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

Synthesis and in vitro Anticancer Activity of N-MethylisoxazoliniumSalts with Carboxyl or Ester Groups against Cell Division Cycle 25B Phosphatase and Protein Tyrosine Phosphatase-1

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20μg/m L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<0.5μmol/L).在此基础上,初步讨论了该类化合物的构效关系.

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.