Galaxamide的分离、及其类似物的合成与抗肿瘤活性研究
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摘要
近年来,科学家从海绵、蓝细菌、海鞘、海兔等海洋生物分离得到了许多海洋环肽,这些环肽大部分都具有独特的化学结构和多样的生理活性,如杀虫、抗菌、抗病毒、抗癌、肿瘤促进剂、抗炎和免疫抑制等作用。本文继续从海洋生物中寻找海洋活性化合物,通过研究,从海藻中发现了一种新的具有抗肿瘤活性的环五肽化合物Galaxamide(d1),同时对该化合物及其类似物进行了全合成,并进行了抗肿瘤活性筛选及机理研究。
第二章,对采集于中国南海西沙群岛永兴岛红藻乳状丝节藻的化学成分进行了分离,从中发现了环肽Galaxamide,通过IR,~1H NMR,~(13)C NMR,TOF-MS-ES+,TOF-MSMS ES+,HSQC,TOCSY,HMBC等波谱手段确定了其结构,为环(亮氨酰-N-甲基亮氨酰-亮氨酰-亮氨酰-N-甲基-亮氨酰),用Marfey试剂法确定了分子的构型为SSSSS。
第三章,为解决药源问题,设计合成了化合物Galaxamide,以Boc-亮氨酸和N-甲基亮氨酸苄酯为原料设计了一条合成路线:把Boc-亮氨酸和N-甲基亮氨酸苄酯缩合得到二肽片断,用20%的TFA/二氯甲烷脱除二肽的Boc保护基后与Boc-亮氨酸缩合得到三肽片断,再分别经Pd/C催化常温常压下氢解脱除二肽片断的苄基,用TFA脱除三肽片断的Boc保护基,再进行缩合,得到五肽片断。再分别脱除五肽两端的保护基后,利用混合环合试剂TBTU/HATU/DEPBT关环得到目标产物,三步总收率为42.5%。整个线型肽的合成中我们选择DEPBT作为缩合试剂,发现使用该试剂反应完成后,无需后处理,直接进行柱层析就能得到产物。另外,以同样的方式设计并合成了Galaxamide的五个类似物(d2,d5-d8),关环收率为36.4%—56.9%。
第四章,用Galaxamide及其类似物与部分中间体分别对人乳腺癌细胞株(MCF-7)、人肝癌细胞株(Bel-7402)、人肝癌细胞株(HepG_2)和人宫颈癌细胞株(Hela)四种肿瘤细胞用MTT法进行了体外抗肿瘤活性筛选,并对化合物IC_(50)值小于50μg/ml的化合物进行了统计,发现8个化合物对不同的肿瘤细胞有不同程度的抑制作用,进一步分析这些化合物的构效关系,发现随着N-甲基数增多,化合物的活性有增强的趋势;不同构型环肽(d1,d5,d6)之间的活性有明显的差别。另外,对Galaxamide抗肝癌细胞株Bel-7402的初步机制进行了研究,发现该化合物对肝癌细胞株Bel-7402有明显的抑制作用,考察该化合物对Bel-7402细胞周期的影响,发现大部分细胞被阻滞在G2/M期;Annexin V-FITC/PI实验表明d1能诱导Bel-7402细胞调亡;线粒体膜电位实验表明d1能使Bel-7402细胞线粒体膜电位下降。由此,初步判定d1是通过线粒体途径诱导Bel-7402细胞调亡。
In recent years,scientists have obtained a number of marine cyclic peptides from sponges,blue bacteria,sea squirts,sea hares and other marine organisms;most of these cyclic peptides have unique chemical structure and exhibit a variety of activities, including insecticidal,antibacterial,antiviral,anti-tumor,tumor promoting-agents, anti-inflammatory and immunosuppressive effects.In this dissertation,we described the isolation,structure determination and synthesis of Galaxamide(dl),a rare cytotoxic cyclic pentapeptide from a marine alga Galaxaurafilamentosa.In addition, we demonstrated the synthesis of its analogue and the anti-tumor activity of these compounds.
