Unprecedented inhibition of P-gp activity by a novel ruthenium-cyclopentadienyl compound bearing a bipyridine-biotin ligand

Abstract

Two new ruthenium complexes, [Ru(η 5 -Cp)(PPh 3 )(2,2'-bipy-4,4'-R)] + with R = CH 2 OH (Ru1) or dibiotin ester (Ru2) were synthesized and fully characterized. Both compounds were tested against two types of breast cancer cells (MCF7 and MDA-MB231), showing better cytotoxicity than cisplatin in the same experimental conditions. Since multidrug resistance (MDR) is one of the main problems in cancer chemotherapy, we have assessed the potential of these compounds to overcome resistance to treatments. Ru2 showed exceptional selectivity as P-gp inhibitor, while Ru1 is possibly a substrate. In vivo studies in zebrafish showed that Ru2 is well tolerated up to 1.17 mg/L, presenting a LC 50 of 5.73 mg/L at 5 days post fertilization.

Recent advances in metallopolymer-based drug delivery systems

“…As a typical example, we note the use of polymeric "ruthenium-cyclopentadienyl" conjugates bearing an organometallic fragment and polylactide chains as potential anti-cancer agents with proven cytotoxic activity 133,134 and adequate aqueous stability. 134 In another interesting example, a poly(L-glutamic acid)-gra-methoxy poly(ethylene glycol) (PGA-g-mPEG) has been proposed as a has been for inclusion of cisplatin.…”

A novel screening method for transition metal‐based anticancer compounds using zebrafish embryo‐larval assay and inductively coupled plasma‐mass spectrometry analysis

“…The use of zebrafish may help elucidate the mechanism of action of novel metallodrugs and potential non‐targeted tissues or biochemical pathways. Currently, we have evaluated six Ru‐based anticancer compounds with these techniques (Côrte‐Real, Karas, Gírio, et al, ) (unpublished data). We believe this model could be a promising asset to high‐throughput evaluation of metal‐based anticancer compounds, particularly if coupled with new technologies including robotics to actualize whole organisms and automated chemical delivery systems (Truong et al, ; Wang et al, ).…”

“…Zebrafish embryos were grown in 500 μL of aerated egg water (60 μg/mL Instant Ocean in deionized water) dosed with nominal concentrations of cisplatin (Cas no. 15663‐27‐1), cis ‐diamineplatinum(II) dichloride, Pt (NH 3 ) 2 Cl 2 (≥99.9% trace metals basis purchased from Sigma‐Aldrich, St. Louis, MO) or PMC79 ([Ru(η 5 ‐Cp)(PPh 3 )(2,2′‐bipy‐4,4′‐CH 2 OH)] + , synthesized by us and previously reported (Côrte‐Real, Karas, Gírio, et al, ) (Figure ). Embryos were observed daily and incubated in darkness at 26°C.…”

“…This may allow for expedited bioanalytical screening of critical toxicological endpoints, including the LC 50 and EC 50 values (lethal and effective concentrations for 50% of the population) and the no‐observed‐adverse‐effect level (NOAEL) and lowest‐observed‐adverse‐effect level (LOAEL). To refine the method, cisplatin the mechanism of which has been elucidated, and a novel Ru compound, PMC79, were evaluated (Figure ) (Côrte‐Real, Karas, Gírio, et al, ; Moreira et al, ). PMC79 was found to be more cytotoxic than cisplatin in ovarian (A2780) and breast (MCF‐7 and MDA‐MB‐231) human cancer cells.…”

A New Family of Iron(II)-Cyclopentadienyl Compounds Shows Strong Activity against Colorectal and Triple Negative Breast Cancer Cells

“…We have been exploring the use of half-sandwich ruthenium(II)-cyclopentadienyl-based compounds as prospective anticancer agents [10]. Recently, we have successfully dedicated our studies to cancers without clinical cure, such as triple negative breast cancer (TNBC) [11][12][13][14][15][16] and colorectal cancer (CRC) with KRAS or BRAF mutations [17]. Given the promising results that were obtained with ruthenium, and since iron belongs to the same Group of the Periodic Table, being more abundant and cheaper, the exploitation of iron(II)-cyclopentadienyl-based compounds merits being explored.…”