Hou Shicheng, Xu Henan, Hu Jianshu, Hou Jian, Wang Yan, Jin Zhe, Wan David C C, Hu Chun
Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016. China.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR. China.
Med Chem. 2018;14(1):67-73. doi: 10.2174/1573406413666171002121443.
Osteoporosis (OP) is a common bone disease, most often diagnosed in post-menopausal women. The majority of OP treatments are focused on manipulation of the patient's hormone levels, therefore, they are associated with significant adverse effects.
The study aimed to design, synthesize and evaluate the β-catenin translocation capability and the alkaline phosphatase (ALP) activation activity of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives.
The styrene derivatives were synthesized as raw materials, followed by oxidation and condensation reactions, in which 6-aryl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one derivatives (1) were obtained. The 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones (2) were obtained by a condensation reaction of compound 1 with substituted phenacyl chlorides in acetic acid. The target compounds 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones (3a-3c) were prepared by compound 2 with substituted alkyl chloride by Williamson reaction. As to 6-benzyl-3-aryl-7H-thiazolo[3,2- b]-1,2,4-triazin-7-one derivatives as the target compounds, the benzaldehyde and acetylglycine used as raw materials, followed by Erlenmeyer-Plochl reaction, condensation reaction, hydrolysis reaction, condensation reaction, 6-benzyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one derivatives were obtained, and were converted to the target compounds 6-benzyl-3-(hydroxylaryl)-7Hthiazolo[ 3,2-b]-1,2,4-triazin-7-one derivatives (5a-5d) using reaction with substituted α-phenacyl chlorides. Finally, Williamson reaction were used to yield 6-benzyl-3-aryl-7H-thiazolo[3,2-b]- 1,2,4-triazin-7-ones as target compounds (6a-6e). The β-catenin translocation capability and the ALP activation activity were tested, and the glycogen synthase kinase-3 (GSK-3) inhibition was simulated by molecular docking.
Fourteen 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were synthesized and characterized by mass spectra, proton NMR and infrared spectra, the β-catenin translocation capability and the ALP activation activities of the target compounds were tested and calculated. The EC50 value of the ALP activation activity of 6-(4-chlorobenzyl)-3-{4-[(2-dimethylamino)-2- oxoethoxy]phenyl}-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one (6b) was 11.283 µM. The molecular docking results have showed that the target compounds would be GSK-3 inhibitors.
Based on the results of the biological activity test, the target compounds have exhibited the β-catenin translocation capability and the ALP activation activity.
骨质疏松症（OP）是一种常见的骨病，最常被诊断于绝经后女性。大多数OP治疗方法都集中在调节患者的激素水平上，因此，它们会带来显著的副作用。
本研究旨在设计、合成并评估7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮衍生物的β-连环蛋白转位能力和碱性磷酸酶（ALP）激活活性。
以苯乙烯衍生物为原料进行合成，经过氧化和缩合反应，得到6-芳基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮衍生物（1）。化合物1与取代苯甲酰氯在乙酸中发生缩合反应，得到3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮（2）。通过化合物2与取代烷基氯经威廉姆森反应制备目标化合物3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮（3a - 3c）。对于作为目标化合物的6-苄基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮衍生物，以苯甲醛和乙酰甘氨酸为原料，经过埃伦迈尔-普洛赫尔反应、缩合反应、水解反应、缩合反应，得到6-苄基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮衍生物，并通过与取代α-苯甲酰氯反应转化为目标化合物6-苄基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮衍生物（5a - 5d）。最后，经威廉姆森反应得到作为目标化合物的6-苄基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮（6a - 6e）。测试了β-连环蛋白转位能力和ALP激活活性，并通过分子对接模拟糖原合酶激酶-3（GSK-3）抑制作用。
合成了14种7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮衍生物，并通过质谱、质子核磁共振和红外光谱进行了表征，测试并计算了目标化合物的β-连环蛋白转位能力和ALP激活活性。6-(4-氯苄基)-3-{4-[(2-二甲基氨基)-2-氧代乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮（6b）的ALP激活活性的EC50值为11.283 μM。分子对接结果表明目标化合物为GSK-3抑制剂。
基于生物活性测试结果，目标化合物表现出β-连环蛋白转位能力和ALP激活活性。
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