In the Chapter 2 of this thesis,we described the isolation of Galaxamide from a marine alga Galaxaura filamentosa collected from the Xisha Island of South China Sea.The structure of cyclopeptide was determined as c(Leu-N-MeLeu-Leu-Leu-N -MeLeu) by using spectral methods,including IR,~1HNMR,~(13)CNMR,TOF-MS-ES+, TOF-MSMS ES+,HSQC,TOCSY and HMBC.All leucines of Galaxamide were assigned to L-configuration by Marfey's method.
In Chapter 3,the dipeptide fragment a1 was synthesized by the commercially available tertbutyl-L-leucine with N-methyl-L-leucine benzyl ester.After removal of the Boc group in al using TFA,the product was coupled with Boc-L-leucine leading to the tripeptide b1.Boc group of b1 was removed using TFA to e1 and benzyl was taken off from a1 to e2,respectively.The synthesis of pentapeptide e1 was achieved by coupling of e1 and e2.After the Boc group and benzyl in pentapeptide e1 were removed using TFA and hydrogen reduction in Pd/C,respectively.The dried,crude, free amine/free acid linear pentapeptide was cyclizated using TBTU/HATU/DEPBT as a coupling reagent in three steps with a yield of 42.5%.We found,upon completion, each reaction was concentrated,needed not carry out the postproccessing,and directly subjected to silica gel column chromatography using n-hexane/acetone(20:1) isocratic elution when we prepared the all linear peptide using DEPBT as a coupling reagent.In addition,we synthesized five analogues of Galaxamide in cyclization yield of 36.4%-56.9%.
In Chapter 4,the filtration of anti-tumor activity was determined by MTT assay for Galaxamide,its analogues and synthesis intermediates on four tumor cells, including human breast cancer cell MCF-7,human cervical carcinoma cell Hela and human hepatoma carcinoma cell Bel-7402 and HepG2.The results show that eight compounds obviously inhibit the growth of different tumor cells.Biological activity of the compounds is enhanced with increasing the number of N-methyl in compounds and there were evident differences among different configuration cyclopeptides(d1, d5,d6).In addition,we examined the preliminary mechanism underlying the inhibition of Galaxamide on human hepatoma carcinoma cell Bel-7402.The results indicated that the compounds could evidently inhibit Bel-7402 cell,induce the cell aptotosis and kill cells at last through arousing G2/M arrest of the cell cycle,and reduce mitochondria membrane potential.
第二章,对采集于中国南海西沙群岛永兴岛红藻乳状丝节藻的化学成分进行了分离,从中发现了环肽Galaxamide,通过IR,~1H NMR,~(13)C NMR,TOF-MS-ES+,TOF-MSMS ES+,HSQC,TOCSY,HMBC等波谱手段确定了其结构,为环(亮氨酰-N-甲基亮氨酰-亮氨酰-亮氨酰-N-甲基-亮氨酰),用Marfey试剂法确定了分子的构型为SSSSS。
第三章,为解决药源问题,设计合成了化合物Galaxamide,以Boc-亮氨酸和N-甲基亮氨酸苄酯为原料设计了一条合成路线:把Boc-亮氨酸和N-甲基亮氨酸苄酯缩合得到二肽片断,用20%的TFA/二氯甲烷脱除二肽的Boc保护基后与Boc-亮氨酸缩合得到三肽片断,再分别经Pd/C催化常温常压下氢解脱除二肽片断的苄基,用TFA脱除三肽片断的Boc保护基,再进行缩合,得到五肽片断。再分别脱除五肽两端的保护基后,利用混合环合试剂TBTU/HATU/DEPBT关环得到目标产物,三步总收率为42.5%。整个线型肽的合成中我们选择DEPBT作为缩合试剂,发现使用该试剂反应完成后,无需后处理,直接进行柱层析就能得到产物。另外,以同样的方式设计并合成了Galaxamide的五个类似物(d2,d5-d8),关环收率为36.4%—56.9%。
第四章,用Galaxamide及其类似物与部分中间体分别对人乳腺癌细胞株(MCF-7)、人肝癌细胞株(Bel-7402)、人肝癌细胞株(HepG_2)和人宫颈癌细胞株(Hela)四种肿瘤细胞用MTT法进行了体外抗肿瘤活性筛选,并对化合物IC_(50)值小于50μg/ml的化合物进行了统计,发现8个化合物对不同的肿瘤细胞有不同程度的抑制作用,进一步分析这些化合物的构效关系,发现随着N-甲基数增多,化合物的活性有增强的趋势;不同构型环肽(d1,d5,d6)之间的活性有明显的差别。另外,对Galaxamide抗肝癌细胞株Bel-7402的初步机制进行了研究,发现该化合物对肝癌细胞株Bel-7402有明显的抑制作用,考察该化合物对Bel-7402细胞周期的影响,发现大部分细胞被阻滞在G2/M期;Annexin V-FITC/PI实验表明d1能诱导Bel-7402细胞调亡;线粒体膜电位实验表明d1能使Bel-7402细胞线粒体膜电位下降。由此,初步判定d1是通过线粒体途径诱导Bel-7402细胞调亡。
