151911-22-7Relevant articles and documents
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.
Kinetic Resolution of Aromatic β-Amino Acids Using a Combination of Phenylalanine Ammonia Lyase and Aminomutase Biocatalysts
Weise, Nicholas J.,Ahmed, Syed T.,Parmeggiani, Fabio,Turner, Nicholas J.
supporting information, p. 1570 - 1576 (2017/05/05)
An enzymatic strategy for the preparation of (R)-β-arylalanines employing phenylalanine aminomutase and ammonia lyase (PAM and PAL) enzymes has been demonstrated. Candidate PAMs with the desired (S)-selectivity from Streptomyces maritimus (EncP) and Bacillus sp. (PabH) were identified via sequence analysis using a well-studied template sequence. The newly discovered PabH could be linked to the first ever proposed biosynthesis of pyloricidin-like secondary metabolites and was shown to display better β-lyase activity in many cases. In spite of this, a method combining the higher conversion of EncP with a strict α-lyase from Anabaena variabilis (AvPAL) was found to be more amenable, allowing kinetic resolution of five racemic substrates and a preparative-scale reaction with >98% (R) enantiomeric excess. This work represents an improved and enantiocomplementary method to existing biocatalytic strategies, allowing simple product separation and modular telescopic combination with a preceding chemical step using an achiral aldehyde as starting material. (Figure presented.).
The bacterial ammonia lyase EncP: A tunable biocatalyst for the synthesis of unnatural amino acids
Weise, Nicholas J.,Parmeggiani, Fabio,Ahmed, Syed T.,Turner, Nicholas J.
supporting information, p. 12977 - 12983 (2015/10/28)
Enzymes of the class I lyase-like family catalyze the asymmetric addition of ammonia to arylacrylates, yielding high value amino acids as products. Recent examples include the use of phenylalanine ammonia lyases (PALs), either alone or as a gateway to deracemization cascades (giving (S)- or (R)-α-phenylalanine derivatives, respectively), and also eukaryotic phenylalanine aminomutases (PAMs) for the synthesis of the (R)-β-products. Herein, we present the investigation of another family member, EncP from Streptomyces maritimus, thereby expanding the biocatalytic toolbox and enabling the production of the missing (S)-β-isomer. EncP was found to convert a range of arylacrylates to a mixture of (S)-α- and (S)-β-arylalanines, with regioselectivity correlating to the strength of electron-withdrawing/-donating groups on the ring of each substrate. The low regioselectivity of the wild-type enzyme was addressed via structure-based rational design to generate three variants with altered preference for either α- or β-products. By examining various biocatalyst/substrate combinations, it was demonstrated that the amination pattern of the reaction could be tuned to achieve selectivities between 99:1 and 1:99 for β:α-product ratios as desired.
