含羧基或酯基的N-甲基异噁唑啉盐的合成及其对细胞分裂周期25B磷酸酯酶和蛋白酪氨酸磷酸酶1的体外抗癌活性
收稿日期: 2016-04-15
修回日期: 2016-07-12
网络出版日期: 2016-09-06
基金资助
国家自然科学基金（Nos.21462043，21062019）资助项目.
Synthesis and in vitro Anticancer Activity of N-Methylisoxazolinium-Salts with Carboxyl or Ester Groups against Cell Division Cycle 25B Phosphatase and Protein Tyrosine Phosphatase-1
Received date: 2016-04-15
Revised date: 2016-07-12
Online published: 2016-09-06
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 21462043, 21062019).
以硫酸二甲酯作为N-甲基化试剂，与相应的异噁唑啉1a~1g或3a~3g反应，并在盐酸中以三氯化铁作为阴离子交换试剂，合成了14个未见文献报道的2-甲基-3-乙氧基羰基-5-芳基-3a，6a-二氢-4，6-二氧代氮杂茂并[3'，4'-d]异噁唑四氯化铁酸盐衍生物2a~2g和2-甲基-3-羧基-5-芳基-3a，6a-二氢-4，6-二氧代氮杂茂并[3'，4'-d]异噁唑四氯化铁酸盐衍生物4a~4g，其结构经1H NMR，IR 和元素分析确证，并进行了初步药物活性筛选.化合物2和4显示了不同程度的抗癌活性.体外抗癌活性试验表明，当样品浓度为20 μg/mL时，化合物2a~2g和4a~4g对细胞分裂周期25B磷酸酯酶（Cdc25B）的抑制率分别在97.32%~99.94%之间和97.45%~99.92%之间.化合物2a~2g和4d~4g对含SH2结构域蛋白酪氨酸磷酸酯酶-1（SHP1）具有良好的抑制活性，其抑制率分别在52.18%~97.15%和86.66%~99.45%之间.只有4a~4c的抑制率在15.21%~47.11%之间（IC50<0.5 μmol/L）.在此基础上，初步讨论了该类化合物的构效关系.
关键词： 羧基; 酯基; N-甲基异噁唑四氯化铁酸盐; 合成; 体外抗癌活性
穆赫塔尔·伊米尔艾山, 萨提瓦力迪·海力力, 麦麦提依明·马合木提 . 含羧基或酯基的N-甲基异噁唑啉盐的合成及其对细胞分裂周期25B磷酸酯酶和蛋白酪氨酸磷酸酶1的体外抗癌活性[J]. 有机化学, 2017 , 37(2) : 496 -502 . DOI: 10.6023/cjoc201604033
Fouteen 2-methyl-3-ethylcarboxy-5-aryl-3a,6a-dihydro-4,6-dioxopyrrolino[3',4'-d]-isoxazoliniumtetrachloro-ferrate derivatives 2a~2g and 2-methyl-3-carboxyl-5-aryl-3a,6a-dihydro-4,6-dioxopyrrolino[3',4'-d]-isoxazolinium-tetra-chloroferrate derivatives 4a~4g were synthesized by using dimethylsulfate as a N-methylating reagent and ferric(III)-chloride as anion exchange reagent in hydrochloric acid. The structures of the target compounds 2 and 4 were characterized by 1H NMR, IR spectra and elemental analysis. The preliminary in vitro anticancer activity on the compounds showed that most compounds possess anti-cancer activity at some extent. At the test concentration of 20 μg/mL, compounds 2a~2g and 4a~4g showed inhibition activities in the range of 97.32%~99.94% and 97.45%~99.92% against cell division cycle 25B phosphatase (Cdc25B), respectively. At the test concentration of 20 μg/mL, compounds 2a~2g and 4d~4g showed inhibition activities in the range of 52.18%~97.15% and 86.66%~99.45% against SH2-containing protein tyrosine phosphatase-1 (SHP1), respectively. Compounds 4a~4c only have the inhibition activities in the range of 15.21%~47.11%, which is lower than IC50 against SHP1. Preliminary discussion was carried out on the structure-activity relationship of the target compounds.
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