本文選題：氟喹諾酮 + 查爾酮��； 參考：《河南大學(xué)》2014年碩士論文

【摘要】：查爾酮是以1,3-二苯基丙烯酮或含有α,β-不飽和酮為基本骨架、且廣泛存在于多種藥用植物中的一類化合物,因其具有多種藥理活性而備受關(guān)注。對(duì)其結(jié)構(gòu)的修飾除多集中于苯環(huán)取代基的變化外,用雜環(huán)或稠雜環(huán)替代經(jīng)典的苯環(huán)以改善其藥效學(xué)或藥動(dòng)學(xué)性質(zhì),促進(jìn)其向成藥性方向發(fā)展,已成為新查爾酮化合物研究的重點(diǎn)。氟喹諾酮類藥物是以1-取代-6-氟-7-雜環(huán)-喹啉-4-酮-3-羧酸為結(jié)構(gòu)特征的新型抗菌藥。基于其作用靶拓?fù)洚悩?gòu)酶(TOPO)也是抗腫瘤藥物的重要靶點(diǎn),企圖轉(zhuǎn)化其抗菌活性到抗腫瘤活性已成為氟喹諾酮發(fā)展面臨的新挑戰(zhàn)。然而,對(duì)抗腫瘤氟喹諾酮的研究多源于對(duì)抗菌氟喹諾酮N-1位和C-7位取代基及C-3位羧基生物等排體的變化,產(chǎn)生的候選化合物均因體內(nèi)利用度或毒性或穩(wěn)定性等亟待要解決的生物學(xué)問題而未進(jìn)入臨床評(píng)價(jià)。因此,尋找新的結(jié)構(gòu)修飾途徑和方法,獲得新結(jié)構(gòu)的先導(dǎo)化合物可能是解決成藥性問題的關(guān)鍵。 基于已有的抗腫瘤氟喹諾酮構(gòu)-效關(guān)系,C-3位羧基并非是抗腫瘤活性所必需的藥效團(tuán),可用其等排體替代。本論文為進(jìn)一步發(fā)現(xiàn)氟喹諾酮新的修飾方法,結(jié)合查爾酮類化合物的結(jié)構(gòu)特征及其廣泛的抗腫瘤活性,通過對(duì)抗菌氟喹諾酮C-3羧基的修飾,發(fā)展了一類新型結(jié)構(gòu)的氟喹諾酮類查爾酮衍生物,并經(jīng)目標(biāo)化合物的體外抗腫瘤活性篩選結(jié)果,評(píng)價(jià)了結(jié)構(gòu)修飾的合理性,為未來新化合物的設(shè)計(jì)提供依據(jù)。 1.目標(biāo)化合物的設(shè)計(jì)與合成 本文以商業(yè)氟喹諾酮羧酸為原料,經(jīng)親核取代、硼氫化鈉還原脫羧,得到中間體C-7二乙醇胺二氫氟喹諾酮,再與芳香醛發(fā)生Claisen-Schmidt反應(yīng),得到相應(yīng)的查爾酮類似物,產(chǎn)物經(jīng)IR,1HNMR光譜數(shù)據(jù)進(jìn)行表征。 2.體外抗腫瘤活性評(píng)價(jià) 采用MTT實(shí)驗(yàn)方法,測(cè)試了新合成的28個(gè)化合物對(duì)人Panc胰腺癌、T24膀胱癌、PU145前列腺癌、HGC27胃癌、Capan胰腺癌體外生長(zhǎng)抑制活性。結(jié)果表明,大部分化合物對(duì)人Panc胰腺癌、T24膀胱癌、PU145前列腺癌、HGC27胃癌、Capan胰腺癌均具有較強(qiáng)的生長(zhǎng)抑制作用。 3.結(jié)論 本文設(shè)計(jì)合成了28個(gè)C-7二乙醇胺取代的氟喹諾類酮衍生物,經(jīng)1H-NMR、IR、光譜數(shù)據(jù)確證為目標(biāo)化合物。體外抗腫瘤活性測(cè)試結(jié)果顯示,對(duì)人五種癌細(xì)胞均有不同程度的抑制作用。表明C-3羧基和C-7哌嗪基并非是抗腫瘤所必須的基團(tuán),分別可以用亞甲基和二乙醇胺基替代。
[Abstract]:Chalcone is a kind of compound, which is based on 1 ~ 3- diphenyl propylene ketone or contains 偽, 尾 -unsaturated ketone, and widely exists in many medicinal plants. It has attracted much attention because of its various pharmacological activities. The modification of its structure is mainly focused on the changes of the substituents of benzene rings. The substitution of heterocyclic or dense heterocycles for classical benzene rings can improve its pharmacodynamic or pharmacokinetic properties and promote its development towards the direction of drug formation. It has become the focus of the study of neocalcone compounds. Fluoroquinolones are novel antimicrobial agents characterized by 1-substituted-6-fluoro-7-heterocyclic-quinoline-4-ketone-3-carboxylic acid. Because topoisomerase (Topo) is also an important target of antitumor drugs, it has become a new challenge for the development of fluoroquinolones to transform its antibacterial activity to antitumor activity. However, most of the studies on antitumor fluoroquinolones are due to the changes of the N-and C-7 substituents and C-3 carboxyl isoforms of antibacterial fluoroquinolones. The candidate compounds have not been evaluated because of biological problems, such as in vivo availability, toxicity or stability. Therefore, finding new ways and methods of structural modification and obtaining leading compounds with new structures may be the key to solve the problem of drug properties. Based on the existing structure-activity relationship of antitumor fluoroquinolones, C-3 carboxyl groups are not the necessary pharmacophore for antitumor activity. In order to find out a new modification method of fluoroquinolones, combining with the structural characteristics of chalcone compounds and their extensive antitumor activities, the modification of C-3 carboxyl groups of fluoroquinolones was carried out in this paper. A new class of fluoroquinolones derivatives was developed, and the rationality of structural modification was evaluated by screening the antitumor activity of the target compounds in vitro, which provided the basis for the design of new compounds in the future. 1. In this paper, the intermediate C-7 diethanolamine dihydrofluoroquinolone was synthesized from commercial fluoroquinolone carboxylic acid by nucleophilic substitution, sodium borohydride reductive decarboxylation, and Claisen-Schmidt reaction with aromatic aldehydes. The corresponding chalcone analogue was obtained and characterized by IR ~ 1H NMR spectra. MTT assay was used to evaluate the antitumor activity in vitro. The growth inhibitory activity of 28 new compounds against human Panc pancreatic carcinoma, bladder cancer, human bladder cancer, HGC27, gastric cancer and Capan pancreatic carcinoma was tested in vitro. The results showed that most of the compounds had strong growth inhibitory effects on human Panc pancreatic carcinoma, bladder cancer, human bladder cancer, and HGC27, HGC27, gastric cancer and Capan pancreatic carcinoma. Conclusion 28 C-7 diethanolamine substituted fluoroquinolone derivatives were designed and synthesized. The results of in vitro anti-tumor activity test showed that all five kinds of cancer cells were inhibited to some extent. The results showed that C-3 carboxyl group and C-7 piperazine group were not necessary groups for antitumor and could be replaced by methylene group and diethanolamine group respectively.
【學(xué)位授予單位】：河南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5

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