系列黄酮类化合物的合成以及生物活性评价
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摘要
黄酮类化合物是天然产物中的一大类,具有广泛的生物活性。大多数此类化合物溶解性能较差、生物利用度不高、生物活性不够强而限制了其药用开发。如果以黄酮类化合物作为先导,对其进行结构修饰,研究结构与其活性之间的关系。通过活性优化就有可能发现活性更好、具有药用开发前景的衍生物。因此,设计和合成结构多样性黄酮类化合物库就显得非常必要。
本文在对改进的Baker-Venkataraman重排反应系统研究的基础上,设计合成了29个黄酮类化合物,建立了一个小规模化合物库。其中7个未见文献报道,还有5个β-丙二酮类化合物也是首次报道。这为黄酮类化合物生物活性的评价奠定了基础。
为了增强黄酮类化合物的脂溶性和药效作用,本文将合成得到的6-羟基黄酮和7-羟基黄酮在碳酸钾的丙酮溶液中与苯甲酰氯反应,得到了4种未见文献报道的6-苯甲酰氧基黄酮和7-苯甲酰氧基黄酮及其衍生物。化合物的脂溶性得到了改善。为了增强黄酮类化合物的水溶性和药效作用,将7-羟基黄酮和1-氯-3-溴丙烷反应生成7-(3-氯丙氧基)-黄酮,接着与诺氟沙星发生亲核取代。首次成功的将诺氟沙星连在了黄酮的7-位羟基上。化合物的水溶性得到了改善。
以HeLa细胞为靶细胞,采用MTT法对合成的黄酮及p-丙二酮类化合物进行了抗肿瘤活性初步筛选。优选出具有潜在抗肿瘤活性的化合物25,31和13b。其IC50值分别为19.4μM,87.9μM和95.5μM。用滤纸片法对合成的黄酮和p-丙二酮类化合物进行抗菌活性初步筛选。优选出的化合物25对铜绿假单胞菌和大肠杆菌具有较强的抑制作用。其MIC值分别为2.5mg/mL和0.313mg/mL。该化合物对金黄色葡萄球菌无抑制作用。其余化合物对铜绿假单胞菌和金黄色葡萄球菌均无明显的抗菌活性。1-(2-羟基苯基)-3-(4'-氯苯基)-1,3-丙二酮、4'-氯-7-羟基黄酮对铜绿假单胞菌swarmming运动能力有一定的抑制作用。4'-甲基-6-苯甲酰氧基黄酮对铜绿假单胞菌swarmming运动能力有一定的促进作用。
Flavonoids are a large group of natural products with a wide range of biological activities. Most of them lack enough bioavailability. The bioactivity of this type compound is also not strong enough for the drug development. If the flavonoids are used as lead compound, the structure modification and structure activity relation study will improve the potency of bioactivity and bioavailibility. Optimized structure based on SAR study will have possibility to be found for the drug discovery. Therefore, the design and synthesize of diverse structure of this type compounds are necessary.
In this dissertation,29flavonoids were designed and syntheseized based on the modified Baker-Venkataraman's rearrange reaction.7of which have not reported before.5of β-malonyl ketone compounds were syntheseized for the first time. The prepared compounds provided a possibility for the biological activity assay.
In order to enhance the solubility in lipophilic solvent and pharmacodynamic effects of flavonoids, four6-benzoyloxyflavone and7-benzoyloxyflavone and their derivatives are prepared by the reaction of6-hydroxyflavone and7-hydroxyflavone with benzoyl chloride in acetone solution in the presenee of potassium carbonate. All of the four compounds are not repeorted so far in the literature. The solubility of these compounds in lipophilic solvent is improved indeed.
In order to enhance the water-solublity and pharmacodynamic effects of flavono-ids, the7-(3-chloropropyloxy)-flavone was synthesized by the reaction of7-hydroxyflavone with1-chloro-3-bromine propane. Then norfloxacin was connected to position7in A-ring of flavone by the nucleophilic substitution of7-(3-chloropropyloxy)-flavonewith norfloxacin. The water-solublity of the synthesized compound has been improved greatly.
Anti-tumor activities of the synthesized flavonoids and β-malonyl ketone compounds were evaluated against HeLa cells lines in vitro by the standard MTT method. The result showed that compounds25,31,and13b have antiproliferative activities against HeLa cell lines with IC50values of19.4μM,87.9μM and95.5μM respectively。
Antibacterial activities of flavonoids and P-malonyl ketone compounds were studied by the method of filter paper. The results showed that compound25have activity to inhibit P. aeruginosa and E. coli with IC50values of2.5and0.313mg/mL respectively and has no activity to inhibit Staphylococcus aureus. The remaining38compounds have no antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. The compounds1-(2-hydroxy phenyl)-3-(4'-chlorophenyl)-1,3-propanedione and4'-chloro-7-dihydroxyflavone can inhibit swarmming athletic ability of Pseudomonas aeruginosa. While the compound4'-methyl-6-benzoyloxyflavone can improve swarmming athletic ability of Pseudomonas aeruginosa.