In recent years,scientists have obtained a number of marine cyclic peptides from sponges,blue bacteria,sea squirts,sea hares and other marine organisms;most of these cyclic peptides have unique chemical structure and exhibit a variety of activities, including insecticidal,antibacterial,antiviral,anti-tumor,tumor promoting-agents, anti-inflammatory and immunosuppressive effects.In this dissertation,we described the isolation,structure determination and synthesis of Galaxamide(dl),a rare cytotoxic cyclic pentapeptide from a marine alga Galaxaurafilamentosa.In addition, we demonstrated the synthesis of its analogue and the anti-tumor activity of these compounds.
In the Chapter 2 of this thesis,we described the isolation of Galaxamide from a marine alga Galaxaura filamentosa collected from the Xisha Island of South China Sea.The structure of cyclopeptide was determined as c(Leu-N-MeLeu-Leu-Leu-N -MeLeu) by using spectral methods,including IR,~1HNMR,~(13)CNMR,TOF-MS-ES+, TOF-MSMS ES+,HSQC,TOCSY and HMBC.All leucines of Galaxamide were assigned to L-configuration by Marfey's method.
In Chapter 3,the dipeptide fragment a1 was synthesized by the commercially available tertbutyl-L-leucine with N-methyl-L-leucine benzyl ester.After removal of the Boc group in al using TFA,the product was coupled with Boc-L-leucine leading to the tripeptide b1.Boc group of b1 was removed using TFA to e1 and benzyl was taken off from a1 to e2,respectively.The synthesis of pentapeptide e1 was achieved by coupling of e1 and e2.After the Boc group and benzyl in pentapeptide e1 were removed using TFA and hydrogen reduction in Pd/C,respectively.The dried,crude, free amine/free acid linear pentapeptide was cyclizated using TBTU/HATU/DEPBT as a coupling reagent in three steps with a yield of 42.5%.We found,upon completion, each reaction was concentrated,needed not carry out the postproccessing,and directly subjected to silica gel column chromatography using n-hexane/acetone(20:1) isocratic elution when we prepared the all linear peptide using DEPBT as a coupling reagent.In addition,we synthesized five analogues of Galaxamide in cyclization yield of 36.4%-56.9%.
In Chapter 4,the filtration of anti-tumor activity was determined by MTT assay for Galaxamide,its analogues and synthesis intermediates on four tumor cells, including human breast cancer cell MCF-7,human cervical carcinoma cell Hela and human hepatoma carcinoma cell Bel-7402 and HepG2.The results show that eight compounds obviously inhibit the growth of different tumor cells.Biological activity of the compounds is enhanced with increasing the number of N-methyl in compounds and there were evident differences among different configuration cyclopeptides(d1, d5,d6).In addition,we examined the preliminary mechanism underlying the inhibition of Galaxamide on human hepatoma carcinoma cell Bel-7402.The results indicated that the compounds could evidently inhibit Bel-7402 cell,induce the cell aptotosis and kill cells at last through arousing G2/M arrest of the cell cycle,and reduce mitochondria membrane potential.
引文
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