长果大头茶的化学成分及生物活性研究&咔唑生物碱Claulansine F的合成及生物活性研究
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摘要
长果大头茶是山茶科大头茶属植物,主要分布在我国西南部、缅甸和越南北部。本课题组前期对大头茶属植物黄药大头茶和广西大头茶进行了化学成分和生物活性研究,获得了以三萜皂苷、黄酮为主的化学成分,生物活性研究表明部分化合物具有细胞毒、抗炎、保肝和降血糖等活性。目前尚无有关长果大头茶的化学成分和生物活性的报道。
药理活性筛选发现长果大头茶茎95%乙醇提取物水悬液萃取后的正丁醇部位具有降血糖活性。为寻找有效成分,本论文运用色谱学和波谱学方法,对长果大头茶茎95%乙醇提取物正丁醇部位进行了化学成分研究,从中分离得到20个化合物并鉴定了其化学结构,均为三萜皂苷,依次为3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1_→2)]-β-D-葡萄糖醛酸-16α-羟基-齐墩果-12-烯-28-酸(1),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-16α-羟基-齐墩果-12-烯-28-酸(2),3β-0-β-D-葡萄糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(3),3β-O-β0-D-半乳糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(4),3β-O-a-L-鼠李糖(1→3)-β-D-葡萄糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(5),3β0-O-β-D-半乳糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16α,28-二羟基-齐墩果-12-烯(6),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1-→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-齐墩果-12-烯(7),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1→2)]-β-D-葡萄糖醛酸-15a,16a,28-三羟基-21β,22a-二当归酰氧基齐墩果-12-烯(8),3β-O-β-D-半乳糖(1→2)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(9),3β-O-a-L-阿拉伯糖(1→3)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(10),3β-O-a-L-阿拉伯糖(1→2)-a-L-阿拉伯糖(1→3)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(11),3β-O-a-L-鼠李糖(1→2)-a-L-阿拉伯糖(1→3)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(12),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[fβ-D-半乳糖(1→2)]-ββ-D-葡萄糖醛酸-16α-羟基-齐墩果-12-烯-28-葡萄糖酯(13),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-22a-当归酰氧基齐墩果-12-烯(14),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-22a-当归酰氧基齐墩果-12-烯(15),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1-→2)]-β-D-葡萄糖醛酸-15a,16a,28-三羟基-22a-当归酰氧基齐墩果-12-烯(16),3β-0-β-D-木糖(1→2)-α-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-15a,16a,28-三羟基-21β-乙酰氧基-22a-当归酰氧基齐墩果-12-烯(17),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-21β,22a-二当归酰氧基齐墩果-12-烯(18),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-21β,22a-二当归酰氧基齐墩果-12-烯(19),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-βD-葡萄糖醛酸-15a,16a,28-二羟基-21β,22α-二当归酰氧基齐墩果-12-烯(20)。其中化合物1-8为新化合物,依次命名为longicarposide A-H。体外降血糖活性筛选表明,化合物1和16对醛糖还原酶抑制率超过50%。在细胞毒活性筛选模型中,化合物8、14、15、16和18对HCT-8、Bel-7402、BGC-823、A549和A2780五种肿瘤细胞株显示出了非选择细胞毒活性,化合物17、19和20表现出了选择性细胞毒性。
本课题组在研究黄皮化学成分和生物活性过程中获得一系列咔唑生物碱,其中部分化合物显示了体外神经细胞保护活性。新化合物Claulansine F在硝普钠诱导的大鼠大脑神经元模型中显示了强于阳性对照药依达拉奉的保护作用。Claulansine F在细胞中显示了与依达拉奉相似的自由基清除作用,对硝普钠诱导的PC12细胞凋亡的保护呈剂量依赖性。为进一步开展动物模型评价和毒性、机制及构效关系研究,我们设计并合成了Claulansine F。
以2-甲基-5硝基苯胺为原料,经过9步反应最终合成了Claulansine F,总收率为3.3%。利用制备的取代苯胺和碘甲醚,在乙酸钯催化下经过Buchwald-Hartwig反应合成了二苯胺型中间体,继而在钯的催化下进行分子内氧化脱氢得到了咔唑。这是首次全合成Claulansine F。所得产物与从天然产物中分离得到的Claulansine F理化数据完全一致。本论文还对中间体和最终产物进行了进一步生物活性研究,Claulansine F在大鼠脑梗塞模型中,有效减少了梗塞面积,与阳性对照药依达拉奉相当,说明Claulansine F在脑中的自由基清除作用仍然有效。
Polyspora longicarpa Chang, belonging to Polyspora of the Theaceae family, is distributed widely in the southwestern China and northern Vietnam and Cambodia. Our previous researches on Polyspora chrysandra Cowan and Polyspora kwangsiensis had provided a diverse array of new saponins and flavonoids, with a range of bioactivities such as cytotoxic, anti-inflammatory, hepatoprotective and hypoglycemic activities. Until now, there are no reports on chemical constituents and bioactivities of Polyspora longicarpa Chang.
