哌嗪类化合物的合成与表征及其生物活性的测定
摘要
本课题研究的主要目的为：合成含有前手性的哌嗪衍生物，通过微生物的筛选，初步探索其转化为手性哌嗪衍生物的条件，同时对这些化合物进行生物活性测试，探明其是否具有活性；尽量探索出更多的合成路线，为本课题组的后续工作做好铺垫。
在本课题的研究过程中，我们使用乙氧羰基作为保护基团，选择了苯乙酮类化合物(苯乙酮、对甲氧基苯乙酮、对氟苯乙酮和2,4-二氟苯乙酮)作为哌嗪的前手性基团，合成了一系列具有前手性的哌嗪衍生物。并对1-乙氧羰基-4-苯乙酮基哌嗪氢溴酸盐这一系列化合物进行了抗肿瘤活性试验，另外还初步探索了2-甲基哌嗪、扁桃酸和1-环氧丙基哌嗪等化合物的合成路线。
一论文工作期间合成化合物20个，其中未见文献报道化合物2个，从结构分析，可以用于微生物转化的前手性化合物有17个。
二合成方法操作简便易行，产率较高，具有很好的工业应用前景。
三1-乙氧羰基-4-苯乙酮基哌嗪氢溴酸盐这一系列化合物对于人肺腺癌细胞A549，均有很好的抑制率，其ID_(50)均在37.5(μmol/L)以内，特别是1-乙氧羰基-4-(2，4-二氟苯乙酮基)-哌嗪氢溴酸盐活性最强，当浓度是2.344μmol/L时抑制率已达38.5％，且随着浓度的增加对细胞的抑制作用迅速增加，当9.375μmol/L时大部分细胞已被抑制。因此这一系列化合物具有潜在的抗肿瘤药用价值，也许能够改良吡酮酸类药物的抗肿瘤活性。这部分工作及其结果未见文献报道。
四通过微生物转化的尝试，我们得到了苯甲酸，但这不是我们期望的产物，所以还需要应该进一步的筛选微生物。我们通过碱性水解的化学方法得到了产物之一，但是因产率太低，目前还不适用，以后可以进行酸性水解试验。
五合成的1-乙酰基-3-甲基哌嗪、1-苯甲酰基-3-甲基哌嗪、扁桃酸乙酯以及1-环氧丙基哌嗪等类化合物均可以进行生物转化，这三条路线也非常有发展前途。
The main purpose of this study is to synthesis prochiral piperazine derivatives. To explore initially the conditions which transformed into chiral piperazine derivatives through microbial screening, to prove whether they have activity through bioactivity test; and to explore more synthesis routes for our following work.
In this study, we used ethoxycarbonyl as a protection group, and chose acetophenone compounds (acetophenone, p-Methoxyacetophenone, p-fluoroacetophenone and 2,4-difluoroacetophenone) as piperazine prochiral group to synthesized a series of prochiral piperazine derivatives. At the same time we tested anticancer activity of the compounds such as 1-ethoxycarbonyl-4-acetophenonepiperazine dihydrobrohide. Moreover we initially explored the synthetic routes of many compounds such as 2-methylpiperazine, mandelic acid and 1-epoxypropylpiperazine.
1. 20 compounds have been prepared in this thesis, 2 of which have never reported. 17 of them can be used for microbialtransformation from the point of structural analysis.
2. As the method is simple, easy, and with relatively high yield, it is of good use in industry.
3. A series of compounds such as 1-ethoxycarbonyl-4-acetophenonepiperazine dihydrobrohide have good inhibition ratio on human lung adenocarcinoma cell line A549, whose ID_(50) were all within 37.5(umol/L). Especially 1-ethoxycarbonyl-4-(2,4 -difluoro-acetophenone)-piperazine dihydrobrohide is more active than any other compounds. The inhibition rate has reached 38.5% when the concentration is only 2.344μmol/L, and the more the concentration increase the more the inhibition rate increase quickly. Most cells were inhibited when the concentration is 9.375μmol/L. So some of these compounds have shown the potential value of anti-cancer medicinal. It may be able to improve the antitumor activity of pyridonecarboxylic acids. The results of this parts have never reported.
4. Through the microbialtransformation, we got benzoic acid. But it was not the product which we expected. So further screening of microorganism is needed. We obtained one of the products through the alkaline hydrolysis method, but this method still not applicable because of the low yield. The acidic hydrolysis can be tested in futrue.
5. 1-Acetyl-3-methylpiperazine, 1-Benzoyl-3-methylpiperazine, Ethylmandelate and 1-oxiranylmethylpiperazine etc. which we synthetized can all be used for microbialtransformation. These three routes are also promising.
