Correlation between the Stereochemistry and Bioactivity in Octahedral Rhodium Prolinato Complexes

Abstract

Controlling the relative and absolute configuration of octahedral metal complexes constitutes a key challenge that needs to be overcome in order to fully exploit the structural properties of octahedral metal complexes for applications in the fields of catalysis, materials sciences, and life sciences. Herein, we describe the application of a proline-based chiral tridentate ligand to decisively control the coordination mode of an octahedral rhodium(III) complex. We demonstrate the mirror-like relationship of synthesized enantiomers and differences between diastereomers. Further, we demonstrate, using the established pyridocarbazole pharmacophore ligand as part of the organometallic complexes, the importance of the relative and absolute stereochemistry at the metal toward chiral environments like protein kinases. Protein kinase profiling and inhibition data confirm that the proline-based enantiopure rhodium(III) complexes, despite having all of the same constitution, differ strongly in their selectivity properties despite their unmistakably mutual origin. Moreover, two exemplary compounds have been shown to induce different toxic effects in an ex vivo rat liver model.

Evaluation of New Palladium Cages as Potential Delivery Systems for the Anticancer Drug Cisplatin

“…This technology allows cells to remain in their natural environment with maintenance of the original cell–cell and cell–matrix contacts, which is absent in classical 2D cell cultures in vitro. Notably, the technique is a FDA‐approved model for drug toxicity and metabolism studies, and it has been previously used for the assessment of toxicity of metal‐based compounds, such as cisplatin, experimental organometallic compounds, aminoferrocene‐containing pro‐drugs, and ruthenium‐based kinase inhibitors …”

“…Notably, the technique is aF DA-approved modelf or drug toxicitya nd metabolism studies,and it has been previously used for the assessment of toxicity of metal-based compounds, such as cisplatin, [22] experimental organometallic compounds, [23] aminoferrocene-containing pro-drugs, [24] and ruthenium-based kinase inhibitors. [25] The rigid bidentate pyridyl ligands 1a-d were synthesized according to procedures reported in the Experimental Section (see the Supporting Information Figure S13 in the Supporting Information).…”

Anticancer Gold N‐Heterocyclic Carbene Complexes: A Comparative in vitro and ex vivo Study

“…This technique is an FDA‐approved model for drug toxicity and metabolism studies . Recently, we have successfully used the precision‐cut tissue slices technique to study the toxic effects of experimental anticancer organometallic compounds, aminoferrocene‐containing prodrugs, ruthenium‐based kinase inhibitors, as well as supramolecular metallacages as possible drug delivery systems …”

“…[37,38] This techniquei sa nF DA-approvedm odel for drug toxicity and metabolism studies. [37,38] Recently,w eh ave successfully used the precision-cut tissue slices technique to study the toxic effects of experimental anticancer organometallic compounds, [31,39,40] aminoferrocene-containing prodrugs, [41] ruthenium-basedk inase inhibitors, [42] as well as supramolecular metallacages as possible drug delivery systems. [43] The carbene( 1-butyl-3-methylimidazol-2-yilidene)gold(I)-chloridoA u(BMIm)Cl( 1)a nd the bis-carbene bis(1-butyl-3methylimidazole-2-yilidene)gold(I) hexafluorophosphate [Au(B-MIm) 2 ]PF 6 (2)w ere synthetized according to previously reported procedures, [34] and adapted establishedp rotocols.…”

Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations

“…This technique is an FDA-approved modelf or drug toxicitya nd metabolism studies. [25][26][27][28][29][30][31] With respect to the investigation of the mechanism of action, in recent years there has been increasing interest in poly(ADPribose) polymerase (PARP) inhibitors as anticancer agents, including Au III compounds, [32][33][34][35][36] as ac ascade of apoptosis-promoting signals starts upon enzymei nactivation. These inhibitors can be either used alone or in combination with other well-establishedD NA-damaging drugs, thus amplifying their cytotoxic effect.…”