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Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones

2012Journal article Open access
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dc.contributor.authorPalmeira, Andreia
dc.contributor.authorVasconcelos, M. Helena
dc.contributor.authorPaiva, Ana
dc.contributor.authorFernandes, Miguel X.
dc.contributor.authorPinto, Madalena
dc.contributor.authorSousa, Emília
dc.date.accessioned2023-02-09T14:44:55Z
dc.date.available2023-02-09T14:44:55Z
dc.date.issued2012
dc.description.abstractFor many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C–N cross-coupling reaction. The obtained aminated thioxanthones were highly effective at inhibiting P-gp and/or causing growth inhibition in a chronic myelogenous leukemia cell line, K562. Six of the aminated thioxanthones had GI50 values in the K562 cell line below 10 mM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI50 concentration (1.90 mM) 6-fold lower than doxorubicin (11.89 mM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1H-benzimidazol-2-yl)ethanamine]-4-propoxy-9H-thioxanthen-9-one (45), which caused an accumulation rate of rhodamine-123 similar to that caused by verapamil in the K562Dox resistant cell line, and a decrease in ATP consumption by P-gp. At a concentration of 10 mM, compound 45 caused a decrease of 12.5-fold in the GI50 value of doxorubicin in the K562Dox cell line, being 2-fold more potent than verapamil. From the overall results, the aminated thioxanthones represent a new class of P-gp inhibitors with improved efficacy in sensitizing a resistant P-gp overexpressing cell line (K562Dox) to doxorubicin.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPalmeira, A., Vasconcelos, M. H., Paiva, A., Fernandes, M. X., Pinto, M., & Sousa, E. (2012). Dual inhibitors of P-glycoprotein and tumor cell growth:(re) discovering thioxanthones. Biochemical pharmacology, 83(1), 57-68.pt_PT
dc.identifier.doi10.1016/j.bcp.2011.10.004pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.13/5022
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationStrategic Project - UI 4040 - 2011-2012
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectThioxanthonespt_PT
dc.subjectP-glycoproteinpt_PT
dc.subjectMultidrug resistancept_PT
dc.subjectAnticancerpt_PT
dc.subjectDual ligandspt_PT
dc.subject.pt_PT
dc.subjectFaculdade de ciências Exatas e da Engenhariapt_PT
dc.titleDual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthonespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleStrategic Project - UI 4040 - 2011-2012
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI4040%2F2011/PT
oaire.citation.endPage68pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage57pt_PT
oaire.citation.titleBiochemical Pharmacologypt_PT
oaire.citation.volume83pt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameFernandes
person.givenNameMiguel Xavier
person.identifier.ciencia-idED1D-3C7A-467C
person.identifier.orcid0000-0002-1840-616X
person.identifier.ridA-4373-2013
person.identifier.scopus-author-id35466972500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3
relation.isAuthorOfPublication.latestForDiscovery8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3
relation.isProjectOfPublication85f8b1e6-0236-47a6-b77b-6d8826f36004
relation.isProjectOfPublication.latestForDiscovery85f8b1e6-0236-47a6-b77b-6d8826f36004

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