Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.

Autor: Ibba R; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. Electronic address: ribba@uniss.it., Sestito S; Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100, Sassari, Italy. Electronic address: ssestito@uniss.it., Ambrosio FA; Department of Health Sciences, University 'Magna Græcia' of Catanzaro, Campus 'S. Venuta', 88100, Catanzaro, Italy. Electronic address: ambrosio@unicz.it., Marchese E; Department of Health Sciences, University 'Magna Græcia' of Catanzaro, Campus 'S. Venuta', 88100, Catanzaro, Italy. Electronic address: e.marchese@unicz.it., Costa G; Department of Health Sciences, University 'Magna Græcia' of Catanzaro, Campus 'S. Venuta', 88100, Catanzaro, Italy; Net4Science Academic Spin-Off, University 'Magna Græcia' of Catanzaro, Campus 'S. Venuta', 88100, Catanzaro, Italy. Electronic address: gcosta@unicz.it., Fiorentino FP; Kitos Biotech Srls, Tramariglio, Alghero, SS, Italy. Electronic address: fpfiorentino@kitosbiotech.org., Fusi F; Department of Biotechnologies, Chemistry and Pharmacy, University of Siena, 53100, Siena, Italy. Electronic address: fabio.fusi@unisi.it., Marchesi I; Kitos Biotech Srls, Tramariglio, Alghero, SS, Italy. Electronic address: imarchesi@kitosbiotech.org., Polini B; Department of Pathology, University of Pisa, 56100, Pisa, Italy. Electronic address: beatrice.polini@farm.unipi.it., Chiellini G; Department of Pathology, University of Pisa, 56100, Pisa, Italy. Electronic address: grazia.chiellini@unipi.it., Alcaro S; Department of Health Sciences, University 'Magna Græcia' of Catanzaro, Campus 'S. Venuta', 88100, Catanzaro, Italy; Net4Science Academic Spin-Off, University 'Magna Græcia' of Catanzaro, Campus 'S. Venuta', 88100, Catanzaro, Italy. Electronic address: alcaro@unicz.it., Piras S; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. Electronic address: piras@uniss.it., Carta A; Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. Electronic address: acarta@uniss.it.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Oct 05; Vol. 276, pp. 116647. Date of Electronic Publication: 2024 Jul 07.
DOI: 10.1016/j.ejmech.2024.116647
Abstrakt: Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of Ca V 1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Carta reports financial support was provided by Ministry of Education and Merit. Simona Sestito reports financial support was provided by Ministry of Education and Merit. 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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