Grant: Research Tools and Instruments - Category 1 (<$150,000)

A major part of our program in organic synthesis and chemistry of natural products involves the synthesis and evaluation of new biologically active compounds derived from natural product leads. Recently, new compounds related to oseltamivir (Tamiflu?) have been shown to be more active than Tamiflu in sialidase inhibition and are also active against pancreatic cancer. We also have prepared new unnatural derivatives of pancratistatin that show high activities against several human cancer cell lines. These two projects now require a systematic investigation of libraries of additional derivatives by rapidly screening them for activity, lipid and water solubility, and increased bioavailability. The major objective of this project, therefore, is to produce large numbers (hundreds) of derivatives rapidly on a small scale for testing and to provide direction for scale-up and further study. The requested instrument (liquid chromatograph/mass spectrometer) is ideal for rapid identification of large numbers of derivatives on a milligram and sub-milligram scale. It obviates the need to do the syntheses necessary for other currently accessible methods of identification. There will hence be a large savings in resources and materials by working only on the scale required for biological evaluation. Our ongoing program in biocatalysis also requires rapid screening of new substrates for enzymatic dihydroxylation of aromatics. Our project on the enzymatic N-demethylation of opiate alkaloids also requires screening many monooxygenase enzymes and analyzing for optimum conditions of N-demethylation. We anticipate that the instrument will be used more than 40 hours per week for the analyses described above in connection with several areas of our research program. We anticipate significant results in the preparation of anti-cancer compounds and in identification and commercialization of new biological protocols for production of opiate-based compounds.