不產(chǎn)生影響。結(jié)構(gòu)類(lèi)似的苯并咪唑類(lèi)化合物61卻能夠以新的作用模式與哺乳動(dòng)物的微管蛋白結(jié)合。因此，本文將化合物61作為先導(dǎo)化合物，設(shè)計(jì)合成了一系列苯并咪唑類(lèi)衍生物，期望得到化學(xué)結(jié)構(gòu)簡(jiǎn)單、作用機(jī)制新穎、抗腫瘤活性顯著的新型微管蛋白抑制劑。 本文以5-氟-2-硝基苯胺和不同取代的苯酚為起始原料，，通過(guò)親核取代、硝基還原、合環(huán)、氨化、水解、�；确磻�(yīng)，共計(jì)合成26個(gè)目標(biāo)化合物，經(jīng)數(shù)據(jù)庫(kù)檢索結(jié)構(gòu)均為首次報(bào)道。采用腫瘤細(xì)胞生長(zhǎng)抑制實(shí)驗(yàn)對(duì)上述目標(biāo)化合物的抗腫瘤活性進(jìn)行篩選，結(jié)果顯示，該類(lèi)化合物對(duì)腫瘤細(xì)胞系NCI-H460、COLO205、K562、A431、HepG2、Hela和MDA-MB-435S均具有較好的抑制活性。其中化合物65、71、80和82的抗腫瘤活性與陽(yáng)性藥紫杉醇相當(dāng)，活性最好的化合物80對(duì)腫瘤細(xì)胞系NCI-H460、COLO205、K562、A431、HepG2、Hela和MDA-MB-435S的IC50值分別為0.040、0.050、0.006、0.026、1.774、0.452和0.052μM（紫杉醇IC50值分別為0.010、0.003、0.004、0.007、0.990、0.410、0.009μM）。 本文還以活性最好的化合物80為代表對(duì)苯并咪唑甲脲類(lèi)化合物的作用機(jī)制進(jìn)行了初步探討。免疫熒光實(shí)驗(yàn)和腫瘤細(xì)胞周期阻滯實(shí)驗(yàn)結(jié)果顯示，化合物80在濃度為0.100μM時(shí)即可抑制NCI-H460細(xì)胞紡錘體的形成，使其停滯于細(xì)胞分裂周期的G2/M期，并具有劑量依賴性。表明該類(lèi)化合物能夠通過(guò)影響腫瘤細(xì)胞微管蛋白正常功能的發(fā)揮，抑制紡錘體形成，影響腫瘤細(xì)胞正常周期的運(yùn)轉(zhuǎn)，誘導(dǎo)凋亡。計(jì)算機(jī)模擬模型顯示，化合物80分別與β-微管蛋白Glu71形成一個(gè)氫鍵，與α-微管蛋白Arg2形成兩個(gè)氫鍵、Asp251形成一個(gè)氫鍵，可能以全新的結(jié)合模式作用于微管蛋白αβ異二聚體相連的界面。 初步的構(gòu)效關(guān)系研究表明，苯并咪唑環(huán)C-2位反式酰胺上連接甲基氨基時(shí)，化合物活性顯著提高，用乙基氨基、乙基、環(huán)丙基、芐基替代時(shí)活性均有所下降。苯并咪唑環(huán)C-5位上連接苯氧基時(shí)，化合物活性最好，用1-萘氧基、環(huán)己氧基及芐氧基替代時(shí)化合物活性均有一定程度的降低。苯并咪唑環(huán)C-5位上苯氧基的苯環(huán)間位連接取代基時(shí)化合物活性最好，其次是對(duì)位，取代基的種類(lèi)對(duì)化合物活性影響不大。 本文為研發(fā)化學(xué)結(jié)構(gòu)簡(jiǎn)單、作用機(jī)制新穎、抗腫瘤作用顯著的新型微管蛋白抑制劑提供了新的思路。
[Abstract]:Microtubules are the basic components of the cytoskeleton, involved in the maintenance of cell shape, intracellular material transport, signal transduction, cell division and other important process. As the basic unit of tubulin microtubules, is one of the most important targets for anticancer drug research. There are a variety of tubulin inhibitors as first-line anticancer drugs in clinical application, play an important role in prolonging the survival time of patients and improve the quality of life. However, tubulin inhibitors the current complex structure is difficult to synthesis, easy to produce drug resistance defects of high toxic side effects. Therefore, looking for the mechanism of novel small molecule tubulin inhibitors with high efficiency and low toxicity has become one of the research focus of today's society.
Benzimidazole antiparasitic drug widely used in clinical, the mechanism is combined with tubulin of mammalian host parasite, almost no impact. Benzimidazole compounds with similar structures 61 are able to tubulin role model and mammalian new combination. Therefore, this paper will compound 61 as a lead compound, a series of benzimidazole the derivatives were designed and synthesized, desired chemical mechanism has the advantages of simple structure, novel, novel tubulin inhibitors antitumor activity significantly.
In this paper, 5- fluorine -2- nitro aniline and different substituted phenols as starting materials by nucleophilic substitution, reduction of nitro group, cyclization, hydrolysis, amination, acylation reaction, total synthesis of 26 target compounds, the database structure are reported for the first time. By screening, growth inhibition of antitumor activity of the target compounds the tumor cells showed that NCI-H460, the compounds on tumor cell lines COLO205, K562, A431, HepG2, Hela and MDA-MB-435S have good inhibitory activity. The antitumor activity of compounds 65,71,80 and 82 with positive drug paclitaxel, 80 compounds the best activity of NCI-H460, COLO205 cell lines K562, A431, HepG2, Hela and MDA-MB-435S IC50 values were 0.040,0.050,0.006,0.026,1.774,0.452 and 0.052 M (paclitaxel IC50 = 0.010,0.003,0.004,0.007,0.990,0.410,0.009 M).
Based on the 80 best represented the activity mechanism of benzimidazole methyl urea compounds were discussed. Immunofluorescence assay and tumor cell cycle arrest results showed that 80 compounds at the concentration of NCI-H460 can inhibit the formation of spindle cells of 0.100 M, the arrest in G2/M cell cycle period. In a dose-dependent manner. Indicated that the compounds can affect tumor cells through tubulin function, inhibit the formation of spindle, the influence of tumor cell apoptosis induced by the normal cycle of operation. The computer simulation model shows that compound 80 and beta tubulin Glu71 forms a hydrogen bond, and alpha tubulin Arg2 form two a hydrogen bond, Asp251 forms a hydrogen bond, may be in the alpha beta tubulin dimer linked to ISO two new combination model of the role of the interface.
Preliminary study on structure-activity relationship showed that when connecting methyl amino benzimidazole ring C-2 trans amide compounds, activity was significantly increased with ethyl amino ethyl, cyclopropyl, benzyl substitution decreased. C-5 benzimidazole ring connected phenoxy compounds, the best activity, with 1- naphthyloxy reduce, cyclohexyloxy and benzyloxy substitution compounds to a certain extent. Benzimidazole ring position C-5 phenoxy benzene compounds between the best activity of substituent, followed by Para, types of the substituents has little influence on the activity of the compounds.
This paper provides a new way of thinking for the new microtubulin inhibitor with simple chemical structure, novel mechanism and a significant anti-tumor effect.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R914

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