889945-82-8Relevant articles and documents
Preparation and application of novel eEF2K depressant
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Paragraph 0051-0053; 0055, (2018/05/01)
The invention relates to preparation and application of an eEF2K depressant and belongs to the technical field of antitumor pharmacy. A technical problem to be solved by the invention is to provide acompound as the eEF2K depressant. The compound comprises a compound represented by a formula shown in the description or pharmaceutically acceptable salts thereof. The compound or pharmaceutically acceptable salts thereof can serve as the eEF2K depressant, have certain anti-tumor activity and can effectively depress the growth of cancer cells. The compound disclosed by the invention has an obviousdepression action on a variety of tumor cells, particularly three-negative mammary cancer cells.
Design, synthesis and structure-activity relationship of a focused library of β-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer
Guo, Yongzhi,Zhao, Yuqian,Wang, Guan,Chen, Yi,Jiang, Yingnan,Ouyang, Liang,Liu, Bo
, p. 402 - 418 (2017/12/07)
Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a β-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity. After several rounds of kinase and anti-proliferative activity screening, we discovered an eEF2K inhibitor (21l) with best eEF2K enzymatic activity (IC50 of 5.5 μM) and anti-proliferative activity (MDA-MB-231 cells, IC50 of 12.6 μM, MDA-MB-436 cells, IC50 of 19.8 μM). Moreover, we found that 21l could induce cell death via the apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. Subsequently, we evaluated its anti-tumor activity and apoptosis-inducing mechanisms in vivo. These results suggested that 21l inhibited tumor growth by apoptosis in the xenograft mouse model of breast cancer (MDA-MB-231 and MDA-MB-436). Collectively, our results demonstrate a novel small-molecule inhibitor targeting eEF2K with mechanism of apoptosis and a therapeutic potential in breast cancer.
Synthesis, in vitro and in vivo biological evaluation, and comprehensive understanding of structure-activity relationships of dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids
Zhu, Yongqiang,Wu, Gang,Zhu, Xinrong,Ma, Yuheng,Zhao, Xin,Li, Yuejie,Yuan, Yunxia,Yang, Jie,Yu, Sen,Shao, Feng,Lei, Meng
supporting information; experimental part, p. 8619 - 8626 (2011/03/20)
An extensive structure-activity relationship (SAR) study of 72 dipeptidyl boronic acid proteasome inhibitors constructed fromβ -amino acids is reported. SAR analysis revealed that bicyclic groups at the R1 position, 3-F substituents at the Rsu
Stereoselective chemoenzymatic preparation of β-amino esters: Molecular modelling considerations in lipase-mediated processes and application to the synthesis of (S)-dapoxetine
Rodriguez-Mata, Maria,Garcia-Urdiales, Eduardo,Gotor-Fernandez, Vicente,Gotor, Vicente
supporting information; experimental part, p. 395 - 406 (2010/06/15)
A wide range of optically active 3-amino-3-arylpropanoic acid derivatives have been prepared by means of a stereoselective chemoenzymatic route. The key step is the kinetic resolution of the corresponding β-amino esters. Although the enzymatic acylations of the amino group with ethyl methoxyacetate showed synthetically useful enantioselectivities, the hydrolyses of the ester group catalyzed by lipase from Pseudomonas cepacia have been identified as the optimal processes concerning both activity and enantioselectivity. The enantiopreference of this lipase in these reactions has been explained, at the molecular level, by using a fragment-based approach in which the most favoured binding site for a phenyl ring and the most stable conformation of the 3-aminopropanoate core nicely match the (S)-configuration of the major products. The conversion and enantioselectivity values of the enzymatic reactions have been compared in order to understand the influence of the different substitution patterns present in the phenyl ring. This chemoenzymatic route has been successfully applied to the preparation of a valuable intermediate in the synthesis of (S)-dapoxetine, which has been chemically synthesised in excellent optical purity.
