靛红衍生物的多样性合成及其生物活性研究
文献类型：学位论文
| 作者 | 陈刚 |
| 学位类别 | 博士 |
| 答辩日期 | 2007-06-01 |
| 授予单位 | 中国科学院昆明植物研究所 |
| 授予地点 | 昆明植物研究所 |
| 导师 | 郝小江 |
| 关键词 | 靛红 衍生物 多样性合成 生物活性 |
| 其他题名 | Diversity-Oriented Synthesis and Bioactivity Evaluation of Isatin Derivatives |
| 学位专业 | 植物学 |
| 中文摘要 | 本论文主要包括两个方面的工作，即靛红（吲哚-2，3-二酮）衍生物的多样性合成及其生物活性研究：共合成了8个系列的靛红衍生物，优化了反应条件、讨论了反应机理；同时，对化合物在抑菌、抗病毒、抗肿瘤、神经保护等方面的生物活性进行了初步筛选。此外，还对靛红及其衍生物的生物活性研究进展进行了文献综述。 第一章通过取代反应合成了（N-取代）-靛红，又经甲基酮与靛红/（N-取代）-靛红的Aldol加成反应合成了系列类似物。对合成的化合物进行了抗H2O2致PC12细胞损伤和抑制P388小鼠白血病和A-549人肺腺癌肿瘤细胞活性的初步筛选，发现（N-取代）-靛红有一定的活性，而3-羟基-3-（2´-氧-丙基）-吲哚-2-酮类似物没有活性或者活性很低，并对可能的作用机制进行了讨论。 第二章鉴于3-羟基-3-（2´-氧-丙基）-吲哚-2-酮对TMV的系统诱导抗性，研究了高效、快速、规模化合成该化合物的方法。发现了b-CD包结的带有苯基取代的胺类能够快速、高产率地催化反应，并且催化剂易分离、可重复使用。 第三章研究了L-脯氨酸及其衍生物催化3-羟基-3-（2´-氧-丙基）-吲哚-2-酮及其类似物的不对称合成。L-脯氨酸催化丙酮与靛红的反应产物ee值不高，但是以（N-取代）-靛红为底物可以得到最高79% ee值的产物。此外，对该结果产生的机制进行了讨论。 第四章以靛红和苯乙炔为原料，在Et2Zn的作用下不添加催化剂合成了一系列3-羟基-3-苯乙炔基-吲哚-2-酮化合物，讨论了反应可能的机理。活性研究发现多数该类化合物在抗肿瘤、神经保护方面的活性不高，仅有少数分子显示了好的活性。 第五章通过靛红与苯胺、羟氨、肼、酰肼、氨基硫脲等缩合得到了一系列3-亚胺基-吲哚-2-酮类化合物，进而又经Mannich反应得到了Mannich碱衍生物。经活性筛选，3-亚胺基-吲哚-2-酮类化合物显示了较好的神经保护、抗肿瘤活性，3-苯基亚胺基靛红Mannich的衍生物还显示了较好的抗稻瘟菌的活性。 第六章合成了一系列3-芳基亚甲基-吲哚-2-酮和（N-取代）-3-硝基基亚甲基-吲哚-2-酮类化合物，研究了这些化合物的神经保护、抗肿瘤等活性。发现了4个3-芳基亚甲基-吲哚-2-酮分子对caspase-3有一定的抑制活性；3个化合物对抗H2O2致PC12细胞损伤有较好的活性，（N-取代）-3-硝基基亚甲基-吲哚-2-酮类化合物则没有好的活性，并且有一定的细胞毒性；3-芳基亚甲基-吲哚-2-酮类化合物对P388小鼠白血病和A-549人肺腺癌肿瘤细胞都有好的抑制作用。 第七章以(E)-β-硝基苯基乙烯、靛红/（N-取代）-靛红和a-氨基酸为原料，合成了一系列螺环化合物，研究该反应的区域选择特点，发现该类反应的产物均与查尔酮、靛红/（N-取代）-靛红和a-氨基酸1，3偶极环加成反应得到的产物在区域选择性上并不一致，其吸电子取代基连接于不同的位置。对产物初步的生物活性研究发现：该类化合物多数对H2O2致PC12细胞损伤有保护作用化合物，可能与其分子能够与金属离子形成稳定的络合物，或者硝基的特殊作用有关；对P388小鼠白血病和A-549人肺腺癌肿瘤细胞都有一定的抑制作用，化合物95浓度在10-5M时对两种肿瘤细胞仍有一定的抑制作用。 第八章以2-酰基（苯甲酰基、酯基、酰胺）苯乙烯、靛红/（N-取代）-靛红和a-氨基酸为原料，合成了一系列螺环化合物，综合研究该反应的区域选择特点，发现该类反应的产物都与查尔酮、靛红/（N-取代）-靛红和a-氨基酸1，3偶极环加成反应得到的产物在区域选择性上是一致的。对该系列化合物初步的生物活性研究发现：对H2O2致PC12细胞损伤没有好的保护作用；4个化合物对P388小鼠白血病和A-549人肺腺癌肿瘤细胞都有较好的抑制作用。 第九章研究了靛红、a-氨基酸和2-取代苯乙烯1，3偶极环加成反应的机理。针对该类反应的区域选择性进行了讨论，提出了一个π-π叠合反应过渡态控制区域选择的机理，合理的解释了不同取代基的2-取代苯乙烯参与反应得到不同区域选择产物的原因，并通过B3LYP/6-31G(d)计算，得到了较理想的结果。 第十章对本论文中合成的化合物进行了抑制SARS冠状病毒3CL蛋白活性的筛选，发现了若干化合物具有较好的活性，并对各种类型的化合物与SARS冠状病毒3CL蛋白底物识别口袋的作用进行了初步的讨论，认为邻二羰基、Micheal受体和硝基可能是底物与蛋白结合的重要官能团。 第十一章为综述部分，对靛红及其合成衍生物的生物活性研究进展进行了文献综述。 |
| 英文摘要 | This thesis includes: diversity-oriented synthesis derived from isain and the bioactivity screening of the derivatives. Eight series of isatin derivatives were synthesized, and the bioactivities on antibacterial, antivirus, antitumor and neuroprotection of these compounds were investigated. Meanwhile, the progress of biological study of isatin and its derivatives were reviewed in the thesis. In the first chapter, a series of compounds was synthesized by Aldol addition with isatin and methyl ketone catalized by diethyl amine. The possible mechanism was also discussed. And the bioactivities on protective effect on the apoptosis of PC12 cells induced by H2O2, cytotoxicity against lung cancer cell line A549 and P388 cell line was screened. These (N-substituted) isatins were showed potent antioxidant activity against H2O2-induced impairment in PC12 cells and cytotoxicity against lung cancer cell line A549 and P388 cell line. 3-hydroxy-3-(2-oxo-propyl)-1,3-dihydro-indol-2-one is a new chemical activator discoveried by our group, which activats plant systemic acquired resistance (SAR). The synthetic method on a large scale was investigated in the second chapter. It was found that inclusion compounds of b-CD with phenyl-substituted amine could catalyse the Aldol condensation of isatin and aceton quckly with high yield, and the catalyst could be reused. The third chapter described L-proline and its derivatives could catalyze asymmetric Aldol condensation of acetone and isatin / (N-substituted) isatins. The reaction between acetone and (N-substituted) isatins catalized by L-proline was much faster than that of acetone and isatin, presenting the desired products with 30-79% ee. The mechanism of this reaction was also discussed, and it was suggested that a stronger hydrogen bond receptor, as well as a stronger hydrogen bond donor in the transition state, could decrease the