000136378 001__ 136378
000136378 005__ 20260112133328.0
000136378 0247_ $$2doi$$a10.1039/d4qi00755g
000136378 0248_ $$2sideral$$a139211
000136378 037__ $$aART-2024-139211
000136378 041__ $$aeng
000136378 100__ $$aGil-Moles, María
000136378 245__ $$aA dual approach to cancer treatment: gold(i) terpyridine derivatives as DNA binders and inhibitors of mammalian thioredoxin reductase
000136378 260__ $$c2024
000136378 5060_ $$aAccess copy available to the general public$$fUnrestricted
000136378 5203_ $$aGold(I) complexes featuring a phosphine-substituted terpyridine (4′-PPh2terpy), along with various ancillary ligands, have been successfully synthesised. All derivatives, characterised by the general formula [Au(L)(4′-PPh2terpy)] (where L represents phosphine, chloride, alkynyl, or thiolate), exhibit remarkable activity against diverse tumour cell lines, including HT-29, MCF-7, and MDA-MB-231, with particularly noteworthy efficacy against the triple negative breast cancer MDA-MB-231 cell line. Notably, all complexes demonstrate superior efficacy compared to the reference auranofin, showcasing IC50 values ten-fold lower. Additionally, they exhibit a certain level of selectivity towards healthy cells (primary fibroblasts). The ability of different ancillary ligands to undergo ligand exchange reactions with thiol groups, such as NAC, has been assessed via NMR. A correlation between the leaving group capacities of various ligands and the speed of ligand exchange reactions has been observed, following this order: alkynyl < phosphine < thiolate < chloride. Moreover, efforts were made to elucidate potential biological targets and the underlying mechanism of action through which these Au(I) compounds impede cell proliferation. Flow cytometry measurements have indicated several cellular responses, including apoptotic cell death, cell cycle arrest in the G0/G1 phase, increased ROS production, and a decrease in mitochondrial membrane potential (ΔΨ). DNA binding studies revealed that the selected derivatives interact with DNA by intercalation. Additionally, investigations on the inhibition of the TrxR system yielded compelling findings. The Au(I) complexes exhibited potent enzyme inhibition, albeit variations were noted based on the ancillary ligand employed. A clear correlation emerged between the inhibition observed and the capability to displace the ancillary ligand with the selenol moieties of TrxR (the effectiveness follows the same order as observed in the study of ligand exchange reactions). Notably, the chloride ligand yielded the most promising results, demonstrating inhibition levels comparable to auranofin, one of the foremost TrxR inhibitors. This suggests a dual approach for cancer therapy with complexes targeting two key biological targets.
000136378 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2022-139739NB-I00$$9info:eu-repo/grantAgreement/ES/DGA/E07-23R$$9info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136861NB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/RED2022-134074-T
000136378 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttps://creativecommons.org/licenses/by-nc/4.0/deed.es
000136378 590__ $$a6.4$$b2024
000136378 592__ $$a1.276$$b2024
000136378 591__ $$aCHEMISTRY, INORGANIC & NUCLEAR$$b4 / 42 = 0.095$$c2024$$dQ1$$eT1
000136378 593__ $$aInorganic Chemistry$$c2024$$dQ1
000136378 594__ $$a9.9$$b2024
000136378 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000136378 700__ $$aOlmos, M. Elena
000136378 700__ $$aLópez-de-Luzuriaga, José M.
000136378 700__ $$aOtt, Ingo
000136378 700__ $$0(orcid)0000-0003-0553-0695$$aGimeno, M. Concepción
000136378 773__ $$g11, 15 (2024), 4802-4814$$pInorg. chem. front$$tInorganic Chemistry Frontiers$$x2052-1545
000136378 8564_ $$s987387$$uhttps://zaguan.unizar.es/record/136378/files/texto_completo.pdf$$yVersión publicada
000136378 8564_ $$s2787871$$uhttps://zaguan.unizar.es/record/136378/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000136378 909CO $$ooai:zaguan.unizar.es:136378$$particulos$$pdriver
000136378 951__ $$a2026-01-12-13:10:43
000136378 980__ $$aARTICLE