Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands

Abstract

Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N , N -bidentate ligands ( R )- and ( S )-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure ( R )- and ( S )-forms of the ligand, depending on the organometallic moiety, either the S M , R or R M , S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η 6 - p -cymene) compounds, whereas the R M , R or S M , S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η 5 -pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the ( R )-enantiomer of the ligand being more potent than the ( S )-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active.

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity

“…We have previously reported similar effects for a half-sandwich complex of osmium bearing 2-(1-amino2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3 H )-one as an N , N -bidentate ligand. 60 We demonstrated that this complex was also able to rapidly reduce the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical cation in an in vitro assay suggesting that it may actually diminish the DHR123 oxidation rate. Taking into account the structural similarity between 3c / 4c and the aforementioned complex, it can be inferred that such compounds may behave as antioxidants.…”

“…The presence of an organometallic moiety may also increase the ability of the compound to generate reactive oxygen species (ROS), which are detrimental to the cell, 40,41 or lead to highly active anticancer agents with a multimodal mechanism of activity. 42–46 We and others have recently demonstrated that Rh and Ir half-sandwich complexes derived from 2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3 H )-one exhibit a higher KSP inhibitory activity than the ligand itself 47 while the Ru half sandwich complexes derived from monastrol showed low activity. 48 Also, conjugating a ferrocenyl moiety with monastrol positively impacted the cytotoxicity and KSP inhibitory activity.…”

A Rhein‐Based Rh(III) Arene Complex with Anti‐tumor Cell Proliferative Activity Inhibits RNA Demethylase FTO

“…[ 8‐9 ] Recent studies revealed that enzymes were the potential binding targets for the metal‐arene complexes. [ 10 ] Several classes of proteins with different roles, including kinases and DNA‐repair proteins have been characterized as the targets of metallodrugs in vitro and in vivo . [ 11 ] Using an integrated proteomics‐based target‐ response profiling approach, a series of Ru(II)‐arene (RAPTA) compounds were determined to inhibit thioredoxin reductase and cathepsin B, [ 12 ] or mainly target the cytoskeletal protein plectin to affect the motility of cancer cells.…”

Design, Synthesis, and Evaluation of Biological Activity of Ferrocene‐Ispinesib Hybrids: Impact of a Ferrocenyl Group on the Antiproliferative and Kinesin Spindle Protein Inhibitory Activity

“…[21] We also found that half-sandwich complexes of Ru, Rh, Ir and Os featuring a 2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one ligand showed high cytotoxicity and the ability to inhibit KSP activity. [22] These results encouraged us to investigate the effect of a ferrocenyl organometallic group on the antiproliferative activity of ispinesib and its (S)-enantiomer in comparison to related organic derivatives (Figure 1). We report structure-activity relationship (SAR) studies based on antiproliferative activity, impact on cell cycle, induction of reactive-oxygen species formation, molecular docking and KSP inhibitory activity.…”