Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines

Abstract

The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed against cancer. However, to the best of our knowledge, aziridine derivatives showing inhibitory activity towards proteasome have never been described before. Herein we report a new class of selective and nonPIs bearing an aziridine ring as a core structure. In vitro cell-based assays (two leukemia cell lines) also displayed anti-proliferative activity for some compounds. In silico studies indicated non-covalent binding mode and drug-likeness for these derivatives. Taken together, these results are promising for developing more potent PIs.

Synthesis of SARS-CoV-2 Mpro inhibitors bearing a cinnamic ester warhead with in vitro activity against human coronaviruses

“…[14][15][16] Taking into account the relevant reactivity of conjugated double bonds towards nucleophiles, we decided to exploit the cinnamic ester moiety for the design of novel peptide-based SARS-CoV-2 M pro inhibitors, in the context of our ongoing research activity aimed at the identification of protease inhibitors. [17][18][19] In this study we present a panel of 11 unprecedented p-aminocinnamic ethyl esters derivatives, which are joined to a L-Phe residue variously decorated at the N-terminus with carbamate, urea and indole-bearing amide recognition functionalities. The enzymatic assays against viral proteases revealed that these compounds are selective inhibitors of SARS-CoV-2 M pro with IC 50 values in the lower micromolar range, in comparison to that of PL pro (no inhibition at 20 μM).…”

Recent advances in the accessibility, synthetic utility, and biological applications of aziridines

“…2). 105 Other anticancer aziridine bearing molecules were reported by Cheke et al as inhibitors of the stem cell growth factor receptor often known as the c-KIT kinase domain. This is one of the 20 subfamilies of human receptor tyrosine kinases (RTKs) which is one of the main studied targets to fight cancer.…”

Selective noncovalent proteasome inhibiting activity of trifluoromethyl‐containinggem‐quaternary aziridines

“…AMBER 14 force field was used for the simulation. [29] The MD simulations of the complexes were performed with the YASARA structure package according to our previously reported procedures. [46,47]…”

“…Considering the results achieved so far regarding the development of noncovalent PIs [ 28–31 ] and in agreement with preliminary docking studies, the inhibitory activity of a set of bis‐homologated chloromethyl(trifluoromethyl)aziridines (CMTMAs) was evaluated toward this anticancer target. [ 32 ]…”

“…On the other hand, promising diverse noncovalent inhibitors (e.g., 4, 5, and 6) have been identified, showing reduced toxicity and providing a different mechanism for solid tumors due to the rapid binding and dissociation kinetics of the noncovalent interactions (Figure 2b). [14] Considering the results achieved so far regarding the development of noncovalent PIs [28][29][30][31] and in agreement with preliminary docking studies, the inhibitory activity of a set of bis-homologated chloromethyl(trifluoromethyl)aziridines (CMTMAs) was evaluated toward this anticancer target. [32] 2 | RESULTS AND DISCUSSION…”