In our preliminary screening, the n-BuOH part of95%EtOH extract of the stems was found to exhibit anti-inflammatory and hypoglycemic activities. As part of searching for bioactive constituents, we investigated the n-BuOH part of95%EtOH extract of the stems. By using various chromatographic and spectroscopic techniques,20triterpenoid saponins had been isolated and elucidated. They were3-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-oic acid (1),3-O-β-D-xylopyranosyl-(1→2)-α-L-arabino-pyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-oic acid (2),3β-O-β-D-glucopyranosyl-(1→2)-[a-L-arabino-pyranosyl-(1→3)]-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-gluco-pyranoside (3),3β-O-β-D-galactopyranosyl-(1→2)-[α-L-arabinopyranosyl-(1→3)]-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (4),3β-O-a-L-rhamnopyranosyl(1→3)-β-D-glucopyranosyl-(1→2)-[a-L-arabinopyranosyl-(1→3)]-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (5),3β-O-β-D-galacto-pyranosyl-(1→2)-[a-L-arabinopyranosyl-(1→3)]-β-D-glucurono-pyranosyl-16α,28-dihydroxy-olean-12-ene (6),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16α,28-dihydroxy-olean-12-ene (7),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabino-pyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-15a,16a,28-trihydroxy-21β,22α-diangeloyloxy-olean-12-ene (8),3β-O-β-D-galactopyranosyl-(1→2)-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (9),3β-O-α-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (10),3β-O-α-L-arabinopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (11),3β-O-α-L-rhamnopyranosyl(1→2)-a-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (12),30-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1 →2)]-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (13),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a,28-dihydroxy-22a-angeloyloxy-olean-12-ene (14),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyI-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a,28-dihydroxy-22α-angeloyloxy-olean-12-ene (15),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-15a,16a,28-trihydroxy-22a-angeloyloxy-olean-12-ene (16),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-15a,16a,28-tirhydroxy-21β-acetyl-22a-angeloyloxy-olean-12-ene (17),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a,28-dihydroxy-21β,22a-diangeloyloxy-olean-12-ene (18),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucurono-pyranosyl-16a,28-dihydroxy-21β,22a-diangeloyloxy-olean-12-ene (19),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1-D-glucuronopyranosyl-15a,16a,28-dihydroxy-21β,22a-diangeloyloxy-olean-12-ene (20). Compounds1-8are new compounds, which were given the trival names longicarposide A-H, respectively. For the hypoglycemic bioassay, compound1and16inhibited aldose reductase with a rate over50%. For the cytotoxic bioassay, compounds8,14,15,16and18exhibited nonselective cytotoxicity against HCT-8, Bel-7402, BGC-823, A549and A2780cell lines while compounds17,19and20exhibited selective cytotoxicity.
Our previous investigations on the constituents and bioactivities of Clausena lansium (Lour.) Skeels had found a series of carbazole alkaloids which showed excellent neuroprotective activities in vitro. The new compound claulansine F exhibited better neuroprotective activities than the positive drug edaravone toward the apoptosis of rat cortical neuron. It acted as a free radical scavenger against reactive oxygen species (ROS) like edaravone and protected PC12cells in a dose-dependent manner against toxicity induced by sodium nitroprusside. In order to perform further researches on animal modle, toxicity, mechanism and structure-activity relationship,we carried out a synthetic study for the preparation claulansine F.
A nine-step route was developed with2-methy-5-nitroaniline as the starting material, leading to the total synthesis of claulansine F with the overall yield3.3%. The coupling of prepared arylamine with commercial4-iodoanisole via a palladium-catalyzed Buchwald-Hartwig amination led to the diarylamine. An air-mediated oxidative cyclization catalyzed by palladium had been applied to the foundation of the carbazole skeleton. Claulansine F, obtained by total synthesis for the first time, has been characterized by comparison of its spectroscopic data with those of the natural product. Further investigations of bioactivities on the intermediates and Claulansine F were carried out in this thesis. Claulansine F significantly decreased the area of infarction induced by cerebral ischemia in the brain of rats, which indicated that the mechanism of free radicals scavenging still worked in vivo.
