手性含脯氨酸环二肽的合成、抗菌抗肿瘤活性及作为不对称催化剂的研究
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摘要
环二肽,是结构最简单的环肽化合物,在自然界中分布广泛,大多具有显著的生理活性和药理活性。它们所表现出的抗菌、抗癌、抗病毒等活性引起了合成化学家和药物化学家的研究兴趣。生物活性环二肽在抗生素、癌抑制剂等方面有潜在的应用前景,设计并合成系统的环二肽化合物库,研究其抗菌、抗肿瘤活性与分子结构的关系具有重要的理论与实际意义。
以L-脯氨酸为母核,以其它常用或非常用氨基酸为配体,采用改进的实验路线合成了16种具有二环刚性结构的手性含脯氨酸环二肽,并研究其抗菌、抗肿瘤活性。发现环(L-脯-L-酪)、环(L-脯-L-苏)、环(L-脯-L-丝)对金黄色葡萄球菌有较明显的抑制作用,MIC分别为160、80、80μg/mL;环(L-脯-L-色)对大肠杆菌有抑制作用,MIC为320μg/mL;环(L-脯-L-苯丙)对白色念珠菌有抑制作用,MIC为320μg/mL;而16种含脯氨酸环二肽在浓度为2.5 mM时对肿瘤细胞Hela和MCF-7均无明显的抑制作用,抑制率小于10%。
自从将环二肽应用于手性氰醇的合成以来,环二肽作为不对称催化剂已引起重视。环二肽作为有机小分子催化剂,具有结构简单、合成方便、易于构建结构与活性的关系等优点,但这类催化剂在适用性方面有一定的局限,设计并合成能应用于不对称催化的环二肽催化剂具有重要的意义。
将合成的16种环二肽作为不对称催化剂用于苯甲醛与二乙基锌的反应,发现能与锌原子形成配合物的环二肽环(L-脯-L-丝)、环(L-脯-L-苏)、环(L-脯-L-组)、环(L-脯-L-色)、环(L-脯-D-组)、环(L-脯-D-色)具有较好的不对称催化活性,产物1-苯基-1-丙醇的产率最高达41%,e.e.值最高达21.3%,并且发现产物的构型取决于脯氨酸的构型。详细考察了溶剂、催化剂用量、温度等因素对反应的影响,确定以甲苯为溶剂,环二肽用量为苯甲醛的10%,0℃反应为该反应最适条件。研究表明含脯氨酸环二肽催化二乙基锌对苯甲醛的不对称加成反应具有一定效果,为本课题的进一步深入研究打下基础。
Cyclic dipeptides (CDPs) are the smallest cyclic peptides known.They exist widely in nature.Recently CDPs have attracted attention due to their biological and pharmacological properties including antibacterial, antifungal, antineoplastic, antiviral activities.Bioactive CDPs have prospects on antibiotics and cancer inhibitors. It is important that design and synthesize CDPs compound libraries, study relationships between their antibacterial, antineoplastic activity and molecular structure in theory and practice.
We designed a CDPs compound library based on L-Proline as the parent nucleus, other usual and unusual amino acid as ligand. And sixteen chiral cyclic dipeptides with Proline were synthesized which possessed bicyclo-rigid structure by improving synthetic route and their antibacterial and antineoplastic activity was also studied. In the test of the compounds for the inhibitory effect against bacterium and fungus, cyclic(L-Pro-L-Tyr), cyclic(L-Pro-L-Thr),cyclic(L-Pro-L-Ser) exhibited significant inhibitory effect against Staphylococcus aureus with MIC of 160,80,80μg/mL, respectively.And cyclic (L-Pro-L-Trp) showed inhibitory effect against Escherichia coli with MIC of 320μg/mL; cyclic (L-Pro-L-Phe) showed inhibitory effect against Candida albicans with MIC of 320μg/mL. Antineoplastic activity was tested using two cultured cell lines: MCF-7 and HeLa which were exposed to 2.5 mM CDPs. No obvious inhibitory activity could be detected, however, less than 10% growth inhibition of MCF-7 and Hela cells.
CDPs have fascinated chemists on acting as asymmetric catalyst since Oku and Inoue published a pioneering study of CDPs as catalysts for the asymmetric addition of hydrogen cyanide to benzaldehyde.CDPs as small organic molecules catalysts have sdvantages of simple structure,easy synthesis and easy to build the relationship between structure and activity.But these catalysts have limitation in applicability to some extent.So design and synthesize CDPs catalysts which can be applied to asymmetric catalytic reactions is of great significance.
Experiments were carried out by using sixteen synthetic chiral CDPs with Proline as catalyst for asymmetric addition of diethylzinc to benzaldehyde. Cyclic (L-Pro-L-Ser), cyclic (L-Pro-L-Thr), cyclic (L-Pro-L-His), cyclic (L-Pro-L-Trp), cyclic (L-Pro-D-His) and cyclic (L-Pro-D-Trp), which can form complexes with the zinc atom, have showed good asymmetric catalytic activity. The yield of product 1-phenyl-1-propanol was up to 41%, enantiomeric excess up to 21.3%. And it is found that the configuration of the product depended on the configuration of Proline.Additionly solvent, catalyst amount and temperature were studied.The experiment showed that 0℃, toluene as solvent and the CDP’s amount of 10% benzaldehyde ware the optimal reaction conditions.Our study indicated that chiral cyclic dipeptides with Proline can asymmetric catalyze addition reaction of diethylzinc to benzaldehyde which made the foundation for further study.
