Employees – University of Copenhagen

Forward this page to a friend Resize Print Bookmark and Share

Department of Drug Design and Pharmacology > Employees

Monika Marianna Kruszyk

Monika Marianna Kruszyk

No title

Metabolite identification is a crucial part of drug development and the synthesis of putative metabolites is an indispensible aspect of my PhD project. Traditionally, the synthesis of metabolites has been considered a very significant challenge – often based on trial-and-error as the site of metabolism was unknown apriory.

The PhD project first aims to explore the validity of (calculated) NMR chemical shifts to predict the outcome of electrophilic aromatic substitution reactions and of radical reactions applied to (hetero)aromatic systems. Based on a survery of the literature we have found that lowest C-H 13C NMR signal as calculated by ChemDraw correlates with the regiochemical outcome of bromination reactions.1 A similar trend has been observed for the site of oxidative metabolism by cytochrome P450 enzymes, the most important of the liver enzymes responsible for small molecule clearence. The opposite pattern has been found for radical reactions (i.e., the regioselectivity correlates with the highest calculated chemical shift). The latter class of transformations seems to occur with a selectivity similar to the one observed for aldehyde oxidase, a notoriously difficult-to-understand oxidative enzyme.

Drug metabolites are of great importance to pharmaceutical industry, as they are essential in all phases of drug discovery. There are several questions that must be answered before the drug reaches the market, including the toxicity and pharmacological effect. First issue is to identify which metabolites are formed in humans. In this case we would like to explore the predictive ‘power’ of NMR chemical shifts to pin-point the site of oxidation by cytocrome P450 and aldehyde oxidase. However, metabolite synthesis is still a challenging problem, therefore the development of a chemical synthesis method is needed, to access the potential metabolites, preferably as a late-stage functionalization of the parent drug-like molecule.

ID: 176976722