海洋生物碱pityriacitrin及类似物、大黄素糖衍生物的合成与抗肿瘤活性评价
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摘要
本论文分两部分:第一部分是海洋生物碱pityriacitrin及类似物的合成与抗肿瘤活性评价,第二部分是大黄素糖衍生物的合成与抗肿瘤活性评价。
1.β-咔啉衍生物是一类广泛分布于自然界的生物碱。近年来的研究表明,β-咔啉生物碱具有抗肿瘤活性,而且某些β-咔啉生物碱对肿瘤细胞具有较高的选择性,这些研究结果激起了人们对β-咔啉类抗癌衍生物的兴趣。
由于海洋天然提取物一般量很少,并且提取过程比较复杂,限制了进一步的结构优化及药理学研究和活性筛选。因此,作为资源解决途径的化学合成方法自然受到化学工作者们的高度重视。Pityriacitrin作为一种从海洋中分离得到的β-咔啉生物碱,到目前为止,还没有关于它的化学合成方面的报道。因此,我们决定合成pityriacitrin,获得足够量的目标化合物,以满足进一步研究的需要;并设计合成它的一系列类似物,通过比较活性的差异,期望能从中发现有很好的抗肿瘤活性的化合物。
采用改进的Pictet-Spengler反应,通过一锅法成功地合成了海洋天然产物β-咔啉生物碱pityriacitrin(9),并合成了它的一系列类似物10-16。同时,还分离得到了三个3位羧基未脱除的β-咔啉化合物17-19。其中,pityriacitrin B(17)也是一个天然产物,并首次被化学合成。所有产物均通过质谱、高分辨质谱、核磁共振氢谱、核磁共振碳谱、红外光谱进行了结构表征。该反应是在经典的Pictet-Spengler反应的基础上进行改进的,操作简单,条件温和,可以作为一种方便有效的合成1位芳香羰基取代的β-咔啉生物碱的方法。实验发现,色氨酸5位上羟基的有无对反应的难易及收率没有明显影响。
海洋天然产物pityriacitrin(9)对乳腺癌细胞MCF7、MDA231和前列腺癌细胞PC3的抑制活性较差,抗肿瘤活性不高。而在其基础上进行结构改造得到的化合物中,则有一些表现出了良好的抗肿瘤活性。在5'位引入甲氧基或者在6位引入羟基后,得到的化合物10(IC50 = 6.94、18.82、49.89μM)和13(IC50 = 12.94、6.35、16.37μM)的抗肿瘤活性很高;咔啉环上3位羧基的保留对抗肿瘤活性很重要;而5'位甲氧基与3位羧基同时存在的化合物18的抗肿瘤活性最高(IC50 = 3.4、12.09、32.3μM)。
2.大黄素为三环共平面结构,具有DNA嵌入剂的基本结构特征,但大黄素本身与DNA的结合力不强,抗肿瘤活性较弱,溶解性也很差。近几年来我们合成并研究了糖修饰的抗肿瘤活性化合物,发现糖基的引入大大增加了先导化合物的水溶性,有的还增加了先导化合物的抗肿瘤活性,特别是可以增加大共轭平面基团的抑制肿瘤细胞生长活性。
因此,为了改善其溶解性,增加水溶性,同时为了找到具有更好的抗肿瘤活性药物,我们对大黄素的3位羟基进行了化学修饰。通过相转移催化法,在3位分别引入了乙酰化的半乳糖基和木糖基,得到了1,8-二羟基-3-甲基-6-(2,3,4,6-四-O-乙酰基-1-脱氧-β-半乳糖)-蒽醌(3)和1,8-二羟基-3-甲基-6-(2,3,4-三-O-乙酰基-1-脱氧-β-木糖)-蒽醌(4);并对化合物4脱乙酰基保护,得到了1,8-二羟基-3-甲基-6-(1-脱氧-β-木糖)-蒽醌(5)。所有目标产物均为新化合物,并通过质谱、高分辨质谱、核磁共振氢谱、核磁共振碳谱进行了结构表征。所合成的大黄素糖衍生物对乳腺癌细胞MDA231表现出了较好的抑制率,具有中等强度的抗肿瘤活性。
The thesis is composed of two parts: the first one is synthesis and anti-tumor activity of the marine alkaloid pityriacitrin and its derivatives, and the second one is synthesis and anti-tumor activity of emodin glycoside analogues.
1.β-Carbolines exist widely in nature as a thoroughly investigated family of indole alkaloids. They have attracted more and more interests because of their anti-tumor activity.
Pityriacitrin possesses theβ-carboline moiety to which an indole ring is attached at C-1 by carbonyl group, isolated from a marine bacterium of the genus Paracoccus (strain F-1547), and also from the yeast Malassezia furfur. Chemical synthesis of pityriacitrin has not been reported in the literature. Marine alkaloids are normally isolated in very small quantity, which hinders us to research their biological activities and further structure modification. So, it’s necessary to find out chemical methods to synthesize them. Laboratory synthesis of marine alkaloids in larger quantity will allow us to perform a more complete study of their biological activities.
