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A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities. | LitMetric

A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities.

Eur J Med Chem

Nobel Institute of Biomedicine, Zhuhai, 519000, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, 518172, China. Electronic address:

Published: April 2021

AI Article Synopsis

  • Researchers have extensively explored proteasome inhibitors for treating diseases like cancer, autoimmune disorders, and viral infections.
  • The study developed novel α-keto phenylamide derivatives targeting both the primed and non-primed sites of the proteasome, optimizing their potency through various modifications.
  • Several derivatives showed strong proteasome inhibition and anticancer effects, with one specifically effective against SARS-CoV-2, indicating potential for new antiviral treatments for COVID-19.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873610PMC
http://dx.doi.org/10.1016/j.ejmech.2021.113267DOI Listing

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