通过抑制DKK1-Wnt/β-catenin通路，设计、合成和研究了新型吡咯[2,3-d]嘧啶衍生物的抗骨肉瘤活性。
Design, synthesis and anti-osteosarcoma activity study of novel pyrido[2,3-d]pyrimidine derivatives by inhibiting DKK1-Wnt/β-catenin pathway.
发表日期：2023 Sep 09
作者：
Yanni Shen, Qian Xie, Yiling Wang, Jianhui Liang, Cuilu Jiang, Xiaoping Liu, Yan Wang, Chun Hu
来源：
BIOORGANIC CHEMISTRY
摘要：
骨肉瘤是青少年常见的主要恶性骨肿瘤。Wnt/β-连环蛋白被证明在骨肉瘤中起着促癌作用，并且被过度活化。因此，该途径已成为骨肉瘤的有趣治疗靶点。在此，我们报道了一系列基于以前工作的新型吡咯并[2,3-d]嘧啶类衍生物的设计、合成和生物活性。其中，代表性化合物2-{[1,3-二甲基-7-(4-甲基哌嗪-1-基)-2,4-二氧杂-1,2,3,4-四氢吡咯[2,3-d]嘧啶-5-基]氨基}-N-[4-(三氟甲氧基)苯基]乙酰胺 (7m) 对143B和MG63细胞表现出良好的抗增殖活性，并且对非癌症HSF细胞具有良好的选择性。在Ca2+浓度试验中，化合物7m增加了143B细胞的细胞内Ca2+浓度。此外，7m处理使得DKK1的表达增加，p-β-连环蛋白的表达减少。最后，Hoechst 33,342染色、Annexin-FITC/PI染色和线粒体荧光染色明确显示了化合物7m在143B细胞中诱导细胞凋亡。版权所有 © 2023年。Elsevier Inc.出版。
Osteosarcoma is a common primary malignant bone tumor in adolescents. Wnt/β-catenin has been proved to play a pro-oncogenic role and was overactivated in osteosarcoma. Therefore, this pathway has become an interesting therapeutic target for osteosarcoma. Herein we report the design, synthesis and biological activities of a series of novel pyrido[2,3-d]pyrimidine derivatives based on our previous work. Among these, the representative compound 2-{[1,3-dimethyl-7-(4-methylpiperazin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]amino}-N-[4-(trifluoromethoxy)phenyl]acetamide (7m) has exhibited good antiproliferative activity towards 143B and MG63 cells with good selectivity over non-cancerous HSF cells. In the assay of Ca2+ concentration, the compound 7m increased the intracellular Ca2+ concentration in 143B cells. In addition, the expression of DKK1 increased, and that of p-β-catenin decreased by 7m treatment. Finally, the Hoechst 33,342 staining, Annexin-FITC/PI staining and mitochondrial fluorescence staining have clearly demonstrated that compound 7m induced apoptosis in 143B cells.Copyright © 2023. Published by Elsevier Inc.