- Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations
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Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure-activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.
- Cai, Jiongheng,Chen, Yadong,Chen, Yun,Cheng, Jie,Cheng, Zitian,Heng, Hao,Huang, Fei,Jia, Kun,Li, Hongmei,Lu, Shuai,Lu, Tao,Ren, Jiwei,Sheng, Tiancheng,Song, Shiyu,Tang, Weifang,Wang, Zhijie,Wu, Yingli,Zhu, Yifan
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p. 14664 - 14701
(2021/10/12)
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- Triptycene-based, carboxylate-bridged biomimetic diiron(II) complexes
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A triptycene-based bis(benzimidazole) ester ligand, L3, was designed to enhance the electron-donating ability of the heterocyclic nitrogen atoms relative to those of the first-generation bis(benzoxazole) analogs, L1 and L2. A convergent synthesis of L3 was designed and executed. Three-component titration experiments using UV/Vis spectroscopy revealed that the desired diiron(II) complex could be obtained with a 1:2:1 ratio of L3/Fe(OTf)2(MeCN) 2/external carboxylate reactants. X-ray crystallographic studies of two diiron complexes derived in this manner from L3 revealed their formulas to be [Fe2L3(μ-OH)(μ-O2CR)(OTf)2], where R = 2,6-bis(p-tolyl)phenyl (7) or triphenylmethyl (8). The structures are similar to that of a diiron complex derived from L1, [Fe2L1(μ-OH)(μ- O2CArTol)(OTf)2] (9), a notable difference being that, in 7 and 8, the geometry at iron more closely resembles square-pyramidal than trigonal-bipyramidal. Moessbauer spectroscopic analyses of 7 and 8 indicate the presence of high-spin diiron(II) cores. These results demonstrate the importance of substituting benzimidazole for benzoxazole for assembling biomimetic diiron complexes with syn disposition of two N-donor ligands, as found in O2-activating carboxylate-bridged diiron centers in biological systems. Copyright
- Li, Yang,Soe, Chan Myae Myae,Wilson, Justin J.,Tuang, Suan Lian,Apfel, Ulf-Peter,Lippard, Stephen J.
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p. 2011 - 2019
(2013/06/05)
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- SUBSTITUTED BENZIMIDAZOLES, BENZOTHIAZOLES AND BENZOXAZOLES
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The present invention relates to substituted benzimidazoles, benzothiazoles and benzoxazoles, processes for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
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Page/Page column 119-120
(2010/12/29)
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