Piano-Stool Ruthenium(II) Complexes with Delayed Cytotoxic Activity: Origin of the Lag Time

Rafols L. ; Josa D. ; Aguilà D. ; Barrios L.A. ; Roubeau O. ; Cirera J. ; Soto-Cerrato V. ; Pérez-Tomás R. ; Martínez M. ; Grabulosa A. ; Gamez P.

Resumen: We have recently reported a series of piano-stool ruthenium(II) complexes of the general formula [RuCl2(¿6-arene)(P(1-pyrenyl)R2R3)] showing excellent cytotoxic activities (particularly when R2 = R3 = methyl). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of the steric hindrance of a bulky phosphane ligand, namely diisopropyl(1-pyrenyl)phosphane (L), on exchange reactions involving the coordinated halides (X = Cl, I). Two ¿6-arene rings were used, i.e. ¿6-methyl benzoate (mba) and ¿6-p-cymene (p-cym), and four complexes were synthesized, namely [RuCl2(mba)(L)] (1Cl2iPr), [RuI2(mba)(L)] (1I2iPr), [RuCl2(p-cym)(L)] (2Cl2iPr), and [RuI2(p-cym)(L)] (2I2iPr). Unexpectedly, all of the complexes exhibited poor cytotoxic activities after 24 h of incubation with cells, in contrast to the related compounds previously reported. However, it was observed that aged DMSO solutions of 2I2iPr (from 2 to 7 days) exhibited better activities in comparison to freshly prepared solutions and that the activity improved over "aging"time. Thorough studies were therefore performed to uncover the origin of this lag time in the cytotoxicity efficiency. The data achieved clearly demonstrated that compounds 2I2iPr and 2Cl2iPr were undergoing a series of transformation reactions in DMSO (with higher rates for the iodido complex 2I2iPr), ultimately generating cyclometalated species through a mechanism involving DMSO as a coordinated proton abstractor. The cyclometalated complexes detected in solution were subsequently prepared; hence, pure [RuCl(p-cym)(¿2C-diisopropyl(1-pyrenyl)phosphane)] (3CliPr), [RuI(p-cym)(¿2C-diisopropyl(1-pyrenyl)phosphane)] (3IiPr), and [Ru(p-cym)(¿S-dmso)(¿2C-diisopropyl(1-pyrenyl)phosphane)]PF6 (3dmsoiPr) were synthesized and fully characterized. Remarkably, 3CliPr, 3IiPr, and 3dmsoiPr are all very efficient cytotoxic agents, exhibiting slightly better activities in comparison to the chlorido noncyclometalated complexes [RuCl2(¿6-arene)(P(1-pyrenyl)R2R3)] described in an earlier report. For comparison purposes, the iodido compounds [RuI2(mba)(dimethyl(1-pyrenyl)phosphane)] (1I2Me) and [RuI2(p-cym)(dimethyl(1-pyrenyl)phosphane)] (2I2Me), bearing the less hindered dimethyl(1-pyrenyl)phosphane ligand, have also been prepared. The cytotoxic and chemical behaviors of 1I2Me and 1I2Me were comparable to those of their chlorido counterparts reported previously.

Idioma: Inglés

DOI: 10.1021/acs.inorgchem.1c00507

Año: 2021

Publicado en: Inorganic Chemistry 60, 11 (2021), 7974-7990
ISSN: 0020-1669

Factor impacto JCR: 5.436 (2021)

Categ. JCR: CHEMISTRY, INORGANIC & NUCLEAR rank: 5 / 46 = 0.109 (2021) - Q1 - T1

Factor impacto SCIMAGO: 1.121 - Inorganic Chemistry (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MCIU/CTQ2015-65040-P
Financiación: info:eu-repo/grantAgreement/ES/MCIU/CTQ2017-88446-R
Financiación: info:eu-repo/grantAgreement/ES/MCIU/PGC2018-098630-B-I00
Financiación: info:eu-repo/grantAgreement/ES/MCIU/PID2019-107006GB-C21
Financiación: info:eu-repo/grantAgreement/ES/MCIU/RED2018-102471-T

Tipo y forma: Artículo (Versión definitiva)