新型细胞分裂周期25磷酸酯酶B和蛋白酪氨酸磷酸酶1B抑制剂三唑并噻二唑-均三嗪的合成

doi:10.11944/j.issn.1000-0518.2017.04.160246

摘要/Abstract

摘要：

以苯亚氨基为桥,设计合成了18个含有三唑并噻二唑和均三嗪双杂环的新型分子(4a~4i和5a~5i),并利用红外光谱、核磁共振谱和高分辨质谱等技术手段对其进行了结构表征。将吗啉和四氢吡咯分别与三聚氯氰发生双取代反应合成三嗪衍生物(1A和1B),然后将1A和1B分别与对氨基苯甲酸反应,合成重要中间体(2A和2B)。通过熔融法将8种脂肪酸与二氨基硫脲缩合得1,2,4-三唑衍生物3a~3h,最后将2A和2B在三氯氧磷和四丁基溴化铵催化下分别与3a~3h反应得目标产物。为了进一步比较3-脂肪基和3-苯基对药效活性的影响,利用相同方法设计合成了目标产物4i和5i。评价了目标产物对细胞分裂周期25磷酸酯酶B(Cdc25B)和蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性。结果发现:所有目标分子对Cdc25B均表现出良好的抑制活性,半抑制浓度(IC₅₀值)在2.40~0.31 mg/L之间,目标分子4a~4f和5a~5i的IC₅₀值均低于阳性参照物Na₃VO₄ [(1.25±0.14) mg/L],有望成为潜在的Cdc25B抑制剂;在PTP1B测试中,14个目标分子具有优良的抑制活性,IC₅₀值在0.98~0.37 mg/L之间,低于阳性参照物齐墩果酸[(1.19±0.27) mg/L],有望成为潜在的PTP1B抑制剂。

关键词: 三唑并噻二唑, 三嗪, 细胞分裂周期25磷酸酯酶B, 蛋白酪氨酸磷酸酶1B

Abstract:

Eighteen novel molecules(4a~4i and 5a~5i) containing 1,2,4-triazole [3,4-b]-1,3,4-thiadiazol and 1,3,5-triazine connected by benzoamino bridge were synthesized. The structures of target molecules were characterized by infrared spectroscopy(IR), nucleic magnetic resonance spectrometry(NMR) and high resolution mass spectrometry(HRMS). Compounds 1A(2,6-dimorpholino-4-chloro-1,3,5-triazin) and 1B(2,6-dipyrrolidin-4-chloro-1,3,5-triazin) were synthesized by the reaction of cyanuric chloride with morpholine or tetrahydropyrrole respectively. The important intermediates 2A and 2B were then afforded by the reaction 1A and 1B with p-aminobenzoic acid respectively. Compounds 3a~3h were obtained by the condensation reaction of eight kinds of aliphatic acids with thiocarbohydrazide using melting method. The target molecules were finally afforded by the reaction of 2A and 2B with 3a~3h respectively under the catalysis of phosphorus oxychloride and tetrabutyl ammonium bromide. In order to compare the effect of 3-aliphatic and 3-benzyl on the bioactivity, 4i and 5i were synthesized according to the same method. The inhibitory activities against cell division cycle 25B(Cdc25B) and protein tyrosine phosphatase 1B(PTP1B) of the target molecules were evaluated. The results show that all of the target molecules have good inhibition against Cdc25B, the values of half inhibition concentration(IC₅₀) are 2.40~0.31 mg/L, the values of IC₅₀ of the target molecules 4a~4f and 5a~5i are lower than contrast reference trisodium vanadate((1.25±0.14) mg/L), they are expected to be the potential inhibitors against Cdc25B; In the test of PTP1B, fourteen target molecules have good inhibitory activity, the values of IC₅₀ are 0.98~0.37 mg/L, which are lower than that of contrast reference oleanolic acid((1.19±0.27) mg/L), and they are expected to be the potential inhibitors against PTP1B.

Key words: triazole [3,4-b]-1,3,4-thiadiazol, triazine, cell division cycle 25B, protein tyrosine phosphatase 1B

张成路, 李传银, 杨蒙, 朱长安, 孙晓娜, 李益政. 新型细胞分裂周期25磷酸酯酶B和蛋白酪氨酸磷酸酶1B抑制剂三唑并噻二唑-均三嗪的合成[J]. 应用化学, 2017, 34(4): 385-393.

ZHANG Chenglu, LI Chuanyin, YANG Meng, ZHU Changan, SUN Xiaona, LI Yizheng. Synthesis of 1,2,4-Triazolo[3,4-b]thiadiazole-S-Triazine, Novel Cell Division Cycle 25B and Protein Tyrosine Phosphatase 1B Inhibitors[J]. Chinese Journal of Applied Chemistry, 2017, 34(4): 385-393.

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