Synthesis of α-fluorocinnamate derivatives as novel cathepsin S inhibitors with in vitro antiproliferative activity against pancreatic cancer cells.
| Autor: | Citarella A; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy. Electronic address: andrea.citarella@unimi.it., Petrella S; Laboratory of Gynecological Preclinical Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via M. Negri 2, 20156 Milan, Italy., Moi D; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Dimasi A; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Braga T; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Ruberto L; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Pieraccini S; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Sironi M; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Micale N; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, I-98166 Messina, Italy., Schirmeister T; Department of Medicinal Chemistry, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany., Damia G; Laboratory of Gynecological Preclinical Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via M. Negri 2, 20156 Milan, Italy., Fasano V; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Silvani A; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Giannini C; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy., Passarella D; Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy. |
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| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Dec 01; Vol. 115, pp. 117987. Date of Electronic Publication: 2024 Nov 05. |
| DOI: | 10.1016/j.bmc.2024.117987 |
| Abstrakt: | Cathepsins, key members of the papain-like family of cysteine proteases, are crucial for proteolysis processes within human cells, including osteolysis, immunomodulation and apoptosis. Recent research has highlighted the significant role of cathepsins, particularly the L, S, K, and B subtypes, in pancreatic cancer. This has driven the development of novel cathepsin inhibitors as potential treatments to inhibit tumor progression, migration and invasion. Targeting cathepsin S (CatS) has shown promise in reducing tumor progression and enhancing the efficacy of chemotherapeutic agents in preclinical models. Building on our previous work where we employed ethyl p-aminocinnamate ester derivatives for covalent inhibition of cysteine proteases, herein we have designed and synthesized three new derivatives basing on an isosteric replacement (H-F) at the level of cinnamate moiety. These derivatives emerged as potent covalent inhibitors of CatS (1.8-2.6 µM) with 2F showing also weak inhibition activity against CatL (20 %) and CatB (29 %). In vitro assays of 2F against pancreatic cancer cell lines BXPC3 and CAPAN1 revealed significant antiproliferative activity, with IC Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrea Citarella reports financial support was provided by University of Milan. Andrea Citarella reports a relationship with University of Milan that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
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