Design, Synthesis, and Evaluation of Cystargolide-based β-lactones as Potent Proteasome Inhibitors
| Autor: | C. Le Chapelain, Liam P. Hallada, Rodolfo Tello-Aburto, Doleshwar Niroula, D. Dotson, Michael Groll, S.K. Ganegamage, Snezna Rogelj |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Proteasome Endopeptidase Complex Cell Survival Protein subunit Antineoplastic Agents 010402 general chemistry Crystallography X-Ray 01 natural sciences Article chemistry.chemical_compound Lactones Structure-Activity Relationship Drug Discovery medicine Tumor Cells Cultured Structure–activity relationship Humans Cytotoxicity Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry General Medicine Dipeptides Carfilzomib 0104 chemical sciences Proteasome Biochemistry chemistry Cell culture Drug Design Proteasome inhibitor Proteasome Inhibitors Intracellular medicine.drug |
| Popis: | The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P(1)), peptidic core, (P(x) and Py), and end-cap (P(z)) of our scaffold. The cystargolide derivative 5k, structurally unique at both P(y) and P(1), exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC(50) = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC(50) = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib. |
| Databáze: | OpenAIRE |
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