Improved reaction conditions for the synthesis of new NKP-1339 derivatives and preliminary investigations on their anticancer potential

Abstract

The very promising results of Na-trans-[RuCl4(1H-indazole)2] (NKP-1339) in clinical studies have fuelled renewed interest in the research and development of ruthenium(III) coordination compounds for cancer therapy. By applying an improved synthetic approach to this class of coordination compounds, six new examples of the general formula (cation)-trans-[RuCl4(azole)2], where (cation) = tetrabutylammonium (Bu4N)(+) (1, 2), sodium (3, 4), azolium (5, 6), and azole = 1-methyl-indazole (1, 3, 5), 1-ethyl-indazole (2, 4, 6), have been prepared. All compounds have been characterized by elemental analysis, electrospray ionization (ESI) mass spectrometry, UV-vis-, and NMR-spectroscopy and, if possible, X-ray diffraction analysis. Furthermore, the influence of the alkyl substituent at the position N1 of the indazole backbone on the stability in aqueous media as well as on the biological activity in three human cancer cell lines (CH1, A549, and SW480) and on the cellular accumulation in SW480 cells is discussed.

Ruthenium(II)-arene complexes with naphthalimide-tagged N,O- and N,N-chelating ligands: Synthesis and biological evaluation

“…It has been established that ruthenium compounds exhibit low toxicities while maintaining high selectivity toward cancer cells in vitro and high efficacy against platinum-drug-resistant tumors [9][10][11][12][13]. The more selective activity of ruthenium compounds is believed to be due to their preferential accumulation in cancer cells and the ability of ruthenium to mimic iron in binding to biomolecules [3,7,9,[11][12][13]. Ruthenium compounds are also believed to have a biological mode of action that is significantly different from those of platinumbased drugs [9,[13][14][15].…”

“…The most attractive profile of NKP-1339 is its high water solubility compared to KP1019. It has been established that ruthenium compounds exhibit low toxicities while maintaining high selectivity toward cancer cells in vitro and high efficacy against platinum-drug-resistant tumors [9][10][11][12][13]. The more selective activity of ruthenium compounds is believed to be due to their preferential accumulation in cancer cells and the ability of ruthenium to mimic iron in binding to biomolecules [3,7,9,[11][12][13].…”

“…This interest is stimulated by the successful entry of KP1019 has also illuminated further interest for the design and development of ruthenium(III) based coordination compounds as anticancer agents [11][12]. The most attractive profile of NKP-1339 is its high water solubility compared to KP1019.…”

Synthesis, structure and antiproliferative activity of dinuclear ruthenium arene complexes with differently coordinated thiosemicarbazones

“…Ruthenium‐based anticancer compounds, which offers the possibility of treating platinum‐resistant cancers due to their different mode of action to clinically applied platinum drugs, are emerging as promising candidates for the development of novel anticancer agents . Among several anticancer ruthenium complexes, imidazolium trans‐[tetrachlorido(1H‐imidazole)(S‐dimethylsulfoxide) ruthenate(III)] (NAMI‐A), imidazolium trans‐[tetrachloridobis(1H‐imidazole)ruthenate(III)] (KP1019), and sodium trans‐[tetrachloridobis(1H‐indazole)ruthenate(III)] (NKP1339), with particular promise are currently in phase II clinical trials . Moreover, the organometallic ruthenium‐arene half‐sandwich complexes with a piano‐stool geometry, such as RAPTA‐C developed by Dyson and coworkers, and RM175 developed by Sadler's group, have also attracted increasing attention for their diverse activities .…”

Development of the application of speciation in chemistry

“…Modifications of this axial ligand affect numerous properties, such as solubility, lipophilicity, and the ligand exchange rate, as well as the ability to bind to HSA and the redox potential of the complex, where all these factors ultimately influence the bioactivity [240,241].…”