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In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of N- and N,C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120451 | PMC |
| http://dx.doi.org/10.1080/14756366.2022.2158187 | DOI Listing |
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- In a study of 22 cancer cell lines, PDIA1 and PDIA3 were found to be the most abundant isoforms, while PDIA17 showed varying expression levels across different cell lines.
- Inhibition of PDIA1 and PDIA3 led to significant anti-proliferative effects in breast cancer cells, with the most notable effects seen in hormone-sensitive MCF-7 cells, suggesting potential strategies for targeted cancer therapies.
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