Abstracts F1 - F2
Category F. Drug Metabolism, Toxicity and Pharmacogenomics
F1. On-Line Monitoring of Catecholamines in vivo Using Microdialysis Coupled to Microchip Electrophoresis with Electrochemical Detection
Rachel A. Saylor1,2and Susan M. Lunte1,2,3
1Department of Chemistry, 2Ralph N. Adams Institute for Bioanalytical Chemistry, 3Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas
Microdialysis is a powerful separation technique capable of monitoring the concentration changes of multiple analytes in the extracellular fluid of the brain. This technique generates small sample volumes in a continuous flow stream. Traditional methods used for sample analysis forfeit temporal information regarding dynamic processes due to the larger volumes necessary for analysis. Additionally, sample acquisition methods traditionally involve some form of tethering or anesthetizing the animal under study, greatly reducing the available behavioral information. In order to preserve both temporal resolution and behavioral information, the ideal analysis system is one that can be employed on-line, has fast analysis times of small sample volumes, and can be placed on a freely-roaming animal. In this study, we present an approach for coupling microdialysis sampling to microchip electrophoresis and electrochemical detection at a carbon electrode for monitoring neurochemicals in the dopamine metabolic pathway. The device is comprised of a double T PDMS/glass hybrid microchip with detection at a pyrolyzed photoresist film carbon electrode, and was used to separate five analytes in the dopamine metabolic pathway in under 100 s. The developed method was used to monitor the dopamine metabolic pathway in vivo in rats after the administration of L-DOPA. The complete device and associated instrumentation can be used remotely and on-animal, for near-real time in vivo monitoring
F2. Synthesis and cytotoxic evaluation of analogues of the tubulin-binding agent soblidotin
Abugafar M. L. Hossion and Blake R. Peterson
The University of Kansas, Department of Medicinal Chemistry, 2034 Becker Dr., Lawrence, Kansas 66047
To effectively kill targeted cells, anticancer antibody-drug conjugates generally incorporate highly toxic small molecules. Small molecules with sufficient potency for these applications include analogues of the natural product dolastatin 10 such as soblidotin (Figure 1). This compound selectively disrupts tumor vasculature and potently inhibits the polymerization of tubulin. In an effort to create more effective antibody-drug conjugates, we synthesized soblidotin and derivatives, and we are investigating the biological properties of these compounds. Many of these agents are highly cytotoxic against human breast cancer (SKBR3), prostate cancer (PC3) and leukemia (Jurkat) cell lines with IC50 values ranging 0.2 nM to 100 nM. The synthesis and properties of these compounds will be described.
Figure 1. Chemical structures of dolastatin 10 and soblidotin (left), and an X-ray structure of tubulin bound to soblidotin (right, soblidotin shown as a CPK model, PDB 3E22).