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

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.

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

“…Among the series of novel α-ketophenylamide derivatives as anticancer agents, derivative 22 (Figure ) was selected as a representative compound to be tested in the SARS-CoV-2 cell infection assay, and it was found to actively block viral infection in in vitro models (EC 50 of 1.28 μM in the plaque reduction assay). Despite the lack of target inhibition data, the antiviral effect exhibited in the cell assay could be attributed to the inhibition of M PRO due to its structural similarity with the above-mentioned α-ketoamide derivatives …”

Main Chemotypes of SARS-CoV-2 Reproduction Inhibitors

“…The fi rst group of compounds with a signifi cant antiviral effect is peptidomimetics 1-23 [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] (Figs. 1, 2).…”

“…Compounds of this group can be conditionally divided into aryl(hetaryl)aminoacetic acid derivatives 1 [30], 3 [32], 6 [33], and 10 [36] and benzotriazolylacetic acid derivatives 2 [31], 4 [32], and 5 [32], serine and isoserine derivatives 7-9 [34,35] (Fig. 1), as well as compounds 11-23 [36][37][38][39][40][41][42][43][44][45][46][47][48] (Fig. 2), which contain several amino acid units, often leucine units 11 [36,37,38], 12 [39], 14 [41], 15 [36,42], 19 [45], 20 [42], and 22 [47].…”

“…1), as well as compounds 11-23 [36][37][38][39][40][41][42][43][44][45][46][47][48] (Fig. 2), which contain several amino acid units, often leucine units 11 [36,37,38], 12 [39], 14 [41], 15 [36,42], 19 [45], 20 [42], and 22 [47]. A common feature of peptidomimetics is that they contain lipophilic substituents (most frequently tert-alkyl, aromatic, or heteroaromatic), which suggests the importance of binding to hydrophobic sites of the target.…”

Synthesis of aspirin-curcumin mimic conjugates of potential antitumor and anti-SARS-CoV-2 properties

“…This is why new effective agents are still in demand. Due to the reports mentioned for the anti-SARS-CoV-2 properties of diverse antitumor active agents [69] , [70] , [71] , the targeted conjugates within the current study will be intended for anti-SARS-CoV-2 properties investigation. The successful clinical reports for treating the colon cancer patients with antiviral drugs alone or with antitumor drugs [72] also add good support for the aim of the present study directed towards optimizing new hits of dual functions as antitumor and anti-SARS-CoV-2 with safety properties against normal cells.…”