Hetero-Bis-Conjugation of Bioactive Molecules to Half-Sandwich Ruthenium(II) and Iridium(III) Complexes Provides Synergic Effects in Cancer Cell Cytotoxicity

Abstract

Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2′-bipyridine-4,4′-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.

Automated approach for the evaluation of glutathione-S-transferase P1-1 inhibition by organometallic anticancer compounds

“…The iridium compound 7d is the strongest inhibitor of GST P1 (IC 50 = 6.7 ± 0.7 µM) in the present work, more effective than EA . Compound 7e exhibits significant cytotoxicity on a panel of cancer cell lines, with its biological activity benefiting from the combined action of the metal scaffold and the two enzyme inhibitors 37 .…”

“…A 0.1 mol L −1 phosphate buffer solution (pH 6.5) was applied as a carrier solution for the SIA method. Compounds 2a–d 28 , 3a 29 , 4a–d 30 , 31 , 5a–f 32–34 , 6a–b 35 , 36 , 7a–e 37–40 were prepared in agreement to literature methods and were dissolved in DMSO.…”

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

“…The enzymatic activity of COX-2 (0.25 UN) was fluorimetrically assayed at 576 nm/586 nm and at 25 °C by measuring the rate of arachidonic acid (ARA) conjugation with COX-2 as a function of time, by using a protocol reported earlier. 40 The assay mixture contained 25 μM ADHP, 5 μM hemin, and 37.5 μM ARA in 0.1 M of Tris–HCl buffer at pH 8. The inhibitory efficacy of flurbiprofen, ibuprofen, naproxen, PyOH, Py-FLU , Py-IBU , and Py-NAP were determined by recording the residual activity of COX-2 in the presence of variable concentrations of the analysed compounds (25–3000 μM).…”

“…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). FLU-CO 2 H, IBU-CO 2 H and NAP-CO 2 H are nonsteroidal antiinflammatory drugs (NSAIDs), commonly used in the treatment of fever, pain or inflammation, [47][48][49] and inhibit COX enzymes.…”

Increasing Anticancer Activity with Phosphine Ligation in Zwitterionic Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes

“…Cancer has been a common disease with high incidence, which is widely perceived as one of the leading reasons of death. , Although a series of platinum antitumor drugs such as cisplatin and its derivatives have been applied in clinical practice, the serious side effects have made scientists commit themselves to searching for more efficient and less toxic antitumor drugs. − The tumor-killing agents of a number of platinum family metals with reduced side effects and excellent anticancer activity have been widely concerned. − The ruthenium complexes NAMI-A and KP1019 have shown the most promising results in preclinical and clinical trials. , Recently, the organometallic platinum group metal compounds offer rich versatility for the rational design of anticancer complexes. According to the structure type, these platinum group metal-based anticancer complexes can be divided into two main groups: cyclometalated complexes and half-sandwich complexes (Scheme ).…”