- Design, synthesis and biological evaluation of pyridone–aminal derivatives as MNK1/2 inhibitors
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Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So, MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone–aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular, compound 42i (MNK1 IC50 = 7.0 nM; MNK2 IC50 = 6.1 nM) proved to be the most potent compound against TMD-8 cell line with IC50 value of 0.91 μM. Furthermore, 42i could block the phosphorylation level of eIF4E in CT-26 cell line, and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon cancer.
- Yuan, Xinrui,Wu, Hanshu,Bu, Hong,Zheng, Peiyuan,Zhou, Jinpei,Zhang, Huibin
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p. 1211 - 1225
(2019/02/28)
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- Substituted pyrimidine compounds and application thereof
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The invention relates to substituted pyrimidine compounds and an application thereof. The substituted pyrimidine compounds are compounds shown in a formula I (the specific structure is shown in the specification or claims), stereoisomers of the compounds or pharmaceutically acceptable salts of the compounds. An in-vitro activity test proves that the substituted pyrimidine compounds have cholinesterase inhibiting activity, metal ion chelation, inhibition of generation of metal ion induced free radicals, inhibition of metal ion induced Abeta aggregation and the like. Therefore, the substituted pyrimidine compounds are expected to be used for preparing Alzheimer's disease treating and/or preventing drugs.
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Paragraph 0102; 0103; 0104; 0105; 0106
(2016/10/08)
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- Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents
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Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.
- Li, Xiaokang,Wang, Huan,Lu, Zhengyu,Zheng, Xinyu,Ni, Wei,Zhu, Jin,Fu, Yan,Lian, Fulin,Zhang, Naixia,Li, Jian,Zhang, Haiyan,Mao, Fei
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p. 8326 - 8344
(2016/10/03)
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