2008 Annual Report 1a.Objectives (from AD-416) The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharmaceuticals or agrichemicals, and to identify, characterize, and develop medicinal plants for production of pharmaceuticals as potential alternative crops. 1b.Approach (from AD-416) The approach includes a program of: (1) Discovery of secondary metabolites from natural resources with anti-infective and anti-cancer activities based on molecular and cell-based assays; (2) Characterizing mechanisms of action, selectivity, toxicity, and functional activity for the best candidate compounds with anti-microbial and anti-cancer properties in secondary assays and in animal models; and, (3) Selection, agronomics and analysis of medicinally important plants and their derived products. 3.Progress Report Maintained our basic discovery operations, with emphasis on the discovery of antifungals, anticancer, anti-inflammatory agents and immunomodulating agents. Continued to source plant materials for screening from the Missouri Botanical Garden, New York Botanical Garden, Kenya Academy of Sciences, our own plant collections and from a myriad of collaborators. Added 918 plant samples to our inventory this year. Screened over 4,200 natural product crude extracts, semi-purified fractions and purified compounds in 07-08 for biological activities against specific molecular targets and/or whole cell systems. As part of our continuing effort in the search for anti-infective, anti-cancer, and immunomodulator/anti-inflammatory leads from natural sources, we completed bioassay-guided chemical investigation on more than 22 species for 07-08. As a result, more than 50 including 25 new natural products were identified from plants, marine sponges, and fungi. They showed potent phytotoxic, antifungal, antibacterial, and/or antimalarial activities. A patent application is to be filed for one of these classes of compounds as potential antifungal and antimalarial agents. Over 50 of our isolated actives have been characterized in more detailed follow-up assays to determine their mode of action, pharmaceutical properties, toxicity, and selectivity across a range of assays. In addition to these basic discovery operations, we have selected a number of these compounds for more advanced study, whether for characterizing mechanisms of action, determining suitability for further pharmaceutical development, or evaluation in disease models in preclinical studies, or in field applications in the case of agrichemicals. Identified 6 new antimalarial leads in the past year, and 8 new antifungal leads that have been scaled up and progressed to animal testing. One synthetic anti-cancer agent has been further tested in animals. Tested the efficacy of several urushiol derivatives [the toxic principle of poison ivy] for desensitization to poison ivy dermatitis. These have been developed under an Small Business Initiative Research (SBIR) grant from the NIH, in collaboration with ElSohly Laboratories, Inc. Two of these hold great promise for developing desensitizing or protective agents. Our "Living Collection" of medicinal plants has grown to over 1,200 species during the 07/08 FY. Also, our seedbank of medicinal plants now stands at 450 species. Demonstration plots of several medicinal herbs are grown each year in our Medicinal Plant Garden. Evaluated 3 Echinacea species with regard to cultivability, yields, and harvesting techniques, as well as endophyte analysis. Also, Salvia divinorium, Mitragyna speciosa and Smallanthus sonchifolius were cultivated for biomass production. Echinacea tennesseensis, Hydrastis canadensis, Piper nigrum, and Jatropha spp. were explored for developing preliminary data on cultivatability in this region. NP 302; Component 2.C. 4.Accomplishments 1. Antifungal natural products. The National Center for Natural Products Research (NCNPR) has a long-standing antifungal natural product discovery program. This project has been supported by substantial NIH funding for the last 18 years, and many important achievements have resulted, with significant developments in this past year. This project spans from screening and isolation of antifungal compounds from nature through to studies of their mechanisms of action and their potential utility as fungicides and for pharmaceutical applications. Additional National Institutes of Health (NIH) funding to study mechanisms of action of these antifungal compounds has been secured in this year. Important new publications on antifungal mechanisms of action have also resulted [See Agarwal et al., in reference list]. NP 302, Component 2c, Problem Statement 2c. 2. Antimalarial drugs. In the past year, the NCNPR was able to identify and secure external funding from the Dept. of Defense to support research on developing new and safer antimalarial drugs. Malaria kills more than 2 million people each year world-wide, most of them children. Though most malaria deaths occur in the developing world, because of the magnitude of the problem, the economic impact of the disease is felt in wealthier nations, including the United States, who spend billions of dollars each year to combat the disease. In addition, antimalarial drugs have important military applications, especially for prophylaxis in troops deployed in malarious regions. Two publications at the forefront of this field have been published [see Nanayakkara et al., and Tekwani and Walker]. NP 302, Component 2, Problem Statement 2c. 3. Agents for prevention/treatment of poison ivy dermatitis. In the past year, funding was secured from NIH for developing new leads that are effective in animals in the prevention of poison ivy dermatitis. These are in the process of patent coverage. NP 302, Component 2, Problem Statement 2c. 4. Immunostimulant product. A natural product preparation for support of the immune system “Immune XT”, which was developed by the NCNPR, was released in U.S. markets this last year. This product was clinically studied in Europe and marketed there for two years, before being licensed and released in the U.S. this year. NP 302, Component 2, Problem Statement 2c. 5.Significant Activities that Support Special Target Populations None. 6.Technology Transfer