Ruthenium(II)–Tris-pyrazolylmethane Complexes Inhibit Cancer Cell Growth by Disrupting Mitochondrial Calcium Homeostasis

Abstract

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2 – 9 in 77–99% yields. Products 2–9 were fully structurally characterized. They are appreciably soluble in water, where they undergo partial chloride/water exchange. The antiproliferative activity was determined using a panel of human cancer cell lines and a noncancerous one, evidencing promising potency of 1 , 7 , and 8 and significant selectivity toward cancer cells. The tested compounds effectively accumulate in cancer cells, and mitochondria represent a significant target of biological action. Most notably, data provide convincing evidence that the mechanism of biological action is mediated by the inhibiting of mitochondrial calcium intake.

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs

“…To develop new therapeutic agents and tools for studying m Ca 2+ , extensive research efforts have been directed toward the identification of small-molecule MCU inhibitors . To date, several organic − and inorganic − compounds have been discovered to possess MCU-inhibitory activity. Among these compounds, polynuclear Ru complexes are the oldest known MCU inhibitors, and recently developed analogues have shown promise for this application.…”

Anticancer ruthenium(ii) tris(pyrazolyl)methane complexes with bioactive co-ligands

“…The 31 P NMR spectra of 2–7 show the signal related to PPh 3 as a singlet occurring in a restricted chemical shift interval (50.3–51.2 ppm), that is significantly shifted with respect to 1 ( δ = 40.1 ppm). 32 The 19 F NMR spectrum of 5 consists of a singlet at ca . −118 ppm.…”

“…1B). 32 We found that 1 is an excellent starting material to obtain various derivatives upon substitution of one of the PPh 3 ligands, and some of these derivatives exhibited a marked antiproliferative activity against a panel of cancer cell lines, mediated in part by the inhibition of mitochondrial calcium intake. 32…”

“…32 We found that 1 is an excellent starting material to obtain various derivatives upon substitution of one of the PPh 3 ligands, and some of these derivatives exhibited a marked antiproliferative activity against a panel of cancer cell lines, mediated in part by the inhibition of mitochondrial calcium intake. 32 Herein, we present a general strategy to obtain pyridine adducts of 1, also incorporating different bioactive units which have been previously conjugated with anticancer metal structures, including ruthenium arene complexes, [33][34][35][36] improving their biological activity. Specifically, ethacrynic acid (EA-CO 2 H), [37][38][39][40] flurbiprofen (FLU-CO 2 H), 40,41 ibuprofen (IBU-CO 2 H) [42][43][44] and naproxen (NAP-CO 2 H) 45,46 (Scheme 1).…”

“…The cations of 2 and 3 closely resemble to those previously reported for related [RuCl(κ 3 -tpm)(PPh 3 )(L)]Cl compounds, with respect to the overall geometries and bonding parameters. 32 The Ru(1)-N( 5) distances [2.065(4) and 2.069(3) Å in 2 and 3, respectively], being in trans with respect to the pyridine ligand, are slightly shortened compared to Ru(1)-N(1) [2.094(4) and 2.120(4) Å], which are trans to the triphenylphosphine ligand. This data evidence the better electron-withdrawing effect of the pyridine group with respect to PPh 3 .…”