本文選題：1 + 8萘酰亞胺��； 參考：《河南大學(xué)》2014年碩士論文

【摘要】：近些年來多胺修飾的多胺綴合物在抗癌試劑方面的應(yīng)用引起了人們的廣泛關(guān)注,研究表明：天然或合成多胺有潛力發(fā)展成為一種有效利用細(xì)胞膜上多胺轉(zhuǎn)運(yùn)體(PAT)的靶向載體,它們可能具備提高化合物細(xì)胞選擇性和生物活性的能力。 萘酰亞胺類化合物作為抗癌類藥物研究方面,已經(jīng)發(fā)現(xiàn)一些經(jīng)典化合物,如氨萘非特(amonafide)和米托萘胺(nitonafide),其中氨萘非特已處于Ⅲ期臨床試驗(yàn)。但在臨床試驗(yàn)中發(fā)現(xiàn)其一些不足之處,如具有神經(jīng)毒性、骨髓抑制及對(duì)不同腫瘤表現(xiàn)出差異性等。 大量實(shí)驗(yàn)發(fā)現(xiàn)萘酰亞胺類化合物在抗腫瘤方面,表現(xiàn)出較強(qiáng)的抑制作用,同時(shí)在抑制腫瘤轉(zhuǎn)移方面也有較好作用,對(duì)萘酰亞胺類衍生物結(jié)構(gòu)修飾目的是增效及減少毒性等不良反應(yīng),增加該類化合物對(duì)腫瘤細(xì)胞的靶向作用。本文就基于多胺是靶向運(yùn)藥載體,增加藥物的靶向選擇性出發(fā),主要完成以下幾點(diǎn)工作： (1)闡述當(dāng)前多胺及萘酰亞胺類衍生物在藥學(xué)上所具有的現(xiàn)實(shí)意義及近期研究的新進(jìn)展。 (2)通過對(duì)Amonafide氨基和4-溴-1,8萘二甲酸酐的修飾,設(shè)計(jì)合成了2個(gè)系列的線性多胺綴合物并通過“連接臂”結(jié)構(gòu)變化對(duì)其抗腫瘤活性作出測(cè)試,從中篩選出生物活性較好的先導(dǎo)化合物。 本文合成了2個(gè)系列共11個(gè)目標(biāo)化合物,第一個(gè)系列有9個(gè)丙酰化萘酰亞胺類衍生物,第二個(gè)系列為2個(gè)多胺手臂的多胺綴合物。這11個(gè)化合物都是新化合物,且結(jié)構(gòu)均經(jīng)過核磁、質(zhì)譜和元素分析確認(rèn)；此外通過MTT法測(cè)試目標(biāo)化合物對(duì)HepG2(肝癌細(xì)胞)抑制的生物活性。結(jié)果表明目標(biāo)化合物中部分藥物的體外抗腫瘤活性明顯優(yōu)于氨萘菲特(Amonafide),并且其中化合物7c,7d,7e,11i,11j對(duì)HepG2(肝癌細(xì)胞)具有良好的抑制作用。
[Abstract]:In recent years, the application of polyamine-modified polyamine conjugates in anticancer reagents has attracted widespread attention. Studies have shown that natural or synthetic polyamines have the potential to develop into a target carrier for the effective use of polyamine transporter (PATs) on cell membranes. They may have the ability to improve cell selectivity and biological activity of compounds. In the research of naphthalimide compounds as anticancer drugs, some classical compounds, such as aminonaphthalene amonafide, and mitonaphthylamine nitonafidea have been found, among which amineferte has been in phase III clinical trials. In clinical trials, however, some shortcomings were found, such as neurotoxicity, bone marrow suppression, and differences in different tumors. A large number of experiments have found that naphthalimide compounds have a strong inhibitory effect on tumor and have a good effect in inhibiting tumor metastasis. The purpose of structural modification of naphthalimide derivatives is to enhance the toxicity and increase the targeting effect of these compounds on tumor cells. Based on the fact that polyamines are the carrier of targeted drug delivery and the targeting selectivity of drugs is increased, the main work of this paper is as follows: In this paper, the pharmacological significance of polyamines and naphthalimide derivatives and the recent progress in pharmaceutical research are reviewed. Two series of linear polyamine conjugates were designed and synthesized by modification of Amonafide amino groups and 4-bromo-1-butadiene-8-naphthalene dicarboxylic anhydride, and their antitumor activities were tested by structural changes in the "connecting arm". The leading compounds with good biological activity were screened out. In this paper, two series of 11 target compounds have been synthesized. The first series has 9 malonyl naphthalimide derivatives, and the second series is two polyamine conjugates with two polyamines. The 11 compounds were all new compounds, and their structures were confirmed by NMR, MS and elemental analysis. In addition, the bioactivity of the target compounds to HepG2 (hepatoma cells) was tested by MTT assay. The results showed that the antitumor activity of some of the target compounds in vitro was significantly better than that of Amonafidea, and that compound 7cf7d ~ 7e ~ 11i ~ (11) J had a good inhibitory effect on HepG _ 2 (hepatoma cell line).
【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;R96

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本文編號(hào)：1933196