Mono‐ and Dinuclear Phosphorescent Rhenium(I) Complexes: Impact of Subcellular Localization on Anticancer Mechanisms

Abstract

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1-Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase-independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase-independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes.

Valproic Acid‐Functionalized Cyclometalated Iridium(III) Complexes as Mitochondria‐Targeting Anticancer Agents

“…Lipophilicity lg P can strongly influence the cellular uptake, localization, and cytotoxicity of a compound . The lipophilicity of 1 a – 3 a and 1 b – 3 b was determined by the flask‐shaking method.…”

“…Studies on cellular localization of phosphorescent metal complexes can provide further clues for the investigations of anticancer mechanisms . By taking advantage of the rich photophysical properties of cyclometalated Ir III complexes, the intracellular distribution of 1 a – 3 a was investigated by one‐photon microscopy (OPM) and two‐photon microscopy (TPM) confocal luminescence imaging.…”

“…The growth inhibitory effect of the tested compounds towards HeLa, A549, A549R, HepG2 and LO2 cells lines was evaluated by MTT assay as previously described . For the cytotoxicity assay in the presence of the inhibitors ( z ‐VAD‐FMK or NAC), HeLa cells were preincubated with inhibitors at the indicated concentrations for 1 h before the complexes were added.…”

“…The impact of 1 a – 3 a on ROS levels was determined as previously described . Briefly, HeLa cells were treated with 1 a – 3 a at the indicated concentrations for 6 h, collected, and incubated with 10 μ m H 2 DCFDA in serum‐free Dulbecco's modified Eagle's medium (DMEM) for 15 min at 37 °C.…”

Síntese e caracterização de complexos polipiridínicos de Ru(II) com diferentes ligantes carboxilatos e avaliação da reatividade frente ao oxigênio molecular

“…x 10 -3 mol L -1 em diclorometano em solução eletrolítica 0,1 mol L -1 de TBAPF 6 2 (acpy)] + com concentração de 2,9 x 10 -3 mol L -1 a 10 mV s -1 em diclorometano em solução eletrolítica 0,1 mol L -1 de TBAPF 6 2 (acpy)] + com concentração de 2,9 x 10 -3 mol L -1 a 100 mV s -1 em diclorometano em solução eletrolítica 0,1 mol L -1 de TBAPF 6 WHANG e APAYDIN, 2018), corantes sensibilizadores em células solares (GRÄTZEL, 2003;2005;GONG et al, 2012;CARVALHO et al, 2014), OLEDs (Organic Light-Emitting Diodes, Diodos Emissores de Luz Orgânicos) (FANTACCI e DE ANGELIS, 2011;WONG et al, 2014;KIM et al, 2015;SUZUKI et al, 2015), catalisadores em reações de compostos orgânicos (ZENG et al, 2008;PRIER et al, 2013;BEATTY e STEPHENSON, 2015;SHAW et al, 2016), interruptores moleculares (GÜTLICH et al, 2001;LIN et al, 2011;MERINO e RIBAGORDA, 2012;PATROCINIO et al, 2013), polímeros (JANIAK, 2003ROBIN e FROMM, 2006), marcadores celulares (STOEFFLER et al, 1995;FERNANDEZ-MOREIRA et al, 2010;YE et al, 2016), entre outros. Dentre as propriedades dos compostos de coordenação destaca-se a (foto)reatividade frente a reações de transferência eletrônica.…”