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Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases
dc.creator | Fuentes-Aguilar, Alma | |
dc.creator | González-Bakker, Aday | |
dc.creator | Jovanović, Mirna | |
dc.creator | Jovanović Stojanov, Sofija | |
dc.creator | Puerta, Adrián | |
dc.creator | Gargano, Adriana | |
dc.creator | Dinić, Jelena | |
dc.creator | Vega-Báez, José L. | |
dc.creator | Merino-Montiel, Penélope | |
dc.creator | Montiel-Smith, Sara | |
dc.creator | Alcaro, Stefano | |
dc.creator | Nocentini, Alessio | |
dc.creator | Pešić, Milica | |
dc.creator | Supuran, Claudiu T. | |
dc.creator | Padrón, José M. | |
dc.creator | Fernández-Bolaños, José G. | |
dc.creator | López, Óscar | |
dc.date.accessioned | 2024-02-19T13:07:49Z | |
dc.date.available | 2024-02-19T13:07:49Z | |
dc.date.issued | 2024 | |
dc.identifier.issn | 0045-2068 | |
dc.identifier.uri | http://radar.ibiss.bg.ac.rs/handle/123456789/6550 | |
dc.description.abstract | Being aware of the need to develop more efficient therapies against cancer, herein we disclose an innovative approach for the design of selective antiproliferative agents. We have accomplished the conjugation of a coumarin fragment with lipophilic cations (triphenylphosphonium salts, guanidinium) for providing mitochondriotropic agents that simultaneously target also carbonic anhydrases IX and XII, involved in the development and progression of cancer. The new compounds prepared herein turned out to be strong inhibitors of carbonic anhydrases IX and XII of human origin (low-to-mid nM range), also endowed with high selectivity, exhibiting negligible activity towards cytosolic CA isoforms. Key interactions with the enzyme were analysed using docking and molecular dynamics simulations. Regarding their in vitro antiproliferative activities, an increase of the tether length connecting both pharmacophores led to a clear improvement in potency, reaching the submicromolar range for the lead compounds, and an outstanding selectivity towards tumour cell lines (S.I. up to >357). Cytotoxic effects were also analysed on MDR cell lines under hypoxic and normoxic conditions. Chemoresistance exhibited by phosphonium salts, and not by guanidines, against MDR cells was based on the fact that the former were found to be substrates of Pglycoprotein (P-gp), the pump responsible for extruding foreign chemicals; this situation was reversed by administrating tariquidar, a third generation P-gp inhibitor. Moreover, phosphonium salts provoked a profound depolarization of mitochondria membranes from tumour cells, thus probably compromising their oxidative metabolism. To gain insight into the mode of action of title compounds, continuous live cell microscopy was employed; interestingly, this technique revealed two different antiproliferative mechanisms for both families of mitocans. Whereas phosphonium salts had a cytostatic effect, blocking cell division, guanidines led to cell death via apoptosis. | sr |
dc.language.iso | en | sr |
dc.publisher | Elsevier Inc. | sr |
dc.relation | Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033 | sr |
dc.relation | Junta de Andalucía (FQM134) | sr |
dc.relation | the Spanish Government (Project PID2021-123059OB-I00 funded by MCIN/AEI /10.13039/501100011033 / FEDER, UE) | sr |
dc.relation | EU Social Fund (FSE) and the Canary Islands ACIISI - a predoctoral grant TESIS2020010055 | sr |
dc.relation | the Asociación Española Contra el Cáncer (AECC) de Santa Cruz de Tenerife - predoctoral grant PRDTF233958GONZ | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/inst-2020/200007/RS// | sr |
dc.relation | COST Action CA17104 STRATAGEM “New diagnostic and therapeutic tools against multidrug resistant tumors” | sr |
dc.rights | openAccess | sr |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | Bioorganic Chemistry | sr |
dc.subject | Coumarin | sr |
dc.subject | Mitochondriotropic agent | sr |
dc.subject | Carbonic anhydrase inhibitor | sr |
dc.subject | Cytostatic agent | sr |
dc.subject | Apoptosis | sr |
dc.title | Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases | sr |
dc.type | article | sr |
dc.rights.license | BY-NC-ND | sr |
dc.rights.holder | © 2024 The Author(s) | sr |
dc.citation.volume | 145 | |
dc.identifier.doi | 10.1016/j.bioorg.2024.107168 | |
dc.identifier.pmid | 38354500 | |
dc.citation.spage | 107168 | |
dc.type.version | publishedVersion | sr |
dc.identifier.fulltext | https://radar.ibiss.bg.ac.rs/bitstream/id/16932/bitstream_16932.pdf | |
dc.citation.rank | M21~ |