药学学报, 2018, 53(4): 585-591
引用本文:
穆赫塔尔·伊米尔艾山, 萨特瓦尔迪·赫力力, 王婷. 天然蕈毒碱类似物1',2'-二-O-异亚丙基二氧乙基异噁唑啉衍生物的合成及其对Cdc25B和CD45体外抗癌和白细胞共同抗原活性筛选[J]. 药学学报, 2018, 53(4): 585-591.
IMERHASAN Mukhtar, HELIL Setiwaldi, WANG Ting. Synthesis of 1',2'-O-isopropylidendioxyethyl isoxazoline derivatives of natural muscarinic analogs and screening its anti-cancer and leukocyte common antigen activity on Cdc25B and CD45 in vitro[J]. Acta Pharmaceutica Sinica, 2018, 53(4): 585-591.

天然蕈毒碱类似物1',2'-二-O-异亚丙基二氧乙基异噁唑啉衍生物的合成及其对Cdc25B和CD45体外抗癌和白细胞共同抗原活性筛选
穆赫塔尔·伊米尔艾山, 萨特瓦尔迪·赫力力, 王婷
新疆大学化学与化工学院, 新疆 乌鲁木齐 830046
摘要:
从蘑菇中提取的活性物质捕蝇蕈(muscimol)、环丝氨酰(cycloserin)和鹅膏蕈氨酸(ibotenic acid)都含有异噁唑药效团结构,本文以捕蝇蕈(蕈毒碱)为结构模型,采用分子重组法,通过1,3-偶极环加成反应,合成了3-(1',2'-二-O-异亚丙基二氧乙基)-5-芳基-3a,6a-二氢-4,6-二氧代氮杂茂并[3',4'-d]异噁唑啉的蕈毒碱类似物,其结构经UV-Vis、1H NMR、IR和元素分析进行了表征。对合成的化合物进行了体外药物活性筛选,发现结构中的药效团作为潜在的非共价DNA结合体,显示了不同程度的抗癌、抗炎及免疫性疾病活性。初步体外抗癌活性结果表明,当样品浓度为20 μg·mL-1时,化合物3a~3o对细胞分裂周期25B磷酸酯酶(Cdc25B)的抑制率为56.99%~99.94%,甚至当样品浓度为5 μg·mL-1时,除了3f、3h、3i、3m、3o无活性外,其余化合物的抑制率仍为66.85%~99.84%,值得进一步研究。此外,体外白细胞共同抗原(CD45)活性实验结果表明,当样品浓度为20 μg·mL-1时,除了3i无活性外,其余化合物对白细胞共同抗原CD45蛋白酪氨酸磷酸酶A具有良好的抑制活性,其抑制率为63.08%~92.09%。这些具有活性的目标化合物是潜在的Cdc25B和CD45蛋白酪氨酸磷酸酶A抑制剂,在癌症、炎性及免疫性疾病治疗方面具有很好的应用前景。
关键词:    1',2'-二-O-异亚丙基二氧乙基异噁唑啉      合成      体外抗癌活性      白细胞共同抗原活性     
Synthesis of 1',2'-O-isopropylidendioxyethyl isoxazoline derivatives of natural muscarinic analogs and screening its anti-cancer and leukocyte common antigen activity on Cdc25B and CD45 in vitro
IMERHASAN Mukhtar, HELIL Setiwaldi, WANG Ting
College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
Abstract:
Muscimol, cycloserin and ibotenic acid which are extracted from mushroom contain isoxazole pharmacophore structure. By using muscarinic structure as a model compound and molecular recombination method, we synthesized muscarinic analogues compounds 3-(1',2'-di-O-isopropylidenedioxyethyl)-5-aryl-3a, 6a-dihydro-4,6-dioxopyrrolino[3',4'-d]isoxazoline derivatives through 1,3-dipolar cycloaddition reaction. The structures of the target compounds were confirmed by UV-Vis, 1H NMR, IR and elemental analysis. The drug activities of obtained compounds were screened in vitro. The pharmacophore in the structure is a potential non-covalent DNA binding, the compounds have anticancer activity and the leukocyte common antigen activity in a different extent. The preliminary results of in vitro anticancer test suggest that the inhibitory rates of compounds 3a-3o to Cdc25A phosphatase in cell division cycle ranged from 56.99%-99.94%; at the test concentration of 20 μg·mL-1, 3f, 3h, 3i, 3m, 3o were no inhibition activity, and the rest of the compounds shows moderate to good excellent inhibition rate from 66.85% to 99.84%, even at the concentration as low as 5 μg·mL-1. At the test concentration of 20 μg·mL-1, except compound 3i, the rest compounds' inhibition activity of against leukocyte common antigen (LCA) CD45 protein tyrosine phosphatase A, are 63.08%-92.09%. These active compounds are potential inhibitors against Cdc25A and CD45 protein tyrosine phosphatase A, which have great application prospects in the treatment of cancers and Inflammatory and immune diseases.
Key words:    1',2'-O-isopropylidendioxyethyl isoxazole    synthesis    in vitro anticancer activity    leukocyte common antigen activity   
收稿日期: 2017-12-25
DOI: 10.16438/j.0513-4870.2017-1280
基金项目: 国家自然科学基金资助项目(21462043,21062019).
通讯作者: 穆赫塔尔·伊米尔艾山,Tel:13999251745,E-mail:imerhasan@xju.edu.cn
Email: imerhasan@xju.edu.cn
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