本文在对改进的Baker-Venkataraman重排反应系统研究的基础上,设计合成了29个黄酮类化合物,建立了一个小规模化合物库。其中7个未见文献报道,还有5个β-丙二酮类化合物也是首次报道。这为黄酮类化合物生物活性的评价奠定了基础。
为了增强黄酮类化合物的脂溶性和药效作用,本文将合成得到的6-羟基黄酮和7-羟基黄酮在碳酸钾的丙酮溶液中与苯甲酰氯反应,得到了4种未见文献报道的6-苯甲酰氧基黄酮和7-苯甲酰氧基黄酮及其衍生物。化合物的脂溶性得到了改善。为了增强黄酮类化合物的水溶性和药效作用,将7-羟基黄酮和1-氯-3-溴丙烷反应生成7-(3-氯丙氧基)-黄酮,接着与诺氟沙星发生亲核取代。首次成功的将诺氟沙星连在了黄酮的7-位羟基上。化合物的水溶性得到了改善。
以HeLa细胞为靶细胞,采用MTT法对合成的黄酮及p-丙二酮类化合物进行了抗肿瘤活性初步筛选。优选出具有潜在抗肿瘤活性的化合物25,31和13b。其IC50值分别为19.4μM,87.9μM和95.5μM。用滤纸片法对合成的黄酮和p-丙二酮类化合物进行抗菌活性初步筛选。优选出的化合物25对铜绿假单胞菌和大肠杆菌具有较强的抑制作用。其MIC值分别为2.5mg/mL和0.313mg/mL。该化合物对金黄色葡萄球菌无抑制作用。其余化合物对铜绿假单胞菌和金黄色葡萄球菌均无明显的抗菌活性。1-(2-羟基苯基)-3-(4'-氯苯基)-1,3-丙二酮、4'-氯-7-羟基黄酮对铜绿假单胞菌swarmming运动能力有一定的抑制作用。4'-甲基-6-苯甲酰氧基黄酮对铜绿假单胞菌swarmming运动能力有一定的促进作用。
Flavonoids are a large group of natural products with a wide range of biological activities. Most of them lack enough bioavailability. The bioactivity of this type compound is also not strong enough for the drug development. If the flavonoids are used as lead compound, the structure modification and structure activity relation study will improve the potency of bioactivity and bioavailibility. Optimized structure based on SAR study will have possibility to be found for the drug discovery. Therefore, the design and synthesize of diverse structure of this type compounds are necessary.
In this dissertation,29flavonoids were designed and syntheseized based on the modified Baker-Venkataraman's rearrange reaction.7of which have not reported before.5of β-malonyl ketone compounds were syntheseized for the first time. The prepared compounds provided a possibility for the biological activity assay.
In order to enhance the solubility in lipophilic solvent and pharmacodynamic effects of flavonoids, four6-benzoyloxyflavone and7-benzoyloxyflavone and their derivatives are prepared by the reaction of6-hydroxyflavone and7-hydroxyflavone with benzoyl chloride in acetone solution in the presenee of potassium carbonate. All of the four compounds are not repeorted so far in the literature. The solubility of these compounds in lipophilic solvent is improved indeed.
In order to enhance the water-solublity and pharmacodynamic effects of flavono-ids, the7-(3-chloropropyloxy)-flavone was synthesized by the reaction of7-hydroxyflavone with1-chloro-3-bromine propane. Then norfloxacin was connected to position7in A-ring of flavone by the nucleophilic substitution of7-(3-chloropropyloxy)-flavonewith norfloxacin. The water-solublity of the synthesized compound has been improved greatly.
Anti-tumor activities of the synthesized flavonoids and β-malonyl ketone compounds were evaluated against HeLa cells lines in vitro by the standard MTT method. The result showed that compounds25,31,and13b have antiproliferative activities against HeLa cell lines with IC50values of19.4μM,87.9μM and95.5μM respectively。
Antibacterial activities of flavonoids and P-malonyl ketone compounds were studied by the method of filter paper. The results showed that compound25have activity to inhibit P. aeruginosa and E. coli with IC50values of2.5and0.313mg/mL respectively and has no activity to inhibit Staphylococcus aureus. The remaining38compounds have no antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. The compounds1-(2-hydroxy phenyl)-3-(4'-chlorophenyl)-1,3-propanedione and4'-chloro-7-dihydroxyflavone can inhibit swarmming athletic ability of Pseudomonas aeruginosa. While the compound4'-methyl-6-benzoyloxyflavone can improve swarmming athletic ability of Pseudomonas aeruginosa.
引文
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