Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl₂Complexes

Abstract

Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N-heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of Rh III -and Ir III (Cp*)(NHC)Cl 2 (Cp* = η 5 -pentamethylcyclopentadienyl) compounds and comparison of their properties to the Ru II -and Os II (cym) analogues (cym = η 6 -p-cymene). Like the Ru II -and Os II (cym) complexes, the Rh III -and Ir III (Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC 50 ) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC 50 values of ∼1 μM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl 2 complexes may be a scaffold for the development of TrxR inhibitors.

Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Antibacterial Agents and Inhibitors of Bacterial Thioredoxin Reductase

“…The design of drug candidates based on metal NHC complexes has been dominated by gold and silver as metals, however, more recently, an increasing number of metals has demonstrated very promising results, including, for example, rhodium [ 8 , 9 , 10 , 11 , 12 ] and iridium [ 12 , 13 ] species.…”

Multifaceted chemical behaviour of metallocene (M = Fe, Os) quinone methides. Their contribution to biology

“…This is particularly highlighted in the case of the ansa ferrocidiphenol, 27, which is one of the most cytotoxic complexes on cancer cells (IC 50 = 0.089 µM), whereas its quinone methide, 28, is only an average inhibitor of TrxR (IC 50 = 0.15 µM). This lack of correlation has previously been found in other systems, such as NHC-gold complexes [72,73]. In addition, it has been shown that, in cancer cells, 8 the QM derived from the monophenol complex 3, is transformed into the indene 36a via the rearrangement process depicted in Scheme 12 [42].…”

Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment

“…Complex 5 also kills cancer cells by ROS-mediated apoptosis by targeting TrxR, and it further improves compatibility in animal models [ 37 ]. Next, rhodium complexes are also a large class of conventional TrxR inhibitors, such as rhodium(I) complex 6 and rhodium(III) complex 7 [ 78 , 79 ], all of which can kill cancer cells by TrxR-inhibition-mediated ROS regulation ( Figure 3 A). Recently, Chen et al also found that a novel triphenylphosphonium-modified terpyridine platinum(II) complex ( 8 ) is an inhibitor of mitochondrial TxrR with enhancement of caspase-3-independent apoptosis by increasing cellular ROS [ 80 ].…”

“…Contributions from the Ott group, Chen group, Shahraki group, and others have greatly enriched the entry of metal complexes targeting the antioxidant enzyme system as promising anti-cancer agents [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. Despite the importance of metal complexes as antioxidant enzyme inhibitors, no clinical anti-cancer drug targets TrxR, CAT, or Prx currently, which may be due to several major challenges in the field.…”