药理活性筛选发现长果大头茶茎95%乙醇提取物水悬液萃取后的正丁醇部位具有降血糖活性。为寻找有效成分,本论文运用色谱学和波谱学方法,对长果大头茶茎95%乙醇提取物正丁醇部位进行了化学成分研究,从中分离得到20个化合物并鉴定了其化学结构,均为三萜皂苷,依次为3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1_→2)]-β-D-葡萄糖醛酸-16α-羟基-齐墩果-12-烯-28-酸(1),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-16α-羟基-齐墩果-12-烯-28-酸(2),3β-0-β-D-葡萄糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(3),3β-O-β0-D-半乳糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(4),3β-O-a-L-鼠李糖(1→3)-β-D-葡萄糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(5),3β0-O-β-D-半乳糖(1→2)-[a-L-阿拉伯糖(1→3)]-β-D-葡萄糖醛酸-16α,28-二羟基-齐墩果-12-烯(6),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1-→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-齐墩果-12-烯(7),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1→2)]-β-D-葡萄糖醛酸-15a,16a,28-三羟基-21β,22a-二当归酰氧基齐墩果-12-烯(8),3β-O-β-D-半乳糖(1→2)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(9),3β-O-a-L-阿拉伯糖(1→3)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(10),3β-O-a-L-阿拉伯糖(1→2)-a-L-阿拉伯糖(1→3)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(11),3β-O-a-L-鼠李糖(1→2)-a-L-阿拉伯糖(1→3)-β-D-葡萄糖醛酸-16a-羟基-齐墩果-12-烯-28-葡萄糖酯(12),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[fβ-D-半乳糖(1→2)]-ββ-D-葡萄糖醛酸-16α-羟基-齐墩果-12-烯-28-葡萄糖酯(13),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-22a-当归酰氧基齐墩果-12-烯(14),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-22a-当归酰氧基齐墩果-12-烯(15),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1-→2)]-β-D-葡萄糖醛酸-15a,16a,28-三羟基-22a-当归酰氧基齐墩果-12-烯(16),3β-0-β-D-木糖(1→2)-α-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-15a,16a,28-三羟基-21β-乙酰氧基-22a-当归酰氧基齐墩果-12-烯(17),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-葡萄糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-21β,22a-二当归酰氧基齐墩果-12-烯(18),3β-0-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-β-D-葡萄糖醛酸-16a,28-二羟基-21β,22a-二当归酰氧基齐墩果-12-烯(19),3β-O-β-D-木糖(1→2)-a-L-阿拉伯糖(1→3)-[β-D-半乳糖(1→2)]-βD-葡萄糖醛酸-15a,16a,28-二羟基-21β,22α-二当归酰氧基齐墩果-12-烯(20)。其中化合物1-8为新化合物,依次命名为longicarposide A-H。体外降血糖活性筛选表明,化合物1和16对醛糖还原酶抑制率超过50%。在细胞毒活性筛选模型中,化合物8、14、15、16和18对HCT-8、Bel-7402、BGC-823、A549和A2780五种肿瘤细胞株显示出了非选择细胞毒活性,化合物17、19和20表现出了选择性细胞毒性。
本课题组在研究黄皮化学成分和生物活性过程中获得一系列咔唑生物碱,其中部分化合物显示了体外神经细胞保护活性。新化合物Claulansine F在硝普钠诱导的大鼠大脑神经元模型中显示了强于阳性对照药依达拉奉的保护作用。Claulansine F在细胞中显示了与依达拉奉相似的自由基清除作用,对硝普钠诱导的PC12细胞凋亡的保护呈剂量依赖性。为进一步开展动物模型评价和毒性、机制及构效关系研究,我们设计并合成了Claulansine F。
以2-甲基-5硝基苯胺为原料,经过9步反应最终合成了Claulansine F,总收率为3.3%。利用制备的取代苯胺和碘甲醚,在乙酸钯催化下经过Buchwald-Hartwig反应合成了二苯胺型中间体,继而在钯的催化下进行分子内氧化脱氢得到了咔唑。这是首次全合成Claulansine F。所得产物与从天然产物中分离得到的Claulansine F理化数据完全一致。本论文还对中间体和最终产物进行了进一步生物活性研究,Claulansine F在大鼠脑梗塞模型中,有效减少了梗塞面积,与阳性对照药依达拉奉相当,说明Claulansine F在脑中的自由基清除作用仍然有效。
Polyspora longicarpa Chang, belonging to Polyspora of the Theaceae family, is distributed widely in the southwestern China and northern Vietnam and Cambodia. Our previous researches on Polyspora chrysandra Cowan and Polyspora kwangsiensis had provided a diverse array of new saponins and flavonoids, with a range of bioactivities such as cytotoxic, anti-inflammatory, hepatoprotective and hypoglycemic activities. Until now, there are no reports on chemical constituents and bioactivities of Polyspora longicarpa Chang.
