含氮杂环化合物—吡唑衍生物的设计、合成与生物活性研究
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摘要
吡唑环是很多天然化合物的核心结构之一，越来越多的研究表明吡唑类化合物具有消炎、止痛、退热、抑菌、杀菌、抗高血糖、抗癌、抗凝血剂等药理活性。鉴于吡唑化合物在有机合成以及药物中的重要性，有机合成化学家对吡唑的合成与应用进行了广泛的研究。
本研究的主要目的是以环氧烷为原料，利用吡唑化合物的亲核性进行开环反应，探讨新的反应条件，合成一系列新型吡唑衍生物，进行生物活性评价，筛选有潜力的细胞凋亡诱导剂。
本研究工作包括四部分：
1．以3-芳氧基-1，2-环氧丙烷与3-芳基-1H-吡唑-5-甲酸乙酯为原料，通过碱催化开环反应，区域选择性地合成1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物，收率为62～93％。3-(4-氯苯基)-1-(2-羟基-3-(2-硝基苯氧基)丙基)-1H-吡唑-5-甲酸乙酯由~(13)C NMR、~1H NMR、IR、及HRMS进行了表征，其它产物的结构均由~1H NMR、IR、及HRMS进行了表征。
2．在合成1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物的基础上，对其生物活性进行了研究。生物活性实验的结果表明，15种化合物3a-3o均能有效的抑制A549细胞的繁殖。其中，3i能够有效的抑制A549细胞的生长繁殖；3f能很好的分化A549细胞；3g作用于A549细胞时，能有效的诱导细胞逐渐形成空泡从而导致细胞凋亡。
3．以合成的1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物为原料，首先在氢氧化钾醇溶液中进行水解反应，制备1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸衍生物，收率为84～99％。然后得到的1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸衍生物在对甲苯磺酸存在下通过自身关环内酯化得到6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮衍生物，收率54～98％，产物的结构均由~1H NMR、IR、及MS进行了表征。
4．以3-芳氧基-1，2-环氧丙烷与3-芳香基-1H-吡唑-5-甲酸乙酯为原料，在无溶剂微波照射的条件下进行反应，位置选择性地得到6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮衍生物，收率53～78％，产物的结构均由~1HNMR、IR、及MS进行了表征，提出了合理的反应机理。
总之，本论文通过对环氧烷与取代吡唑的亲核开环反应的研究，合成了1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯、1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸、6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮三个系列的吡唑衍生物，并将一种新颖、高效、绿色的微波辐射的反应方法应用到6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮衍生物的合成中，大大缩短了反应时间，提高了反应效率，并简化了反应操作，提出了新的反应机理。同时对1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物进行了生物活性评价，为研究药物诱导癌细胞凋亡的作用机制，探讨结构与药效的关系奠定了基础。
The pyrazole unit is one of the core structure in a number of natural products. Many pyrazole derivatives are known to exhibit a wide range of biological properties such as anti-hyperglycemic, analgesic, anti-inflammatory, anti-pyretic, anti-bacterial, antifungal hypoglycemic, sedative-hypnotic activity, antitumor and anticoagulant activity. Due to the importance of pyrazole in organic synthesis and drug synthesis, much attention has been paid to the application in many fields.
Using the nucleophilic opening reaction of epoxides by pyrazoles, we intend to explore new conditions for the ring opening reaction, synthesize novel compounds with potent bioactivity and study the bioactivity of the obtained products.
Four aspects were included in this paper:
1. Using 3-aryl-1H-pyrazole-5-carboxylate and 2-aryloxymethyl-epoxide as starting materials, 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives were synthesized region-selectively by the base catalyzed ring opening reaction in 62～93% yields. The structure of 3-(4-chlorophenyl)-1-(2-hydroxy-3-(2-nitro-phenoxy)propyl)-1H-pyrazole-5-carboxylate was characterized by ~(13)C NMR, ~1H NMR, IR and HRMS spectral data. The structures of other compounds were confirmed by ~1H NMR, IR and HRMS.
2. We studied the bioactivity of 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives, and the biological evaluation results showed that fifteen compounds could suppress A549 lung cancer cell growth. Among of them, compound 3i was the most effective small molecule in inhibiting A549 cell growth; Compound 3f might most effectively induce A549 cell differentiation; Compound 3g remarkably induced cellular vacuolation.
3. Based on the obtained 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives, 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c] [1, 4]-oxazin-4-one derivatives were synthesized more efficiently in two steps. The hydrolysis reaction of 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives with alcoholic KOH afforded 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylic add derivatives in 84-99% yields. Then the ring-closure reaction of the isolated carboxylic add in the presence of p-TsOH yielded the desired 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c][1, 4]oxazin-4-one derivatives in 54-98% yields. The structures of 15 compounds were characterized by ~1H NMR, IR and MS spectral data.
4. The reaction of 3-aryl-1H-pyrazole-5-carboxylate with 2-aryloxy- methylepoxide under solvent free conditions and microwave irradiation afforded 15 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c][1, 4]-oxazin-4-one derivatives. The reaction was carried rapidly and regioselectively in 53-78% yields. The structures of the products were confirmed by IR, MS and ~1H NMR.
In conclusion, we synthesized a series of useful intermediates and many important products with bioactivity by the nudeophilic ring-opening reaction of epoxides and substituted pyrazoles,. Furthermore, we proposed a novel and effident method that is friendly to environment for the synthesis of 6-(aroxymethyl)-2-aryl-6, 7-dihydro-pyrazolo[5, 1-c][1, 4]oxazin-4-one derivatives. Moreover, we synthesized a series of novel 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives that paves the way for studying the structure-activity relationship of this class of drugs and builds up basis for research and development of novel agents with inhibitory activity against cancer cell growth.