Compared to the general two-step Pictet-Spengler reaction, the modified one-pot oxidation reaction is more efficient and convenient in preparing 1-aromatic carbonyl substitutedβ-carbolines without the need of aromatization step. Using the modified Pictet-Spengler reaction,β-carboline alkaloid pityriacitrin (9) and a series of its derivatives 10-16 have been synthesized. At the same time, another three 3-carboxy substitutedβ-carboline alkaloids 17-19 are obtained. Pityriacitrin B (17) is also synthesized for the first time as a natural compound. All compounds have been characterized by IR, NMR and mass spectrometry. They are all new compounds synthesized by chemical method for the first time.
The in vitro anti-tumor activity of all the synthetic compounds is evaluated against the MCF7、MDA231、PC3 cell lines by the standard MTT assay. Pityriacitrin exhibits poor anti-tumor activity, however, some of its derivatives exhibit good anti-tumor activity against the three cell lines. 5'-methoxy substituted compound 10 (IC50 = 6.94、18.82、49.89μM) and 6-hydroxy substituted compound 13 (IC50 = 12.94、6.35、16.37μM) exhibit high anti-tumor activity. The preserved carboxy on 3 position ofβ-carboline is important to the anti-tumor activity. The 5'-methoxy and 3-carboxy substituted compound 18 exhibits the best anti-tumor activity (IC50 = 3.4、12.09、32.3μM).
2. Emodin possessing planar polycyclic aromatic system has lower DNA binding affinity and lower or less insignificant cytotoxicity against cancer cells. Addition of side chains such as polymethyleneamine, sugar or heterocyclic to emodin chromophore, is usually effective to gain higher DNA binding affinity and anti-tumor activity. In order to improve its DNA binding affinity and anti-tumor activity, some new emodin glycoside derivatives are synthesized by attaching various saccharide side chains to emodin.
Using the phase transfer catalysis method, 1,8-dihydroxy-3-methyl-6-[(2,3,4,6- tetra-O-acetyl-β-D-galactopyranosyl)oxy]-9,10-anthracenedione (3) and 1,8-dihydro- xy-3-methyl-6-[(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)oxy]-9,10-anthracenedione (4) are synthesized. 1,8-Dihydroxy-3-methyl-6-(β-D-xylopyranosyloxy)-9,10-anthrace- nedione (5) is obtained by deprotection of compound 4. They are all synthesized by chemical method for the first time and characterized by NMR and Mass spectrometry.
The in vitro anti-tumor activity is evaluated against the MDA231 cell line by the standard MTT assay. They are proven to possess moderate anti-tumor activity.
1.β-咔啉衍生物是一类广泛分布于自然界的生物碱。近年来的研究表明,β-咔啉生物碱具有抗肿瘤活性,而且某些β-咔啉生物碱对肿瘤细胞具有较高的选择性,这些研究结果激起了人们对β-咔啉类抗癌衍生物的兴趣。
由于海洋天然提取物一般量很少,并且提取过程比较复杂,限制了进一步的结构优化及药理学研究和活性筛选。因此,作为资源解决途径的化学合成方法自然受到化学工作者们的高度重视。Pityriacitrin作为一种从海洋中分离得到的β-咔啉生物碱,到目前为止,还没有关于它的化学合成方面的报道。因此,我们决定合成pityriacitrin,获得足够量的目标化合物,以满足进一步研究的需要;并设计合成它的一系列类似物,通过比较活性的差异,期望能从中发现有很好的抗肿瘤活性的化合物。
采用改进的Pictet-Spengler反应,通过一锅法成功地合成了海洋天然产物β-咔啉生物碱pityriacitrin(9),并合成了它的一系列类似物10-16。同时,还分离得到了三个3位羧基未脱除的β-咔啉化合物17-19。其中,pityriacitrin B(17)也是一个天然产物,并首次被化学合成。所有产物均通过质谱、高分辨质谱、核磁共振氢谱、核磁共振碳谱、红外光谱进行了结构表征。该反应是在经典的Pictet-Spengler反应的基础上进行改进的,操作简单,条件温和,可以作为一种方便有效的合成1位芳香羰基取代的β-咔啉生物碱的方法。实验发现,色氨酸5位上羟基的有无对反应的难易及收率没有明显影响。
海洋天然产物pityriacitrin(9)对乳腺癌细胞MCF7、MDA231和前列腺癌细胞PC3的抑制活性较差,抗肿瘤活性不高。而在其基础上进行结构改造得到的化合物中,则有一些表现出了良好的抗肿瘤活性。在5'位引入甲氧基或者在6位引入羟基后,得到的化合物10(IC50 = 6.94、18.82、49.89μM)和13(IC50 = 12.94、6.35、16.37μM)的抗肿瘤活性很高;咔啉环上3位羧基的保留对抗肿瘤活性很重要;而5'位甲氧基与3位羧基同时存在的化合物18的抗肿瘤活性最高(IC50 = 3.4、12.09、32.3μM)。
2.大黄素为三环共平面结构,具有DNA嵌入剂的基本结构特征,但大黄素本身与DNA的结合力不强,抗肿瘤活性较弱,溶解性也很差。近几年来我们合成并研究了糖修饰的抗肿瘤活性化合物,发现糖基的引入大大增加了先导化合物的水溶性,有的还增加了先导化合物的抗肿瘤活性,特别是可以增加大共轭平面基团的抑制肿瘤细胞生长活性。
因此,为了改善其溶解性,增加水溶性,同时为了找到具有更好的抗肿瘤活性药物,我们对大黄素的3位羟基进行了化学修饰。通过相转移催化法,在3位分别引入了乙酰化的半乳糖基和木糖基,得到了1,8-二羟基-3-甲基-6-(2,3,4,6-四-O-乙酰基-1-脱氧-β-半乳糖)-蒽醌(3)和1,8-二羟基-3-甲基-6-(2,3,4-三-O-乙酰基-1-脱氧-β-木糖)-蒽醌(4);并对化合物4脱乙酰基保护,得到了1,8-二羟基-3-甲基-6-(1-脱氧-β-木糖)-蒽醌(5)。所有目标产物均为新化合物,并通过质谱、高分辨质谱、核磁共振氢谱、核磁共振碳谱进行了结构表征。所合成的大黄素糖衍生物对乳腺癌细胞MDA231表现出了较好的抑制率,具有中等强度的抗肿瘤活性。