以L-脯氨酸为母核,以其它常用或非常用氨基酸为配体,采用改进的实验路线合成了16种具有二环刚性结构的手性含脯氨酸环二肽,并研究其抗菌、抗肿瘤活性。发现环(L-脯-L-酪)、环(L-脯-L-苏)、环(L-脯-L-丝)对金黄色葡萄球菌有较明显的抑制作用,MIC分别为160、80、80μg/mL;环(L-脯-L-色)对大肠杆菌有抑制作用,MIC为320μg/mL;环(L-脯-L-苯丙)对白色念珠菌有抑制作用,MIC为320μg/mL;而16种含脯氨酸环二肽在浓度为2.5 mM时对肿瘤细胞Hela和MCF-7均无明显的抑制作用,抑制率小于10%。
自从将环二肽应用于手性氰醇的合成以来,环二肽作为不对称催化剂已引起重视。环二肽作为有机小分子催化剂,具有结构简单、合成方便、易于构建结构与活性的关系等优点,但这类催化剂在适用性方面有一定的局限,设计并合成能应用于不对称催化的环二肽催化剂具有重要的意义。
将合成的16种环二肽作为不对称催化剂用于苯甲醛与二乙基锌的反应,发现能与锌原子形成配合物的环二肽环(L-脯-L-丝)、环(L-脯-L-苏)、环(L-脯-L-组)、环(L-脯-L-色)、环(L-脯-D-组)、环(L-脯-D-色)具有较好的不对称催化活性,产物1-苯基-1-丙醇的产率最高达41%,e.e.值最高达21.3%,并且发现产物的构型取决于脯氨酸的构型。详细考察了溶剂、催化剂用量、温度等因素对反应的影响,确定以甲苯为溶剂,环二肽用量为苯甲醛的10%,0℃反应为该反应最适条件。研究表明含脯氨酸环二肽催化二乙基锌对苯甲醛的不对称加成反应具有一定效果,为本课题的进一步深入研究打下基础。
Cyclic dipeptides (CDPs) are the smallest cyclic peptides known.They exist widely in nature.Recently CDPs have attracted attention due to their biological and pharmacological properties including antibacterial, antifungal, antineoplastic, antiviral activities.Bioactive CDPs have prospects on antibiotics and cancer inhibitors. It is important that design and synthesize CDPs compound libraries, study relationships between their antibacterial, antineoplastic activity and molecular structure in theory and practice.
We designed a CDPs compound library based on L-Proline as the parent nucleus, other usual and unusual amino acid as ligand. And sixteen chiral cyclic dipeptides with Proline were synthesized which possessed bicyclo-rigid structure by improving synthetic route and their antibacterial and antineoplastic activity was also studied. In the test of the compounds for the inhibitory effect against bacterium and fungus, cyclic(L-Pro-L-Tyr), cyclic(L-Pro-L-Thr),cyclic(L-Pro-L-Ser) exhibited significant inhibitory effect against Staphylococcus aureus with MIC of 160,80,80μg/mL, respectively.And cyclic (L-Pro-L-Trp) showed inhibitory effect against Escherichia coli with MIC of 320μg/mL; cyclic (L-Pro-L-Phe) showed inhibitory effect against Candida albicans with MIC of 320μg/mL. Antineoplastic activity was tested using two cultured cell lines: MCF-7 and HeLa which were exposed to 2.5 mM CDPs. No obvious inhibitory activity could be detected, however, less than 10% growth inhibition of MCF-7 and Hela cells.
CDPs have fascinated chemists on acting as asymmetric catalyst since Oku and Inoue published a pioneering study of CDPs as catalysts for the asymmetric addition of hydrogen cyanide to benzaldehyde.CDPs as small organic molecules catalysts have sdvantages of simple structure,easy synthesis and easy to build the relationship between structure and activity.But these catalysts have limitation in applicability to some extent.So design and synthesize CDPs catalysts which can be applied to asymmetric catalytic reactions is of great significance.
Experiments were carried out by using sixteen synthetic chiral CDPs with Proline as catalyst for asymmetric addition of diethylzinc to benzaldehyde. Cyclic (L-Pro-L-Ser), cyclic (L-Pro-L-Thr), cyclic (L-Pro-L-His), cyclic (L-Pro-L-Trp), cyclic (L-Pro-D-His) and cyclic (L-Pro-D-Trp), which can form complexes with the zinc atom, have showed good asymmetric catalytic activity. The yield of product 1-phenyl-1-propanol was up to 41%, enantiomeric excess up to 21.3%. And it is found that the configuration of the product depended on the configuration of Proline.Additionly solvent, catalyst amount and temperature were studied.The experiment showed that 0℃, toluene as solvent and the CDP’s amount of 10% benzaldehyde ware the optimal reaction conditions.Our study indicated that chiral cyclic dipeptides with Proline can asymmetric catalyze addition reaction of diethylzinc to benzaldehyde which made the foundation for further study.
引文
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