000169225 001__ 169225
000169225 005__ 20260223164759.0
000169225 0247_ $$2doi$$a10.1016/j.jinorgbio.2026.113254
000169225 0248_ $$2sideral$$a148295
000169225 037__ $$aART-2026-148295
000169225 041__ $$aeng
000169225 100__ $$aMayrata, Marayke
000169225 245__ $$aNMR spectroscopy stability studies of Ru-IM, a prodrug candidate for triple negative breast cancer
000169225 260__ $$c2026
000169225 5203_ $$aChemical stability and metal speciation are key determinants of the biological behavior and translational potential of metal-based chemotherapeutic agents, for which ligand exchange and chemical transformation frequently occur under physiological conditions. In these systems, pharmacological activity is defined not by a single molecular entity but by the distribution and interconversion of metal-containing species in solution and biological media. Here, we investigate the time-dependent speciation of the highly water-soluble ruthenium complex [(η6 -p-cymene)Ru(κ-N,O–Ph₃P=N–CO–2-NC₅H₄)]Cl (Ru-IM), which exhibits a shelf life exceeding two years and has demonstrated robust anticancer efficacy in preclinical mechanistic and pharmacokinetic studies in triple-negative breast cancer mouse models. Using NMR spectroscopy, we characterized Ru-IM speciation in D₂O, deuterated phosphate-buffered saline, deuterated Dulbecco's Modified Eagle's Medium (DMEM), and DMEM supplemented with fetal bovine serum. Two dominant speciation pathways were identified: (A) hydrolysis with loss of O=PPh₃ from the IM ligand, which results in loss of anticancer activity, and (B) ruthenium cyclometallation of a phenyl group from the IM ligand, which preserves biological activity. The relative distribution of these species is strongly influenced by concentration, temperature, and medium composition. Notably, Ru-IM remains the predominant species in aqueous solution for at least 24 h, with stability extendable to several days under optimized storage conditions. Collectively, these results support a prodrug activation model, in which RuIM undergoes controlled speciation under biologically relevant conditions to generate an active cyclometalated ruthenium species.
000169225 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E17-23R$$9info:eu-repo/grantAgreement/ES/MICIU/PID2024-155563NB-I00
000169225 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000169225 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000169225 700__ $$aLopez-Sanchez, Alvaro
000169225 700__ $$0(orcid)0000-0001-9779-5820$$aUrriolabeitia, Esteban P.
000169225 700__ $$aMcCarrick, Sophie
000169225 700__ $$aManu, Aaron
000169225 700__ $$aLópez-Hernández, Javier E.
000169225 700__ $$aNeary, Michelle C.
000169225 700__ $$aContel, Maria
000169225 773__ $$g278 (2026), 113254 [12 pp.]$$pJ. inorg. biochem.$$tJournal of Inorganic Biochemistry$$x0162-0134
000169225 8564_ $$s2823427$$uhttps://zaguan.unizar.es/record/169225/files/texto_completo.pdf$$yVersión publicada
000169225 8564_ $$s2399316$$uhttps://zaguan.unizar.es/record/169225/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000169225 909CO $$ooai:zaguan.unizar.es:169225$$particulos$$pdriver
000169225 951__ $$a2026-02-23-14:54:52
000169225 980__ $$aARTICLE