根皮素及其异烟酰基腙稀土配合物的合成、表征及活性研究
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摘要
根皮素,属于二氢查尔酮类化合物,是一种天然活性物质,主要存在于苹果、梨等水果及多种蔬菜汁液中,因根皮素可淡化色斑,使皮肤增白,其效果优于曲酸和熊果苷等目前化妆品中常用的美白剂,目前国外主要将其作为一种新型的化妆品添加剂。除此之外,根皮素还具有丰富的生物学活性。目前已报道的有抗氧化,抗肿瘤,降血糖,保护血管等功能。近年来,各国学者对根皮素的研究主要集中在活性研究及机制探讨方面,化学修饰领域尚未完全开拓。目前,天然药物配位化学逐渐成为新药研发的一个热点,前人工作提示当金属元素与活性有机配体反应形成配合物后,大多会增加其疗效,甚至产生新的药理作用。研究中涉及有黄酮类、黄酮醇类、异黄酮类等,查尔酮类化合物较少。本文选择根皮素根皮素与异烟肼反应合成的新型酰腙为配体,分别与稀土金属元素(La, Nd, Pr, Sm)配位。希望通过化学修饰提高根皮素的生物活性,并且为根皮素的结构研究提供一定理论依据。本论文主要由五个部分组成：
第一章综述了国内外根皮素的研究状况,简要介绍了酰腙类化合物和黄酮类配合物的生物学功能,阐明了本课题的研究目的及意义。
第二章选取了四种具有代表性的镧系金属元素—La(Ⅲ), Nd(Ⅲ), Pr(Ⅲ),Sm(Ⅲ)与根皮素合成了相应的稀土配合物,并采用元素分析,红外光谱和热重分析等手段对合成产物进行了表征,并综合各实验结果推测了根皮素稀土配合物的结构。
第三章选用治疗结核病的首选药物异烟肼,在适宜条件下与根皮素合成了根皮素异烟酰基腙,采用紫外光谱,红外光谱,元素分析,1HNMR,13C NMR等手段对其进行了结构表征。之后以酰腙作为配体,与La(Ⅲ), Nd(Ⅲ), Pr(Ⅲ),Sm(Ⅲ)合成了四种酰腙配合物,采用元素分析,红外光谱和热重分析等手段对合成产物进行了表征,并推测了根皮素酰腙类稀土配合物的结构。
第四章对根皮素,根皮素异烟酰基腙及相应的两个系列八种稀土配合物的抗氧化活性进行了测定,并通过荧光光谱法研究了各配合物与牛血清白蛋白(BSA)的相互作用。抗氧化活性实验包括还原Fe3+能力,清除OH-自由基能力、清除DPPH自由基和ABTS自由基能力及抑制脂质过氧化能力。实验结果表明,不同实验模型,配体及配合物表现出的活性有所不同。还原能力实验中,配合物的活性均高于相应配体,且酰腙类配合物的还原能力显著高于根皮素类配合物。清除羟基自由基实验表明,除酰腙-Pr配合物外,其它配合物的清除能力较配体均得到不同程度提高。在清除DPPH, ABTS自由基以及抑制脂质过氧化能力实验中,各配合物表现出的能力均较配体低,未得到提高。荧光光谱实验表明,八种稀土金属配合物均能与BSA发生相互作用,且对BSA的荧光猝灭均是由于形成复合物的静态猝灭,与BSA的作用方式均以氢键和范德华力为主。
Phloretin, which is an active substance, contained in dihydrochalcone, mainly present in apples, pears and other fruits or vegetables juices.At present, phloretin is used as a new type of cosmetic additives in foreign countries, because phloretin may dilute the stain, whitening skin and the effect is better than the present commonly used arbutin and kojic acid in cosmetics. In addition, phloretin posses lots of biological activities. Antioxidant, anti-tumor, reducing blood sugar, protecting blood vessels has been reported. Currently, the research on phloretin is mainly focused on the activity; the field on the chemical modification is still not fully open up. Nowadays, coordination chemistry of natural medicine has become a hot point in drug research and development, previous work suggests that when the metal element and coordinated with organic ligand, complexes may posses increasing efficacy, and even generate new pharmacological activites. Research involving flavonoids, flavonols, isoflavone, etc, chalcone is not common. In this paper we choose phloretin as a ligand, and synthesised a novel ligand with isoniazid hydrazone, and then coordinated with rare earth (La, Nd, Pr, Sm) respectively. We hope to improve the biological activity of phloretin through chemical modification. and provide a theoretical basis to the structure research of phloretin. This thesis consists of five parts:
Chapter one, reviews the international research status of phloretin, and then take a brief introduction of biological function of hydrazone compounds and flavonoid complex, clarify the direction and significance of this research.