energy of the transition state. In the fourth chapter a series of derivatives of isatin was synthesized by the addition of phenylacetylene to isatin / (N-substituted) isatins promoted by Et2Zn without any employment of specific ligands, and the mechanism was discussed. Most of these compounds showed activities on neuroprotection and cytotoxisities on tumor cell lines(A459, P388). In the fifth chapter, schiff base derivatives of isatin were synthesized by the condensation of isatin and anilin, hydroxyl amine, hydrazine and thiosemicarbazide, forther more, mannich base derivatives were synthesized by the reaction of the schiff base compounds, formaldehydes and secondary amines. The schiff bases derived from isatin and anilin analogies showed potent activities on neuroprotection and cytotoxisities on tumor cell lines (A459, P388), and the mannich bases showed potent activities on anti- Magnaporthe grisea. In the sixth chapter a series of 3-methylene-indol-2-one derivatives was synthesized. During the bioactive screen four 3-aryl-methylene-indol-2-one derivatives showed potent activities on inhibition of caspase-3; three 3-phenyl-methylene-indol-2-one derivatives showed potent antioxidant activities against H2O2-induced impairment in PC12 cells; and almost all of the 3-aryl-methylene-indol-2-one derivatives showed potent cytotoxisities on antitumor (A459, P388), while the 3-nitro-methylene-indol- 2-one with low activity in three aspects. In the seventh chapter, a series of spiro [pyrrolidine-2, 3’-oxindole] derivatives was synthesized by the 1, 3-dipolar-addition reaction of isatin / (N-substituted) isatins, α-amino acids and (E)-β-aryl-nitroolefins. The reactions were in good yields, affording two regioisomers and the regioselectivties and the reaction results were different from the previous reported spiro [pyrrolidine 2, 3’- oxindole] derivatives. The primary bioactive screenings were showed that almost all of the compounds could protect the PC12 cells of H2O2-induced impairment, and some of them had capacities against tumor cell lines (A459, P388). Among them, compound 95 could inhibit the two cells at a higher level under the concentration of 10-5M. In the eighth chapter, another series of spiro [pyrrolidine-2, 3’-oxindole] derivatives was synthesized by the 1, 3-dipolar-addition reaction of isatin / (N-substituted) isatins, α-amino acids and (E)-2-acyl-styrene to investigate the regioselectvity of this reaction, and it was found that all of the reactions had the same regioselectvity as the reaction of isatin, α-amino acids and chalcone, but different from the reaction described in chapter seven. The primary bioactivities screen showed no compound could protect the PC12 cell for H2O2-induced impairment. However, some of the compounds showed activities against tumor cell lines (A459, P388). Based on the different regioselectivity in the reactions discribed in chapter seven and eight, the mechanism was studied associated with caculation of B3LYP/6-31G(d) in chapter nine. A new mechanism was suggested: a π-π stack controlling in the transition state might determine the regioselectivity in the reactions. This mechanism could explain the regioselectivity reasonably. In the tenth chapter, the inhibition abilities of all these compounds against SARS coronavirus 3C-like protease was screened, and many compounds exhibited potent inhibition for the protease. The possible interaction between different kinds of compounds and the substrate-binding pocket of the protean was also discussed. The results suggested that 1,2-dicarbonyl, Micheal acceptor and nitro group were of importance for the inhibition. The the eleventh chapter reviewed the progress of biological study of isatin and its derivatives. |
| 语种 | 中文 |
| 公开日期 | 2011-10-25 |
| 页码 | 229 |
| 源URL | [http://ir.kib.ac.cn/handle/151853/182]  |
| 专题 | 昆明植物研究所_昆明植物所硕博研究生毕业学位论文 |
| 推荐引用方式 GB/T 7714 | 陈刚. 靛红衍生物的多样性合成及其生物活性研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所. 2007. |
入库方式： OAI收割
来源：昆明植物研究所
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