外消旋紫草素肟衍生物的設(shè)計合成及其抗腫瘤活性研究
發(fā)布時間：2018-08-03 12:04
【摘要】：紫草是我國的傳統(tǒng)中藥,有很長的臨床應(yīng)用歷史。紫草中的主要藥用成分是紫草素和其對映體阿卡寧及其酯類化合物。目前,紫草素雖然有著較強的抗腫瘤作用,但其做為抗腫瘤藥物直接在臨床上應(yīng)用還有很長的路要走,這主要是因為這類化合物的選擇性差,細(xì)胞毒作用太大,不僅抑制腫瘤細(xì)胞生長,也抑制大量正常細(xì)胞的生長。所以如何降低紫草素類化合物對正常細(xì)胞的毒性,提高對癌細(xì)胞的選擇性將是開發(fā)臨床上能應(yīng)用的此類抗腫瘤藥物亟待解決的問題。我們對紫草素進行結(jié)構(gòu)改造,希望能找到一種更高效、對正常細(xì)胞低毒的抗腫瘤藥物。設(shè)計一系列外消旋紫草肟衍生物。通過全合成得到中間體外1,4,5,8-氧-四甲基消旋紫草素,1,4,5,8-氧-四甲基消旋紫草素側(cè)鏈羥基經(jīng)過酯化或醚化,再經(jīng)硝酸鈰銨脫甲基氧化得到2位和6位二羰基氧二甲基側(cè)鏈羥基酯化或醚化的紫草素,進一步通過萘環(huán)母核羰基成肟修飾后得到外消旋紫草素肟衍生物。我們共設(shè)計并合成了28個新化合物,包括紫草素1,4-二羰基雙肟化合物21個,紫草素4-羰基單肟化合物7個,其中側(cè)鏈成酯化合物22個,成醚化合物6個。我們通過MTT法測得其對MCF-7,K-562與DU-145人體腫瘤細(xì)胞的抑制活性。體外活性數(shù)據(jù)顯示肟系列的紫草素衍生物對MCF-7,K-562兩種腫瘤細(xì)胞抑制活性較好,而對DU-145腫瘤細(xì)胞抑制作用較差,顯示出一定的作用選擇性。5,8-氧二甲基紫草素的羰基成肟后,腫瘤抑制活性反而增強,活性順序為:1,4-二羰基肟(雙肟)4-羰基肟(單肟)二羰基化合物,肟衍生物的體外活性強于其前體醌。另外,成肟后,側(cè)鏈對活性影響較大,側(cè)鏈羥基成酯后活性明顯提高,成醚效果較差。其中化合物2DMASKO-5活性比較好,對人乳腺癌細(xì)胞MCF-7和人白血病細(xì)胞K562的抑制IC50分別為12.7μM和1.3μM。我們選擇該化合物進行了體內(nèi)抗腫瘤作用研究。體內(nèi)實驗結(jié)果顯示,2-DMSAKO-5腹腔給藥12mg/kg對小鼠EMT6乳腺癌移植瘤抑瘤率為41.4%,對小鼠CT26結(jié)腸癌移植瘤抑瘤率為45.9%,活性均高于陽性對照組5-FU腹腔給藥25 mg/kg組,而對小鼠S180組移植瘤抑瘤活性比較差,沒有陽性對照組效果好。而且2-DMSAKO-5給藥組小鼠體重增長與陰性對照組相同,未發(fā)現(xiàn)與紫草素及其二甲基衍生物體內(nèi)試驗所產(chǎn)生的局部刺激、腹水等類似毒性。通過對紫草素萘茜母核羥基甲基化、羰基肟化修飾,成功地解決了困擾紫草素作為抗腫瘤藥物的毒性和選擇性問題,通過進一步的側(cè)鏈結(jié)構(gòu)優(yōu)化和作用機制的深入研究,有望得到活性、選擇性及成藥性更好的候選化合物進入臨床前研究,為開發(fā)結(jié)構(gòu)新穎、機制獨特、高效低毒的有自主知識產(chǎn)權(quán)的原創(chuàng)性抗腫瘤新藥奠定了基礎(chǔ)。
[Abstract]:Purple herb is a traditional Chinese medicine in China, which has a long history of clinical application. The main medicinal components of Shikonin and its enantiomers, acanine and their esters. At present, although Shikonin has a strong anti-tumor effect, it still has a long way to go as an antitumor drug in clinical application. This is mainly due to the poor selectivity and cytotoxic effect of these compounds. It not only inhibits the growth of tumor cells, but also inhibits the growth of a large number of normal cells. Therefore, how to reduce the toxicity of Shikonin compounds to normal cells and improve the selectivity to cancer cells will be the urgent problems to be solved in the development of this kind of anti-tumor drugs. In order to find a more efficient and low toxic antitumor drug, we modified the structure of Shikonin. A series of racemic oxime derivatives were designed. The side chain hydroxyl of the intermediate was esterified or etherified by the synthesis of the intermediates (1: 4, 4, 5, 5)-oxy-tetramethyl racemyl luciferin, and the side chain hydroxyl of the intermediate was esterified or etherified, and the hydroxyl of the side chain of the intermediate was esterified or etherized. The alkaloids of 2 and 6 position dicarbonyl oxomethyl side chain hydroxy esterification or etherification were obtained by cerium ammonium nitrate demethylation and then modified by naphthalene ring mother nucleus carbonyl oxime to obtain racemic porphyrin oxime derivatives. We have designed and synthesized 28 new compounds, including 21 porphyrin 4-dicarbonyl dioxime compounds, 7 porphyrin 4-carbonyl monooxime compounds, including 22 side chain ester forming compounds and 6 ether forming compounds. The inhibitory activity of MCF-7 K-562 and DU-145 human tumor cells was determined by MTT assay. The in vitro activity data showed that the oxime derivatives had better inhibitory activity on MCF-7 and K-562 tumor cells than on DU-145 tumor cells. The inhibitory activity of tumor was increased in the order of 1: 1, 4-dicarbonyl oxime (dioxime) 4-carbonyl oxime (monoxime) dicarbonyl compound, and the activity of oxime derivative was stronger than that of its precursor in vitro. In addition, after oxime formation, the side chain has a great effect on the activity, the side chain hydroxyl ester formation activity is obviously increased, and the ether formation effect is poor. The inhibitory IC50 of compound 2DMASKO-5 on MCF-7 and K562 cells were 12.7 渭 M and 1.3 渭 M, respectively. We selected the compound to study its anti-tumor effect in vivo. The results of in vivo experiment showed that the inhibitory rate of 12mg/kg on EMT6 breast cancer transplanted tumor was 41.4%, and on CT26 colon cancer transplantation tumor was 45.90.The activity was higher than that of the positive control group (25 mg/kg group). The tumor inhibitory activity of S 180 group was poor, and the effect of positive control group was better than that of positive control group. The weight gain of mice in 2-DMSAKO-5 group was the same as that in negative control group, and no similar toxicity was found with the local stimulation and ascites produced by the in vivo test of Shikonin and its dimethyl derivatives. The toxicity and selectivity of porphyrin as an antitumor drug were solved successfully by hydroxyl methylation and carbonyl oximation modification of the mother nucleus of porphyrin, and the side chain structure optimization and the mechanism of action were further studied. It is expected that candidate compounds with better activity, selectivity and drug formation will be used in preclinical research, which will lay a foundation for the development of novel antitumor drugs with unique structure, unique mechanism and high efficiency and low toxicity, with their own intellectual property rights.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R284.3;R285.5
