Design and Synthesis of Enantiopure Organometallic Kinase Inhibitors as Potential Chemotherapeutics

The exploration of the structural scope of the octahedral coordination mode and investigations of defined structural isomers regarding their physico-chemical properties are of valuable interest for applications in the field of catalysis, materials sciences, and life sciences. The MEGGERS group estab...

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1. Verfasser: Rajaratnam, Rajathees
Beteiligte: Meggers, Eric (Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2016
Chemie
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Zusammenfassung:The exploration of the structural scope of the octahedral coordination mode and investigations of defined structural isomers regarding their physico-chemical properties are of valuable interest for applications in the field of catalysis, materials sciences, and life sciences. The MEGGERS group established a variety of different transition metals as structural templates to gain access to highly potent and selective kinase inhibitors. During this effort, the effectiveness of metal complexes as kinase inhibitors with potential anticancer properties has repeatedly been proven in vitro as well as in vivo. The ambition to establish metals as structural templates led from initial half sandwich complexes to highly sophisticated octahedral complexes. In the current thesis, the challenge to selectively synthesise a desired enantiomer is presented highlighting the application of symmetric polydentate ligands and chiral polydentate ligands. As a first example, regarding the chemical and biological properties, an N-methyl-1,4,7-trithiacyclodecan-9-amine based ruthenium(II) complex, in context of S6 kinase 1 (S6K1) inhibition, is presented. Aberrant activation of S6K1 is found in many diseases, including diabetes, aging, and cancer. The presented ATP competitive organometallic kinase inhibitors were inspired by the pan-kinase inhibitor staurosporine, and specifically inhibit S6K1, and verify the strategy successfully applied previously to target other kinases. Furthermore, the obtained biochemical data demonstrate that the compounds inhibit S6K1 with an IC50 value in the low nanomolar range at 100 μM ATP. Moreover, the crystal structures of S6K1 bound to staurosporine, and two ruthenium(II) based inhibitors reveal that the compounds bind in the ATP binding site and exhibit S6K1-specific contacts, resulting in changes to the p-loop, aC helix, and aD helix compared to the staurosporine bound structure. In vitro assays reveal inhibited S6K phosphorylation in yeast cells. These cumulated biological studies demonstrate that potent, selective, and cell permeable metal based inhibitors can provide a scaffold for the future development of compounds with possible therapeutic applications. However, the so far presented complexes are racemic mixtures. Thus, to apply these compounds for the therapeutic use the pharmacologic and toxicological characterisation of each present structural isomer is obligatory. Therefore, the asymmetric synthesis of desired structural isomers of the metal based kinase inhibitors is highly favourable. Thus, controlling the metal centered relative stereochemistry represents the key to achieve this task. The application of a proline based chiral tridentate ligand to decisively influence the coordination sphere of an octahedral rhodium(III) complex is described as possible solution to face this issue. The mirror-like relationship of synthesised enantiomers and differences between diastereomers were investigated. Furthermore, the application of the established pyridocarbazole pharmacophore ligand as part of the organometallic complexes to obtain kinase inhibitors is demonstrated. Moreover, the importance of the relative stereochemistry at metal in chiral environments like biomolecules is highlighted by both, protein kinase profiling and competitive inhibition studies. The cumulated results confirm that the proline based enantiopure rhodium (III) complexes differ entirely in their selectivity and specificity despite their unmistakably mutual origin. The successful work using proline as a chiral building block inspired to implement other chiral amino acids into the ligand design. For this aim, a versatile set of amino acids were elaborated as starting points for the ligand synthesis. As highly functionalised building blocks, they offer the possibility to orient a particular functional group into a defined site of the enzyme pocket, overall predefined by the chirality at metal. However, the ambitious attempts were limited by the synthetic issues accompanying the implementation of primary amino acids into the ligand design due to steric effects influencing the yields. Nevertheless, the biological data evaluating the obtained complexes offered valuable hints for the future ligand scaffolds.
Beschreibung:255 pages.
ISBN:978-3-8439-2900-4
DOI:https://doi.org/10.17192/z2016.0892