The Search for Mitotic Inhibitors From Marine Derived Fungi

The discovery of mitotic inhibitors, often derived from natural products, represents an important biomolecular mechanism in chemotherapeutic cancer treatments. We have begun a program to identify mitotic inhibitors from secondary metabolites of marine derived fungi, and this project will describe the overall program as well as the results we have obtained to date. Several hundred fungal extracts have been screened with an in vitro assay measuring mitotic inhibition at the UCSC Screening center.  Five fungal strains have been selected for further analysis based on the extract's ability to inhibit mitosis and the potential to discover new molecular leads after analysis of the secondary metabolite profile by liquid chromatography-mass spectrometry (LCMS). In order to identify which specific metabolite(s) in each extract was responsible for mitotic inhibition, a peak library of the extract was generated by semi-preparative high performance liquid chromatography (HPLC) and then tested for mitotic inhibition. The peak library screening data pinpointed the active compound in the extract. Active compounds are then isolated in pure form and retested for mitotic inhibition to confirm activity. The molecular structure of the pure compound will then be determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) experiments. Pure compounds that show promise will be further studied to define the biomolecular mechanism of mitotic inhibition and their potential for the treatment of cancer.