ASMS 2012: ACD/Labs—Taking a bite out of... Small Molecule Characterization Breakfast Seminar

Natural products, in general, and compounds from fungi, specifically, have a long and storied history in the development of medicines. In ongoing studies to explore filamentous fungi for anticancer drug leads, over 100 compounds have been isolated and characterized over the past four years, with approximately 25 to 35 compounds being discovered annually. Over 30% of the isolated leads represent new chemical entities. Of the known compounds, approximately 40% have not been studied previously for anticancer activities, and thus their biological evaluation is germane to the larger goals of the project. Although more than 230,000 compounds have been described from nature, only about 13,000 of these have been from fungi. Thus, our library represents about 1% of the compounds described by fungi.

To expedite the discovery of new leads, and to avoid re-isolation of previously known compounds, a UPLC-PDA-HRMS method was developed for dereplication of fungal secondary metabolites in crude culture extracts. A database was constructed by recording HRMS and MS/MS spectra of compounds isolated to date, utilizing both positive and negative ionization modes. Additional information, such as UV-absorption maxima and retention times, were also recorded. Screener cultures and/or fractions that showed cytotoxic activities were dereplicated before engaging in the isolation/purification process. Examples will be presented that demonstrate the speed and efficiencies with these procedures, particularly in conjunction with software programs that help collate the data. In summary, the dereplication methods allow us to focus limited human and financial resources upon those bioactive samples that have the most promise to yield structurally unique leads.