Organoruthenium(II) Complexes Bearing an Aromatase Inhibitor: Synthesis, Characterization, in Vitro Biological Activity and in Vivo Toxicity in Zebrafish Embryos

Abstract

Third-generation aromatase inhibitors such as anastrozole (ATZ) and letrozole (LTZ) are widely used to treat estrogen receptor-positive ER+ breast cancers in postmenopausal women. Investigating their ability to coordinate metals could lead to the emergence of a new category of anticancer drug candidates with a broader spectrum of pharmacological activities. In this study, a series of ruthenium (II) arene complexes bearing the aromatase inhibitor anastrozole was synthesized and characterized. Among these complexes, [Ru(η 6-C 6 H 6)(PPh 3)(η 1-ATZ)Cl]BPh 4 (3) was found to be the most stable in cell culture media, to lead to the highest cellular uptake and in vitro cytotoxicity in two ER+ human breast cancer cell lines (MCF7 and T47D), and to induce a decrease in aromatase activity in H295R cells. Exposure of zebrafish embryos to complex 3 (12.5 μM) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations.

Rationally Designed Ruthenium Complexes for Breast Cancer Therapy

“…However, the aromatase enzyme inhibitory potential of these complexes was overlooked. More recently, Castonguay et al (2019) reported a series of ruthenium(II) arene complexes bearing a slightly different third-generation aromatase inhibitor, namely anastrozole [40]. In this study, the stability, in vitro cytotoxicity, in vitro aromatase inhibitory activity, and the in vivo toxicity of the complexes on the development of zebrafish embryos were investigated.…”

“…Despite the interesting dual activity observed for this complex, its in vitro cytotoxicity was not studied [54]. treated with cisplatin under the same conditions could not hatch after 96 h, a clear indication of the toxicity of this chemotherapeutic agent [40]. Importantly, Castonguay et al (2020) recently developed a novel ruthenium(II) cyclopentadiene (Cp) complex of anastrozole (3) ( Figure 1) with a high in vitro cytotoxicity not only in ER+ breast cancer cells (IC50 = 0.50 ± 0.09 µM, MCF7; 0.32 ± 0.03 µM, T47D) but also in a TNBC cell line, MDA-MB-231 (IC50 = 0.39 ± 0.09 µM) [51].…”

“…In recent years, the development of agents with enhanced anticancer properties via the coordination of biologically active molecules to metals, more specifically ruthenium, has attracted increasing attention [36][37][38]. Because ruthenium complexes are widely studied for their ability to induce cancer cell death, the introduction of biologically active ligands in their structure can be a promising approach for the development of drug candidates with a broader range of anticancer activities compared to ruthenium complexes or ligands alone [39,40]. This approach can potentially result in the creation of multitargeting drug candidates that could limit the emergence of cancer cell resistance mechanisms by leaving biological systems unable to compensate for the simultaneous action of two or more drugs [41].…”

Cationic RuII Cyclopentadienyl Complexes with Antifungal Activity against Several Candida Species

“…[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] It is noteworthy that ruthenium complexes are currently extensively studied for their anticancer properties and are even now considered as potential alternatives to cisplatin, a chemotherapeutic agent currently widely used in clinical settings. [51][52][53][54][55] For instance, Turel et al reported Ru II complexes bearing antifungal azole-containing drugs clotrimazole, miconazole, and tioconazole that could inhibit the growth of Curvularia lunata. [31] In another study, Sivagamasundari et al noted the antifungal activity of Ru II complexes against Aspergillus flavus.…”

Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

“…Stock solutions for all tested compounds were prepared in DMSO and final DMSO concentration was kept at 1% which does not to affect the growth of N. meningitidis ( Figure 1A). Interestingly, 4 of the 17 active compounds harbored a tetraphenylborate anion (BPh 4 -) and were found to be the only molecules from the screened library to include this moiety (ex: 1-BPh 4 and 2-BPh 4 Figure 2D (19,20)).…”