Oktaedrische Silicium(IV)komplexe: Methodenentwicklung und Anwendung als Enzyminhibitoren

The field of chemical biology often utilizes small organic molecules as tools for the examination of biological processes. Along those lines, the MEGGERS group has established a research program focused on the discovery of organometallic compounds as enzyme inhibitors. In contrast traditional uses in medicine, the MEGGERS group uses transition metals solely to organize organic ligands in three-dimensional receptor space. These metal-centered complexes benefit from extended structural opportunities with a number of possible molecular geometries achievable, including octahedral. As a result, over the last decade MEGGERS et al. have demonstrated rapid access to a number of organometallic compounds with enhanced levels of potency and selectivity for enzyme targets. Until recently, the majority of the research focused on using ruthenium to construct inhibitors. Despite the low-toxicity of ruthenium and the kinetic inertness of its complexes, it became interesting in the possibility of exchanging the transition metal for non‐toxic silicon. This thesis details the synthesis of dicationic silicon(IV) complexes and the development of synthetic modification. Here, the post‐coordinative introduction of functional groups, namely halides, esters and nitro groups was successfully established. In a proof‐of‐principle study, these methods were used to specifically address two different classes of enzymes. The first project centered on the synthesis of silicon‐based protein kinase inhibitors. As a result, dihydroxyphthalimide and naphthalimide ligands were designed as the bioactive pharmacophores. Although these compounds possessed modest micromolar IC50 values against Pim1 at an ATP concentration of 1 μM, they are highly interesting complexes for measurements against other kinases in future studies. In a second project a small library of silicon(IV) complexes was screened against acetylcholine esterase, initially displaying low micromolar inhibition. With esterification of a coordinated hydroxyl group, it was possible to modify these complexes through copper(I) catalyzed click chemistry resulting in novel silicon complexes with nanomolar affinity.