Chapter two, selected representative lanthanide elements-La (Ⅲ), Nd (Ⅲ), Pr (Ⅲ), Sm (Ⅲ) corresponding with phloretin, synthesized four rare earth complexes, and then characterized by using elements analysis, infrared spectroscopy and thermal analysis, and infered structures of the phloretin rare earth complexes.
Chapter three, selected isoniazid, which is the preferred drug in treatment of tuberculosis, under suitable conditions, synthesized isonicotinoyl hydrazone with phloretin, characterized by using ultraviolet spectroscopy, infrared spectroscopy, elemental analysis,1H NMR,13C NMR. Then we choose the hydrazone as a ligand, coordinated with La (Ⅲ), Nd (Ⅲ), Pr (Ⅲ), Sm (Ⅲ) synthesized four Hydrazone Complexes, characterized by elemental analysis, infrared spectroscopy and thermal analysis and infered structures of the hydrazone rare earth complexes.
Chapter four, the antioxidant activity of phloretin, phloretin isonicotinoyl hydrazone and the eight rare earth complexes were measured, and studied the complexes interactions with bovine serum albumin (BSA) by fluorescence spectroscopy. The antioxidant experiment including reduction of Fe3+ ability, scavening OH-radicals, DPPH radical and ABTS radical ability and inhibition of lipid peroxidation. The results show that ligands and complexes exhibit different activities in different experimental models. In the reducing Fe3+ experiment, the activities of the complexes were higher than the corresponding ligands, and complexes of hydrazone reduction were significantly higher than phloretin complexes. In the OH radical scavening assay, the scavenging ability of the complex ligands were increased to varying degrees, excepting hydrazone-Pr complexes. In clear DPPH, ABTS radicals and inhibiting lipid peroxidation experiments, the ability of the complexes showed lower than those of the ligands, not improved. Fluorescence spectroscopy experiments showed that the eight rare earth metal complexes can interact with the BSA and the fluorescence quenching of BSA are due to the formation of static quenching, and the mode of action of BSA are hydrogen bonds and van der Waals force Lord.
第一章综述了国内外根皮素的研究状况,简要介绍了酰腙类化合物和黄酮类配合物的生物学功能,阐明了本课题的研究目的及意义。
第二章选取了四种具有代表性的镧系金属元素—La(Ⅲ), Nd(Ⅲ), Pr(Ⅲ),Sm(Ⅲ)与根皮素合成了相应的稀土配合物,并采用元素分析,红外光谱和热重分析等手段对合成产物进行了表征,并综合各实验结果推测了根皮素稀土配合物的结构。
第三章选用治疗结核病的首选药物异烟肼,在适宜条件下与根皮素合成了根皮素异烟酰基腙,采用紫外光谱,红外光谱,元素分析,1HNMR,13C NMR等手段对其进行了结构表征。之后以酰腙作为配体,与La(Ⅲ), Nd(Ⅲ), Pr(Ⅲ),Sm(Ⅲ)合成了四种酰腙配合物,采用元素分析,红外光谱和热重分析等手段对合成产物进行了表征,并推测了根皮素酰腙类稀土配合物的结构。
第四章对根皮素,根皮素异烟酰基腙及相应的两个系列八种稀土配合物的抗氧化活性进行了测定,并通过荧光光谱法研究了各配合物与牛血清白蛋白(BSA)的相互作用。抗氧化活性实验包括还原Fe3+能力,清除OH-自由基能力、清除DPPH自由基和ABTS自由基能力及抑制脂质过氧化能力。实验结果表明,不同实验模型,配体及配合物表现出的活性有所不同。还原能力实验中,配合物的活性均高于相应配体,且酰腙类配合物的还原能力显著高于根皮素类配合物。清除羟基自由基实验表明,除酰腙-Pr配合物外,其它配合物的清除能力较配体均得到不同程度提高。在清除DPPH, ABTS自由基以及抑制脂质过氧化能力实验中,各配合物表现出的能力均较配体低,未得到提高。荧光光谱实验表明,八种稀土金属配合物均能与BSA发生相互作用,且对BSA的荧光猝灭均是由于形成复合物的静态猝灭,与BSA的作用方式均以氢键和范德华力为主。
