Description:

Speaker

Hilkka Kentamaa, Purdue University

https://www.chem.purdue.edu/hilkka/

Abstract

Adverse drug reactions are believed to be a leading cause of morbidity and mortality in United States healthcare and markedly increase the cost of drug development. Pharmacologically active or toxic drug metabolites and impurities are frequently implicated as potential sources of serious adverse drug reactions. This is one of the major reasons for new drug candidates being withdrawn from the market. The most challenging task in addressing this issue is the rapid detection and structural elucidation of trace levels of unknown drug metabolites and impurities. However, all common analytical methods developed for this task, including nuclear magnetic resonance spectroscopy, gas chromatography, capillary electrophoresis, liquid chromatography, mass spectrometry and tandem mass spectrometry, have serious limitations. Furthermore, only the methods based on tandem mass spectrometry enable the unambiguous identification of organic compounds directly in complex mixtures. While MS2 using collision-activated dissociation (CAD) has been highly successful in identification of known compounds in complex mixtures, this approach often does not allow the unambiguous identification of previously unknown compounds as ionized isomeric compounds often fragment in a similar manner. We are in the process of developing fast, automated methodology based on multi-stage tandem mass spectrometry utilizing functional-group selective bimolecular reactions (instead of CAD) that enables unambiguous structural characterization of previously unknown drug metabolites and impurities in complex mixtures. This involves the development of a library of reagents that can be used to reliably and predictably identify functional groups in previously unknown, protonated polyfunctional analytes, methods for the fast introduction of several reagents into a mass spectrometer to probe for the presence of several functionalities in (protonated) analytes as they elute from HPLC, and automation of the experiment.