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题名: 查尔酮衍生物类似物的合成及其酪氨酸酶活性研究
作者: 牛超
答辩日期: 2014-05-30
导师: 阿吉
专业: 有机化学
授予单位: 中国科学院大学
授予地点: 北京
学位: 博士
关键词: 酪氨酸酶 ; 白癜风 ; 驱虫斑鸠菊 ; 查尔酮 ; 单晶结构
摘要: 白癜风是一种后天、自发的慢性皮肤疾病,其主要症状为皮肤上出现形状不规则的浅色或白色斑驳,多发生于10 周岁以后,发病率为1%左右。目前认为病灶部位皮肤中黑素细胞的的减少甚至消失是引起白癜风的主要原因,但是其具体机制并不明确。例如:人体皮肤和毛囊中黑素细胞内的酪氨酸酶活性减低或消失,导致黑色素生成减少或消失,就会引起白癜风。
酪氨酸酶(Tyrosinase,EC:1.14.18.1)广泛地存在于微生物,动物和植物中,是一种含铜离子的氧化还原酶,酪氨酸酶在黑素合成反应中起重要的催化作用。在分子氧的存在下,酪氨酸酶先将酪氨酸羟化形成多巴(单酚酶或甲酚酶活性),再将多巴氧化为多巴醌(双酚酶或儿茶酚酶活性),后者经过一系列复杂的反应最终生成黑色素。驱虫斑鸠菊(Vernonia anthelmintica Willd.)作为新疆特有植物,是维吾尔医治疗白癜风的常用药物。研究表明驱虫斑鸠菊中的黄酮成分可以激活酪氨酸酶活性,改善黑素的生物合成,对于治疗白癜风起着重要的作用。本论文第一章对酪氨酸酶在黑素合成中的重要作用进行了系统阐述,同时对白癜风治疗药物做了简单的介绍。此外,还介绍了驱虫斑鸠菊在治疗白癜风中的应用。第二章,以驱虫斑鸠菊中的查尔酮化合物为参考,利用经典的缩合反应合成了多羟基查尔酮和二氢黄酮两个系列共22 个化合物,并对所合成的化合物进行了酪氨酸酶活性研究。其中5 个化合物表现出了一定的酪氨酸酶抑制活性,化合物3, 4, 2´, 4´, 6´-五羟基查尔酮(15a)表现出了接近阳性对照-曲酸的抑制活性;化合物7-羟基二氢黄酮(1b)、7, 4´-二羟基二氢黄酮(2b)、 7, 3´, 4´-三羟基二氢黄酮(3b)、5, 7, 3´, 4´-四羟基二氢黄酮(4b)则表现出了酪氨酸酶的激动活性。第三章,通过对先导化合物4-二甲氨基-4´-甲氧基查尔酮(24a, EC50=17.1 μM)的结构改造,设计并合成了取代查尔酮和查尔酮类似物共21 个化合物,对合成的化合物进行了酪氨酸酶活性研究。发现化合物4-二甲氨基-4´-氨基查尔酮(34a)、1-(6-甲氧基萘-2-基)-3-(4-二甲氨基苯基)-2-丙烯-1-酮(1h)、1-(2-吡啶基)-3-(4-二甲氨基苯基)-2-丙烯-1-酮(2h)表现出了比24a 稍弱的酪氨酸酶激动活性。经过培养得到了化合物24a 和1-(4-甲氧基苯基)-3-(9-蒽基)-2-丙烯-1-酮(2i)的单晶。第四章,以4´-氨基查尔酮为原料合成了8 个新型的含苯并噻唑环的查尔酮衍生物及8 个酰胺查尔酮。酪氨酸酶活性测试结果表明:化合物4-氯-4′-对甲苯磺酰胺基查尔酮(4h)、4-氯-4′-苯甲酰胺基查尔酮(4d)、1-(2-氨基-1, 3-苯并噻唑-6-基) -3-(4-氯苯基)-2-丙烯-1-酮(5d)、1-(2-苯甲酰胺基-1, 3-苯并噻唑-6-基) -3-(4-甲基苯基)-2-丙烯-1-酮(7b)、1-(2-苯甲酰胺基-1, 3-苯并噻唑-6-基)-3-(4-氯苯基)-2-丙烯-1-酮(7d)表现出酪氨酸酶激动活性。其中7d 对酪氨酸酶的激动活性最好,其EC50=9.6 μM,好于阳性对照药8-MOP 的EC50=14.8 μM。第五章,基于“点击化学”合成了(E)-1-(4-((1-苄基-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮(1a-15a)和(E)-3-(4-((1-苄基-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-1-苯基-2-丙烯-1-酮(1b-15b)两个系列共30 个全新化合物。酪氨酸酶活性测试结果表明,所有15 个A 环被取代的查尔酮衍生物均表现出酪氨酸酶激动活性,化合物1-(4-((1-(3-甲氧基苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮(3a)、1-(4-((1-(3-氯苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮(8a)、1-(4-((1-(4-氯苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮 (9a)、1-(4-((1-(3, 4-二氯苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮(10a)、1-(4-((1-(3-氟苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮(14a)、1-(4-((1-(4-氟苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-3-苯基-2-丙烯-1-酮(15a)能够激活酪氨酸酶活性,其中10a 和14a 活性最好,优于阳性对照8-MOP;相反,化合物1-苯基-3-(4-((1-(3-甲氧基苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-2-丙烯-1-酮(3b)、1-苯基-3-(4-((1-(4-氰基苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-2-丙烯-1-酮(5b)、1-苯基-3-(4-((1-(4-硝基苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-2-丙烯-1-酮(6b)、1-苯基-3-(4-((1-(4-氯苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-2-丙烯-1-酮(9b)、1-苯基-3-(4-((1-(3, 4-二氯苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-2-丙烯-1-酮(10b)和1-苯基-3-(4-((1-(4-氟苄基)-1H-1, 2, 3-三氮唑-4-基)甲氧基)苯基)-2-丙烯-1-酮(15b)则表现出了较弱的酪氨酸酶抑制活性。经过培养共得到了5 个目标化合物的单晶。本文共和成了89 个化合物,新化合物40 个。其中6 个化合物具有酪氨酸酶抑制活性,18 个化合物具有较好的酪氨酸酶激动活性。本论文的研究结果将为酪氨酸酶激动剂的筛选提供新的化合物,同时为进一步发现和创制新的白癜风治疗药物奠定基础。
英文摘要:
Vitiligo is an acquired, idiopathic, chronic skin disease characterized by circumscribed irregular depigmented macules, generally during the second decade of life and affecting approximately 1% of the population worldwide. Absence of melanocytes from the lesional skin due to their destruction has been suggested to be the key event in the pathogenesis of vitiligo. However, its etiology is still being debated. For example, the less production of melanin resulting from the decrease in the activity of the tyrosinase in melanocytes of human skin and hair follicles, may provoke the vitiligo. Tyrosinase is a copper-containing enzyme which