在本课题的研究过程中，我们使用乙氧羰基作为保护基团，选择了苯乙酮类化合物(苯乙酮、对甲氧基苯乙酮、对氟苯乙酮和2,4-二氟苯乙酮)作为哌嗪的前手性基团，合成了一系列具有前手性的哌嗪衍生物。并对1-乙氧羰基-4-苯乙酮基哌嗪氢溴酸盐这一系列化合物进行了抗肿瘤活性试验，另外还初步探索了2-甲基哌嗪、扁桃酸和1-环氧丙基哌嗪等化合物的合成路线。
一论文工作期间合成化合物20个，其中未见文献报道化合物2个，从结构分析，可以用于微生物转化的前手性化合物有17个。
二合成方法操作简便易行，产率较高，具有很好的工业应用前景。
三1-乙氧羰基-4-苯乙酮基哌嗪氢溴酸盐这一系列化合物对于人肺腺癌细胞A549，均有很好的抑制率，其ID_(50)均在37.5(μmol/L)以内，特别是1-乙氧羰基-4-(2，4-二氟苯乙酮基)-哌嗪氢溴酸盐活性最强，当浓度是2.344μmol/L时抑制率已达38.5％，且随着浓度的增加对细胞的抑制作用迅速增加，当9.375μmol/L时大部分细胞已被抑制。因此这一系列化合物具有潜在的抗肿瘤药用价值，也许能够改良吡酮酸类药物的抗肿瘤活性。这部分工作及其结果未见文献报道。
四通过微生物转化的尝试，我们得到了苯甲酸，但这不是我们期望的产物，所以还需要应该进一步的筛选微生物。我们通过碱性水解的化学方法得到了产物之一，但是因产率太低，目前还不适用，以后可以进行酸性水解试验。
五合成的1-乙酰基-3-甲基哌嗪、1-苯甲酰基-3-甲基哌嗪、扁桃酸乙酯以及1-环氧丙基哌嗪等类化合物均可以进行生物转化，这三条路线也非常有发展前途。
The main purpose of this study is to synthesis prochiral piperazine derivatives. To explore initially the conditions which transformed into chiral piperazine derivatives through microbial screening, to prove whether they have activity through bioactivity test; and to explore more synthesis routes for our following work.
In this study, we used ethoxycarbonyl as a protection group, and chose acetophenone compounds (acetophenone, p-Methoxyacetophenone, p-fluoroacetophenone and 2,4-difluoroacetophenone) as piperazine prochiral group to synthesized a series of prochiral piperazine derivatives. At the same time we tested anticancer activity of the compounds such as 1-ethoxycarbonyl-4-acetophenonepiperazine dihydrobrohide. Moreover we initially explored the synthetic routes of many compounds such as 2-methylpiperazine, mandelic acid and 1-epoxypropylpiperazine.
1. 20 compounds have been prepared in this thesis, 2 of which have never reported. 17 of them can be used for microbialtransformation from the point of structural analysis.
2. As the method is simple, easy, and with relatively high yield, it is of good use in industry.
3. A series of compounds such as 1-ethoxycarbonyl-4-acetophenonepiperazine dihydrobrohide have good inhibition ratio on human lung adenocarcinoma cell line A549, whose ID_(50) were all within 37.5(umol/L). Especially 1-ethoxycarbonyl-4-(2,4 -difluoro-acetophenone)-piperazine dihydrobrohide is more active than any other compounds. The inhibition rate has reached 38.5% when the concentration is only 2.344μmol/L, and the more the concentration increase the more the inhibition rate increase quickly. Most cells were inhibited when the concentration is 9.375μmol/L. So some of these compounds have shown the potential value of anti-cancer medicinal. It may be able to improve the antitumor activity of pyridonecarboxylic acids. The results of this parts have never reported.
4. Through the microbialtransformation, we got benzoic acid. But it was not the product which we expected. So further screening of microorganism is needed. We obtained one of the products through the alkaline hydrolysis method, but this method still not applicable because of the low yield. The acidic hydrolysis can be tested in futrue.
5. 1-Acetyl-3-methylpiperazine, 1-Benzoyl-3-methylpiperazine, Ethylmandelate and 1-oxiranylmethylpiperazine etc. which we synthetized can all be used for microbialtransformation. These three routes are also promising.
引文
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[2] 王文详，刘洪杰．哌嗪的合成与应用[J]．河南化工．1995(7)：28-30
[3] 贺以乐．哌嗪的合成应用及市场趋势[J]．化工中间体．2002，10：3-5
[4] 陈修，陈维洲，曾贵云．心血管药理学[M]．北京：人民卫生出版社，1997
[5] 石津生．高血压药物治疗进展[J]．现代实用医学．2001，13(2)：55-58
[6] Fukiage, Chiho A, Mitsuyoshi I, et al. Angiogenesis inhibitor[P]. US 6214800 20010410
[7] Dhainaut A, Regnier G, A tassi G, et al. New triazine derivatives as potent modulators ofmultidrug resistance[J]. J Med Chem, 1992,35:2481-2496
[8] Dhainaut A, Regnier G, Tiyot A, et al. New purines and purine analogs as modulators of multidrug resistance[J]. J Med Chem, 1996,39:4099-4108
[9] 李建其，黄丽英，张椿年等．芳烷酮哌嗪衍生物及其应用[P]．CN 1381449A 02111786.1
[10] 秦伟程．哌嗪发展前景广阔[J]．上海化工．2001，14：38-39
[11] 张竞．哌嗪的合成及市场．四川化工与腐蚀控制[J]．2002，5(5)：49-52
[12] 尤田耙．于性化合物的现代研究方法[M]．合肥：中国科技大学出版社，1993
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