本研究的主要目的是以环氧烷为原料，利用吡唑化合物的亲核性进行开环反应，探讨新的反应条件，合成一系列新型吡唑衍生物，进行生物活性评价，筛选有潜力的细胞凋亡诱导剂。
本研究工作包括四部分：
1．以3-芳氧基-1，2-环氧丙烷与3-芳基-1H-吡唑-5-甲酸乙酯为原料，通过碱催化开环反应，区域选择性地合成1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物，收率为62～93％。3-(4-氯苯基)-1-(2-羟基-3-(2-硝基苯氧基)丙基)-1H-吡唑-5-甲酸乙酯由~(13)C NMR、~1H NMR、IR、及HRMS进行了表征，其它产物的结构均由~1H NMR、IR、及HRMS进行了表征。
2．在合成1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物的基础上，对其生物活性进行了研究。生物活性实验的结果表明，15种化合物3a-3o均能有效的抑制A549细胞的繁殖。其中，3i能够有效的抑制A549细胞的生长繁殖；3f能很好的分化A549细胞；3g作用于A549细胞时，能有效的诱导细胞逐渐形成空泡从而导致细胞凋亡。
3．以合成的1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物为原料，首先在氢氧化钾醇溶液中进行水解反应，制备1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸衍生物，收率为84～99％。然后得到的1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸衍生物在对甲苯磺酸存在下通过自身关环内酯化得到6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮衍生物，收率54～98％，产物的结构均由~1H NMR、IR、及MS进行了表征。
4．以3-芳氧基-1，2-环氧丙烷与3-芳香基-1H-吡唑-5-甲酸乙酯为原料，在无溶剂微波照射的条件下进行反应，位置选择性地得到6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮衍生物，收率53～78％，产物的结构均由~1HNMR、IR、及MS进行了表征，提出了合理的反应机理。
总之，本论文通过对环氧烷与取代吡唑的亲核开环反应的研究，合成了1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯、1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸、6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮三个系列的吡唑衍生物，并将一种新颖、高效、绿色的微波辐射的反应方法应用到6-(芳香氧基甲基)-2-芳香基-6，7-二氢-4H-吡唑并[5，1-c][1，4]噁嗪-4-酮衍生物的合成中，大大缩短了反应时间，提高了反应效率，并简化了反应操作，提出了新的反应机理。同时对1-(2-羟基-3-芳香氧基丙基)-3-芳香基-1H-吡唑-5-甲酸乙酯衍生物进行了生物活性评价，为研究药物诱导癌细胞凋亡的作用机制，探讨结构与药效的关系奠定了基础。
The pyrazole unit is one of the core structure in a number of natural products. Many pyrazole derivatives are known to exhibit a wide range of biological properties such as anti-hyperglycemic, analgesic, anti-inflammatory, anti-pyretic, anti-bacterial, antifungal hypoglycemic, sedative-hypnotic activity, antitumor and anticoagulant activity. Due to the importance of pyrazole in organic synthesis and drug synthesis, much attention has been paid to the application in many fields.
Using the nucleophilic opening reaction of epoxides by pyrazoles, we intend to explore new conditions for the ring opening reaction, synthesize novel compounds with potent bioactivity and study the bioactivity of the obtained products.
Four aspects were included in this paper:
1. Using 3-aryl-1H-pyrazole-5-carboxylate and 2-aryloxymethyl-epoxide as starting materials, 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives were synthesized region-selectively by the base catalyzed ring opening reaction in 62～93% yields. The structure of 3-(4-chlorophenyl)-1-(2-hydroxy-3-(2-nitro-phenoxy)propyl)-1H-pyrazole-5-carboxylate was characterized by ~(13)C NMR, ~1H NMR, IR and HRMS spectral data. The structures of other compounds were confirmed by ~1H NMR, IR and HRMS.
2. We studied the bioactivity of 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives, and the biological evaluation results showed that fifteen compounds could suppress A549 lung cancer cell growth. Among of them, compound 3i was the most effective small molecule in inhibiting A549 cell growth; Compound 3f might most effectively induce A549 cell differentiation; Compound 3g remarkably induced cellular vacuolation.
3. Based on the obtained 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives, 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c] [1, 4]-oxazin-4-one derivatives were synthesized more efficiently in two steps. The hydrolysis reaction of 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives with alcoholic KOH afforded 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylic add derivatives in 84-99% yields. Then the ring-closure reaction of the isolated carboxylic add in the presence of p-TsOH yielded the desired 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c][1, 4]oxazin-4-one derivatives in 54-98% yields. The structures of 15 compounds were characterized by ~1H NMR, IR and MS spectral data.
4. The reaction of 3-aryl-1H-pyrazole-5-carboxylate with 2-aryloxy- methylepoxide under solvent free conditions and microwave irradiation afforded 15 6-(aroxymethyl)-2-aryl-6, 7-dihydropyrazolo[5, 1-c][1, 4]-oxazin-4-one derivatives. The reaction was carried rapidly and regioselectively in 53-78% yields. The structures of the products were confirmed by IR, MS and ~1H NMR.
In conclusion, we synthesized a series of useful intermediates and many important products with bioactivity by the nudeophilic ring-opening reaction of epoxides and substituted pyrazoles,. Furthermore, we proposed a novel and effident method that is friendly to environment for the synthesis of 6-(aroxymethyl)-2-aryl-6, 7-dihydro-pyrazolo[5, 1-c][1, 4]oxazin-4-one derivatives. Moreover, we synthesized a series of novel 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate derivatives that paves the way for studying the structure-activity relationship of this class of drugs and builds up basis for research and development of novel agents with inhibitory activity against cancer cell growth.
引文
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