133407-82-6Relevant articles and documents
A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities
An, Jing,Chen, Yiling,Ciechanover, Aaron,Fuk-Woo Chan, Jasper,Huang, Lina S.,Huang, Ziwei,Liang, Boqiang,Nie, Linlin,Wang, Juan,Warshel, Arieh,Wu, Meixian,Wu, Yi,Xu, Yan,Ye, Hui,Yuan, Shuofeng,Yuen, Kwok-Yung,Zhou, Jiao
, (2021/02/27)
Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.
Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif
Stein, Martin L.,Cui, Haissi,Beck, Philipp,Dubiella, Christian,Voss, Constantin,Krueger, Achim,Schmidt, Boris,Groll, Michael
, p. 1679 - 1683 (2014/03/21)
The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophi
Synthesis and SAR study of novel peptide aldehydes as inhibitors of 20S proteasome
Ma, Yuheng,Xu, Bo,Fang, Yuan,Yang, Zhenjun,Cui, Jingrong,Zhang, Liangren,Zhang, Lihe
scheme or table, p. 7551 - 7564 (2011/11/14)
Based on the analysis of the crystal structure of MG101 (1) and 20S proteasomes, a new series of peptide aldehyde derivatives were designed and synthesized. Their ability to inhibit 20S proteasome was assayed. Among them, Cbz-Glu(OtBu)-Phe-Leucinal (3c), Cbz-Glu(OtBu)-Leu-Leucinal (3d), and Boc-Ser(OBzl)-Leu-Leucinal (3o) exhibited the most activity, which represented an order of magnitude enhancement compared with MG132 (2). The covalent docking protocol was used to explore the binding mode. The structure-activity relationship of the peptide aldehyde inhibitors is discussed.