Phloretin, which is an active substance, contained in dihydrochalcone, mainly present in apples, pears and other fruits or vegetables juices.At present, phloretin is used as a new type of cosmetic additives in foreign countries, because phloretin may dilute the stain, whitening skin and the effect is better than the present commonly used arbutin and kojic acid in cosmetics. In addition, phloretin posses lots of biological activities. Antioxidant, anti-tumor, reducing blood sugar, protecting blood vessels has been reported. Currently, the research on phloretin is mainly focused on the activity; the field on the chemical modification is still not fully open up. Nowadays, coordination chemistry of natural medicine has become a hot point in drug research and development, previous work suggests that when the metal element and coordinated with organic ligand, complexes may posses increasing efficacy, and even generate new pharmacological activites. Research involving flavonoids, flavonols, isoflavone, etc, chalcone is not common. In this paper we choose phloretin as a ligand, and synthesised a novel ligand with isoniazid hydrazone, and then coordinated with rare earth (La, Nd, Pr, Sm) respectively. We hope to improve the biological activity of phloretin through chemical modification. and provide a theoretical basis to the structure research of phloretin. This thesis consists of five parts:
Chapter one, reviews the international research status of phloretin, and then take a brief introduction of biological function of hydrazone compounds and flavonoid complex, clarify the direction and significance of this research.
Chapter two, selected representative lanthanide elements-La (Ⅲ), Nd (Ⅲ), Pr (Ⅲ), Sm (Ⅲ) corresponding with phloretin, synthesized four rare earth complexes, and then characterized by using elements analysis, infrared spectroscopy and thermal analysis, and infered structures of the phloretin rare earth complexes.
Chapter three, selected isoniazid, which is the preferred drug in treatment of tuberculosis, under suitable conditions, synthesized isonicotinoyl hydrazone with phloretin, characterized by using ultraviolet spectroscopy, infrared spectroscopy, elemental analysis,1H NMR,13C NMR. Then we choose the hydrazone as a ligand, coordinated with La (Ⅲ), Nd (Ⅲ), Pr (Ⅲ), Sm (Ⅲ) synthesized four Hydrazone Complexes, characterized by elemental analysis, infrared spectroscopy and thermal analysis and infered structures of the hydrazone rare earth complexes.
Chapter four, the antioxidant activity of phloretin, phloretin isonicotinoyl hydrazone and the eight rare earth complexes were measured, and studied the complexes interactions with bovine serum albumin (BSA) by fluorescence spectroscopy. The antioxidant experiment including reduction of Fe3+ ability, scavening OH-radicals, DPPH radical and ABTS radical ability and inhibition of lipid peroxidation. The results show that ligands and complexes exhibit different activities in different experimental models. In the reducing Fe3+ experiment, the activities of the complexes were higher than the corresponding ligands, and complexes of hydrazone reduction were significantly higher than phloretin complexes. In the OH radical scavening assay, the scavenging ability of the complex ligands were increased to varying degrees, excepting hydrazone-Pr complexes. In clear DPPH, ABTS radicals and inhibiting lipid peroxidation experiments, the ability of the complexes showed lower than those of the ligands, not improved. Fluorescence spectroscopy experiments showed that the eight rare earth metal complexes can interact with the BSA and the fluorescence quenching of BSA are due to the formation of static quenching, and the mode of action of BSA are hydrogen bonds and van der Waals force Lord.
引文
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