本文編號：2161689
[Abstract]:Purple herb is a traditional Chinese medicine in China, which has a long history of clinical application. The main medicinal components of Shikonin and its enantiomers, acanine and their esters. At present, although Shikonin has a strong anti-tumor effect, it still has a long way to go as an antitumor drug in clinical application. This is mainly due to the poor selectivity and cytotoxic effect of these compounds. It not only inhibits the growth of tumor cells, but also inhibits the growth of a large number of normal cells. Therefore, how to reduce the toxicity of Shikonin compounds to normal cells and improve the selectivity to cancer cells will be the urgent problems to be solved in the development of this kind of anti-tumor drugs. In order to find a more efficient and low toxic antitumor drug, we modified the structure of Shikonin. A series of racemic oxime derivatives were designed. The side chain hydroxyl of the intermediate was esterified or etherified by the synthesis of the intermediates (1: 4, 4, 5, 5)-oxy-tetramethyl racemyl luciferin, and the side chain hydroxyl of the intermediate was esterified or etherified, and the hydroxyl of the side chain of the intermediate was esterified or etherized. The alkaloids of 2 and 6 position dicarbonyl oxomethyl side chain hydroxy esterification or etherification were obtained by cerium ammonium nitrate demethylation and then modified by naphthalene ring mother nucleus carbonyl oxime to obtain racemic porphyrin oxime derivatives. We have designed and synthesized 28 new compounds, including 21 porphyrin 4-dicarbonyl dioxime compounds, 7 porphyrin 4-carbonyl monooxime compounds, including 22 side chain ester forming compounds and 6 ether forming compounds. The inhibitory activity of MCF-7 K-562 and DU-145 human tumor cells was determined by MTT assay. The in vitro activity data showed that the oxime derivatives had better inhibitory activity on MCF-7 and K-562 tumor cells than on DU-145 tumor cells. The inhibitory activity of tumor was increased in the order of 1: 1, 4-dicarbonyl oxime (dioxime) 4-carbonyl oxime (monoxime) dicarbonyl compound, and the activity of oxime derivative was stronger than that of its precursor in vitro. In addition, after oxime formation, the side chain has a great effect on the activity, the side chain hydroxyl ester formation activity is obviously increased, and the ether formation effect is poor. The inhibitory IC50 of compound 2DMASKO-5 on MCF-7 and K562 cells were 12.7 渭 M and 1.3 渭 M, respectively. We selected the compound to study its anti-tumor effect in vivo. The results of in vivo experiment showed that the inhibitory rate of 12mg/kg on EMT6 breast cancer transplanted tumor was 41.4%, and on CT26 colon cancer transplantation tumor was 45.90.The activity was higher than that of the positive control group (25 mg/kg group). The tumor inhibitory activity of S 180 group was poor, and the effect of positive control group was better than that of positive control group. The weight gain of mice in 2-DMSAKO-5 group was the same as that in negative control group, and no similar toxicity was found with the local stimulation and ascites produced by the in vivo test of Shikonin and its dimethyl derivatives. The toxicity and selectivity of porphyrin as an antitumor drug were solved successfully by hydroxyl methylation and carbonyl oximation modification of the mother nucleus of porphyrin, and the side chain structure optimization and the mechanism of action were further studied. It is expected that candidate compounds with better activity, selectivity and drug formation will be used in preclinical research, which will lay a foundation for the development of novel antitumor drugs with unique structure, unique mechanism and high efficiency and low toxicity, with their own intellectual property rights.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R284.3;R285.5
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 龐志功,汪寶琪,李海峰;β-紫草素復(fù)方的藥代動力學(xué)研究[J];西安醫(yī)科大學(xué)學(xué)報;2001年04期
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