is widely distributed in microorganism,animals and plants. Tyrosinase played an important role in the melanin synthesis. The steps in the pathway are the hydroxylation of monophenol to o-diphenol (monophenolase or cresolase activity) and the oxidation of diphenol to o-quinones (diphenolase or catecholase activity), both using molecular oxygen followed by a series of nonenzymatic steps resulting in the formation of melanin. The Vernonia anthelmintica Willd., was an endemic plant in Xinjiang, which was often used in the treatment of Vitiligo in traditional Uighur medicine. It was believed that the flavone compounds of Ver-nohia anthelmintica Willd. played an important role in this treatment. Since it may activate tyrosinase and improve the melanin production. The first chapter reviewed the crucial role of tyrosinase in melanin synthesis,Meanwhile, the drugs for vitiligo were discussed. Additionally, the application of the Vernonia anthelmintica Willd. in treament of vitiligo was introduced as well. In the second chapter, two series of polyhydroxylated chalcones and flavanones were synthesized via the Claisen-Schmidt condensation, taking the chalcone compounds separated from Vernonia anthelmintica Willd. as reference. All the synthesized compounds have been screened for their activity on tyrosinase. The compound 3, 4, 2′, 4′, 6′-pentahydroxychalcone (BDFTP-D101015) possessed similar inhibitory activity on tyrosinase to kojic acid, Five compounds showed some inhibition effect; However, compounds 7-hydroxyflavanone (BDFTP-D102001), 7, 4′-dihydroxyflavanone (BDFTP-D102002), 7, 3′, 4′-trihydroxyflavanone (BDFTP-D102003), 5, 7, 3′, 4′-tetra hydroxyflavanone (BDFTP-D102004) possessed activator effect on tyrosinase. In the third chapter, Based on compound 4-dimethylamino-4′-methoxychalcone(BDFTP-D101024, EC50=17.1μM), a series of substituted chalcones and analogues was designed and synthesized, After evalution of activity on tyrosinase, the compounds 4-dimethylamino-4′-aminochalcone (BDFTP-D101034), 3-(4-(dimethylamino)phenyl)-1-(6-methoxynaphthalen-2-yl)-2-en-1-one (BDFTP-D108001) and 3-(4-(dimethylamino)phenyl)-1-(pyridin-2-yl)-2-en-1-one (BDFTP-D108002) were found to exhibit much lower activator effect on tyrosinase when compared with BDFTP-D101024. Single crystal of BDFTP-D101024 and 3-(anthracen-9-yl)-1-(4-methoxyphenyl)-2-en-1-one (BDFTP-D109002) were got. In the fourth chapter, Eight novel chalcone derivatives containing benzothiazole and eight amide chalcone compounds were synthesized using 4-amiochalcone as raw material. All the 16 compounds were evaluated their activator effect on tyrosinase. Compared with the reference drug 8-Methoxypsoralen, compounds 4-chloro-4′-(4-toluenesulfonamido)chalcone (4h), 4-chloro-4′-benzoylaminochalcone (4d),1-(2-amino-1,3-benzothiazole-6-yl)-3-(4-chlorophenyl)-2-en-1-one(5d), 1-(2-benzoylamino-1, 3-benzothiazole-6-yl)-3-(4-methylphenyl)-2-en-1-one(7b), 1-(2-benzoylamino-1, 3-benzothiazole-6-yl)-3-(4-chlorophenyl)-2-en-1-one(7d) showed some activator effect on tyrosinase. Amomg them, 7d demonstrated better activity with EC50=9.6 μM than 8-Methoxypsoralen , which EC50 was 14.8 μM. Two new series of 1-(4-((1-benzyl-1H-1, 2, 3-triazol-4-yl)methoxy) phenyl)-3-phenyl-2-en-1-one and 3-(4-((1-benzyl-1H-1, 2, 3-triazol-4-yl)methoxy)phenyl)-1-phenyl-
内容类型: 学位论文
URI标识: http://ir.xjipc.cas.cn/handle/365002/3416
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作者单位: 中国科学院新疆理化技术研究所

Recommended Citation:
牛超. 查尔酮衍生物类似物的合成及其酪氨酸酶活性研究[D]. 北京. 中国科学院大学. 2014.
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