Bis‐picolinamide Ruthenium(III) Dihalide Complexes: Dichloride‐to‐Diiodide Exchange Generates Single trans Isomers with High Potency and Cancer Cell Selectivity

Abstract

A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type RuX2L2 (X = Cl or I and L = picolinamide) have been synthesised and characterised. They exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies reveal a mixture of cis and trans isomers for the RuCl2L2 complexes but upon a halide exchange reaction to RuI2L2, only single trans isomers are present. High cytotoxic activity against human cancer cell lines was observed, with potencies for some complexes similar to or better than cisplatin. Conversion to RuI2L2 substantially increased activity towards cancer cell lines by >12-fold. The RuI2L2 complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with >4-fold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, indicating the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. Selected complexes were also tested against non-cancer ARPE-19 cells. The RuI2L2 complexes are more potent than the RuCl2L2 analogues, and also more selective towards cancer cells with a selectivity factor >7-fold.

Pseudo electron-deficient organometallics: limited reactivity towards electron-donating ligands

“…Some stable coordinatively unsaturated 16-electron (16-e) complexes have been isolated in particular by the groups of Koelle, Tilley, Suzuki, among others, [2][3][4][5][6][7][8][9][10][11][12] but little is known about the reactivity of air and moisture stable 16-e complexes and about their properties in solution. Half-sandwich metal complexes are a particular class of organometallics which has attracted an enormous attention for the design of catalysts, 13 anticancer drug candidates, [14][15][16][17][18][19][20][21][22]23,24 and as building blocks for supramolecular chemistry. [25][26][27][28][29][30][31][32][33] The synthetic versatility of half-sandwich metal complexes, and the number of areas in which they are utilized make the development of novel families of such complexes of potential high interest and broad impact for a number of researchers.…”

Anticancer Activity of Electron‐Deficient Metal Complexes against Colorectal Cancer in vitro Models

“…[7][8][9][10][11][12][13][14][15][16] In this broad context, we have developedastrong interesti na ir-and water-stablee lectron-deficient half-sandwich complexes based on acarborane ligand,and have investi-gated their applicationsi nm aterials science [17][18][19][20][21][22][23] and in biology. [7][8][9][10][11][12][13][14][15][16] In this broad context, we have developedastrong interesti na ir-and water-stablee lectron-deficient half-sandwich complexes based on acarborane ligand,and have investi-gated their applicationsi nm aterials science [17][18][19][20][21][22][23] and in biology.…”

“…In recent years, half-sandwichc omplexes of ruthenium, osmium,and iridium have attracted much attention as metallodrug candidates with potential novel mechanisms of action (MoA). [7][8][9][10][11][12][13][14][15][16] In this broad context, we have developedastrong interesti na ir-and water-stablee lectron-deficient half-sandwich complexes based on acarborane ligand,and have investi-gated their applicationsi nm aterials science [17][18][19][20][21][22][23] and in biology. [24][25][26] More recently, we synthesised af amily of electron-deficientm etal complexes based on the benzene-1,2-dithiolato ligand,amore readily available and easier-to-functionalise ligand than carboranes.…”

cis-Tetrachlorido-bis(indazole)osmium(iv) and its osmium(iii) analogues: paving the way towards the cis-isomer of the ruthenium anticancer drugs KP1019 and/or NKP1339

“…22 In the case of octahedral ruthenium and osmium compounds, some cases of isomeric pairs are well-documented for azole heterocycles 23, 24 and bis-picolinamide ruthenium(III) dihalide complexes. 25 The structurally related osmium(III) pyridine derivatives, cis - and trans -[OsCl 4 (Py) 2 ] − are also known, and both were crystallographically characterized. 26 Overall, the number of cytotoxic Werner’s type osmium complexes is increasing.…”