The thesis is composed of two parts: the first one is synthesis and anti-tumor activity of the marine alkaloid pityriacitrin and its derivatives, and the second one is synthesis and anti-tumor activity of emodin glycoside analogues.
1.β-Carbolines exist widely in nature as a thoroughly investigated family of indole alkaloids. They have attracted more and more interests because of their anti-tumor activity.
Pityriacitrin possesses theβ-carboline moiety to which an indole ring is attached at C-1 by carbonyl group, isolated from a marine bacterium of the genus Paracoccus (strain F-1547), and also from the yeast Malassezia furfur. Chemical synthesis of pityriacitrin has not been reported in the literature. Marine alkaloids are normally isolated in very small quantity, which hinders us to research their biological activities and further structure modification. So, it’s necessary to find out chemical methods to synthesize them. Laboratory synthesis of marine alkaloids in larger quantity will allow us to perform a more complete study of their biological activities.
Compared to the general two-step Pictet-Spengler reaction, the modified one-pot oxidation reaction is more efficient and convenient in preparing 1-aromatic carbonyl substitutedβ-carbolines without the need of aromatization step. Using the modified Pictet-Spengler reaction,β-carboline alkaloid pityriacitrin (9) and a series of its derivatives 10-16 have been synthesized. At the same time, another three 3-carboxy substitutedβ-carboline alkaloids 17-19 are obtained. Pityriacitrin B (17) is also synthesized for the first time as a natural compound. All compounds have been characterized by IR, NMR and mass spectrometry. They are all new compounds synthesized by chemical method for the first time.
The in vitro anti-tumor activity of all the synthetic compounds is evaluated against the MCF7、MDA231、PC3 cell lines by the standard MTT assay. Pityriacitrin exhibits poor anti-tumor activity, however, some of its derivatives exhibit good anti-tumor activity against the three cell lines. 5'-methoxy substituted compound 10 (IC50 = 6.94、18.82、49.89μM) and 6-hydroxy substituted compound 13 (IC50 = 12.94、6.35、16.37μM) exhibit high anti-tumor activity. The preserved carboxy on 3 position ofβ-carboline is important to the anti-tumor activity. The 5'-methoxy and 3-carboxy substituted compound 18 exhibits the best anti-tumor activity (IC50 = 3.4、12.09、32.3μM).
2. Emodin possessing planar polycyclic aromatic system has lower DNA binding affinity and lower or less insignificant cytotoxicity against cancer cells. Addition of side chains such as polymethyleneamine, sugar or heterocyclic to emodin chromophore, is usually effective to gain higher DNA binding affinity and anti-tumor activity. In order to improve its DNA binding affinity and anti-tumor activity, some new emodin glycoside derivatives are synthesized by attaching various saccharide side chains to emodin.
Using the phase transfer catalysis method, 1,8-dihydroxy-3-methyl-6-[(2,3,4,6- tetra-O-acetyl-β-D-galactopyranosyl)oxy]-9,10-anthracenedione (3) and 1,8-dihydro- xy-3-methyl-6-[(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)oxy]-9,10-anthracenedione (4) are synthesized. 1,8-Dihydroxy-3-methyl-6-(β-D-xylopyranosyloxy)-9,10-anthrace- nedione (5) is obtained by deprotection of compound 4. They are all synthesized by chemical method for the first time and characterized by NMR and Mass spectrometry.
The in vitro anti-tumor activity is evaluated against the MDA231 cell line by the standard MTT assay. They are proven to possess moderate anti-tumor activity.
引文
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