Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

Abstract

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os II arene complexes [Os(h 6 -arene)(phenylazopyridine)X] + in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF 3 , OH or NO 2 ). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(h 6 -bip)(2-F-azpy)I]PF 6 (9) and the moderately active complex [Os(h 6 -bip)(3-Cl-azpy)I]PF 6 ( 23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

“…The organometallic half-sandwich Os(II) arene compound 1 is a promising candidate for cancer treatment, being highly active toward a range of cancer cells in vitro and showing promising activity in vivo (11,15). Our combined transcriptomic and proteomic studies show that it has a different mechanism of action from cisplatin.…”

“…Osmium, also a third-row transition metal, offers promise for distinct metal-based anticancer agents (7). It exhibits antiproliferative activity in a variety of oxidation states (8)(9)(10), particularly Os(II) in organometallic half-sandwich arene compounds (11). There is particular interest in Os involvement in cellular oxidative stress, potentially a multitargeted mechanism for which resistance could be harder to develop (12).…”

“…Activity comparisons are made with cisplatin because it is the most widely used metal-based drug in the clinic. The MOA of compound 1 is not associated with activation by hydrolysis and DNA binding, but instead appears to involve redox mediation (11,13). We use a systems biology approach to investigate the MOA of compound 1, using pathway analysis to identify the source of redox modulation.…”

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

“…To that can be added the variety of available metals [2] and, for the transition elements, the potential availability of several degrees of oxidation. 3 With organometallic complexes of gold [8,9], those from the group 8 triad, particularly of Fe and Ru, are amongst the most widely studied [10][11][12][13] with the notable exception to date of Os [14][15][16][17]. This heavy element offers a capacity for good stabilization of certain high degrees of oxidation (+VI) and for an excellent metal-to-ligand back-donation at low oxidation states (+II, +III) leading to more stable complexes than those of Fe or Ru in biological media.…”

100 years of metal coordination chemistry: from Alfred Werner to anticancer metallodrugs

“…[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] Recently, different groups have investigated the chemical and biological activity of analogous half-sandwich arene osmium complexes. [77][78][79][80][81][82][83][84][85] Osmium, the heavier congener of ruthenium and a third row transition metal, commonly exhibits slower kinetics than ruthenium, and is often considered to be relatively inert. However, it is apparent that it is possible to tune the biochemical reactivity of arene osmium(II) complexes through understanding their aqueous solution chemistry.…”