In our preliminary screening, the n-BuOH part of95%EtOH extract of the stems was found to exhibit anti-inflammatory and hypoglycemic activities. As part of searching for bioactive constituents, we investigated the n-BuOH part of95%EtOH extract of the stems. By using various chromatographic and spectroscopic techniques,20triterpenoid saponins had been isolated and elucidated. They were3-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-oic acid (1),3-O-β-D-xylopyranosyl-(1→2)-α-L-arabino-pyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-oic acid (2),3β-O-β-D-glucopyranosyl-(1→2)-[a-L-arabino-pyranosyl-(1→3)]-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-gluco-pyranoside (3),3β-O-β-D-galactopyranosyl-(1→2)-[α-L-arabinopyranosyl-(1→3)]-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (4),3β-O-a-L-rhamnopyranosyl(1→3)-β-D-glucopyranosyl-(1→2)-[a-L-arabinopyranosyl-(1→3)]-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (5),3β-O-β-D-galacto-pyranosyl-(1→2)-[a-L-arabinopyranosyl-(1→3)]-β-D-glucurono-pyranosyl-16α,28-dihydroxy-olean-12-ene (6),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16α,28-dihydroxy-olean-12-ene (7),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabino-pyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-15a,16a,28-trihydroxy-21β,22α-diangeloyloxy-olean-12-ene (8),3β-O-β-D-galactopyranosyl-(1→2)-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (9),3β-O-α-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (10),3β-O-α-L-arabinopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (11),3β-O-α-L-rhamnopyranosyl(1→2)-a-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosyl-16α-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (12),30-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1 →2)]-β-D-glucuronopyranosyl-16a-hydroxy-olean-12-en-28-O-β-D-glucopyranoside (13),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a,28-dihydroxy-22a-angeloyloxy-olean-12-ene (14),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyI-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a,28-dihydroxy-22α-angeloyloxy-olean-12-ene (15),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-15a,16a,28-trihydroxy-22a-angeloyloxy-olean-12-ene (16),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucuronopyranosyl-15a,16a,28-tirhydroxy-21β-acetyl-22a-angeloyloxy-olean-12-ene (17),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucuronopyranosyl-16a,28-dihydroxy-21β,22a-diangeloyloxy-olean-12-ene (18),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-glucurono-pyranosyl-16a,28-dihydroxy-21β,22a-diangeloyloxy-olean-12-ene (19),3β-O-β-D-xylopyranosyl-(1→2)-a-L-arabinopyranosyl-(1→3)-[β-D-galactopyranosyl-(1-D-glucuronopyranosyl-15a,16a,28-dihydroxy-21β,22a-diangeloyloxy-olean-12-ene (20). Compounds1-8are new compounds, which were given the trival names longicarposide A-H, respectively. For the hypoglycemic bioassay, compound1and16inhibited aldose reductase with a rate over50%. For the cytotoxic bioassay, compounds8,14,15,16and18exhibited nonselective cytotoxicity against HCT-8, Bel-7402, BGC-823, A549and A2780cell lines while compounds17,19and20exhibited selective cytotoxicity.
Our previous investigations on the constituents and bioactivities of Clausena lansium (Lour.) Skeels had found a series of carbazole alkaloids which showed excellent neuroprotective activities in vitro. The new compound claulansine F exhibited better neuroprotective activities than the positive drug edaravone toward the apoptosis of rat cortical neuron. It acted as a free radical scavenger against reactive oxygen species (ROS) like edaravone and protected PC12cells in a dose-dependent manner against toxicity induced by sodium nitroprusside. In order to perform further researches on animal modle, toxicity, mechanism and structure-activity relationship,we carried out a synthetic study for the preparation claulansine F.
A nine-step route was developed with2-methy-5-nitroaniline as the starting material, leading to the total synthesis of claulansine F with the overall yield3.3%. The coupling of prepared arylamine with commercial4-iodoanisole via a palladium-catalyzed Buchwald-Hartwig amination led to the diarylamine. An air-mediated oxidative cyclization catalyzed by palladium had been applied to the foundation of the carbazole skeleton. Claulansine F, obtained by total synthesis for the first time, has been characterized by comparison of its spectroscopic data with those of the natural product. Further investigations of bioactivities on the intermediates and Claulansine F were carried out in this thesis. Claulansine F significantly decreased the area of infarction induced by cerebral ischemia in the brain of rats, which indicated that the mechanism of free radicals scavenging still worked in vivo.
引文
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