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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.
Using dimethyl sulfate as N-methylating reagent, reacting with 1a ~ 1g or 3a ~ 3g of the corresponding isoxazoline, and using 14 FeCl 3 as anion exchange reagent in hydrochloric acid, 14 compounds have been synthesized The reported 2-methyl-3-ethoxycarbonyl-5-aryl-3a, 6a-dihydro-4,6- dioxoamino [3 ’, 4’-d] isoxazole tetrakis Ferric chloride derivatives 2a to 2g and 2-methyl-3-carboxy-5-aryl-3a, 6a-dihydro-4,6-dioxoamino [3 ’, 4’- d] isooxazolium tetrachloroformate derivatives 4a ~ 4g, the structure confirmed by ~ 1H NMR, IR and elemental analysis, and the preliminary screening of the drug activity.Compounds 2 and 4 showed varying degrees of anti-cancer activity The in vitro anticancer activity assay showed that the inhibitory rates of 2a ~ 2g and 4a ~ 4g on 25C phosphatase (Cdc25B) were between 97.32% ~ 99.94% at the concentration of 20μg / mL and 97.45% ~ 99.92% .The compounds 2a ~ 2g and 4d ~ 4g had good inhibitory activity against the SH2-containing domain tyrosine phosphatase-1 (SHP1) with the inhibition rates of 52.18% -97.15% and 86.66% ~ 99.45%, only 4a ~ 4c were between 15.21% ~ 47.11% (IC50 <0.5μmol / L) On the basis of a preliminary discussion of structure-activity relationships of these compounds.