Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors.
Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors.
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作为新型蛋白激酶 CK2 抑制剂的色酮衍生物的设计、合成和生物学评价。
DOI：
10.1016/j.bmcl.2022.128799
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发表时间：
2022
影响因子：
2.7
通讯作者：
Hao Wang
中科院分区：
文献类型：
--
作者：
Quan Wang;Xiao;Wei;H. Long;Hao Wang
蛋白激酶CK 2是发现抗癌药物的潜在靶点。据报道，黄酮类化合物是有效的CK 2抑制剂。本文基于黄酮类化合物的结构修饰，通过色酮骨架与2-氨基噻唑骨架的杂交，设计合成了一系列色酮-2-氨基噻唑衍生物（1a-d，2a-g，4a-j，5a-k）。其中化合物5i是最有效的CK 2抑制剂（IC_（50）= 0.08 μM），对HL-60肿瘤细胞具有较强的抗增殖活性（IC_（50）= 0.25 μM）。细胞热位移实验（CESTA）证实5 i与CK 2直接结合，并模拟了5 i与CK 2可能的结合方式。进一步的研究表明，5i可诱导HL-60细胞凋亡，并使细胞周期阻滞。Western-blot分析显示5 i c对CK 2下游的α-catenin/Akt通路和PARP/Survivin通路均有抑制作用。
Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2-aminothiazole derivatives (1a-d,2a-g,4a-j,5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound5iwas the most effective CK2 inhibitor (IC50= 0.08 μM) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC50= 0.25 μM). Cellular thermal shift assay (CESTA) confirmed that5idirectly bound to the CK2, and the possible binding mode of5itoward CK2 was also simulated. Further studies showed that5iinduced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that5icould inhibit the downstream of CK2, including α-catenin/Akt pathway and PARP/Survivin pathway.
影响因子：
7.3
作者：
Bestgen B;Krimm I;Kufareva I;Kamal AAM;Seetoh WG;Abell C;Hartmann RW;Abagyan R;Cochet C;Le Borgne M;Engel M;Lomberget T
通讯作者：
Lomberget T