247068-84-4Relevant articles and documents
Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis
Wang, Penghui,Wang, Xuewei,Wang, Zhengning,Zhao, Junfeng
supporting information, p. 10374 - 10381 (2021/07/26)
Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.
Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles
Dong, Xiao-Wu,Zhang, Jian-Kang,Xu, Lei,Che, Jin-Xin,Cheng, Gang,Hu, Xiao-Bei,Sheng, Li,Gao, An-Hui,Li, Jia,Liu, Tao,Hu, Yong-Zhou,Zhou, Yu-Bo
, p. 602 - 614 (2019/01/11)
The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.
BETA-SUBSTITUTED BETA-AMINO ACIDS AND ANALOGS AS CHEMOTHERAPEUTIC AGENTS AND USES THEREOF
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Paragraph 0569; 0885; 0908, (2017/02/28)
β-Substituted β-amino acids, β-substituted β-amino acid derivatives, and β-substituted β-amino acid analogs and (bio)isosteres and their use as chemotherapeutic agents are disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres are selective LAT1/4F2hc substrates and exhibit rapid uptake and retention in tumors expressing the LAT1/4F2hc transporter. Methods of synthesizing the β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and methods of using the compounds for treating cancer are also disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs exhibit selective uptake in tumor cells expressing the LAT1/4F2hc transporter and accumulate in cancerous cells when administered to a subject in vivo. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres exhibit cytotoxicity toward several tumor types.
