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Location: Natural Products Utilization Research

2013 Annual Report

1a. Objectives (from AD-416):
The primary focus of our project is in the development of novel products, compounds and materials needed for specialized products in biotechnological, agrochemical, and pharmaceutical applications. This work also includes the identification of new bioactive ingredients, understanding of their mechanisms of action and methods to determine their concentrations and stability to ensure quality of raw materials, whether used as sources of bioactive principles or for other applications. Objective 1: Discover new leads from plant-based natural resources with anti-infective and anti-cancer, immunomodulator and anti-inflammatory activities using cell-based screens and mechanistic assays using molecular target-based approaches. Sub-objective 1A: Source novel natural resources from terrestrial plants, marine organisms and microbes from around the world for biological testing. Sub-objective 1B: Prepare, maintain and manage Natural Products Repository and Laboratory Information Management System (LIMS). Sub-objective 1C: Evaluate natural product extracts and natural product derived pure compounds for potential anti-cancer, anti-infective, anti-inflammatory, and anti-diabetic properties, and for utility in metabolic and immune disorders. Sub-objective 1D: Isolation and structural elucidation of lead compounds. Objective 2: For the best candidates, characterize mechanisms of action, selectivity, toxicity, functional activity in secondary assays and in animal models of plant-based anti-infective and anti-cancer, immunomodulator and anti-inflammatory compounds. Sub-objective 2A: Characterization of mechanisms of action and functional activity of leads. Sub-objective 2B: Characterization of selectivity and toxicity of lead compounds. Objective 3: Develop methods for analysis of bioactive or medicinally important plants and quality control of their derived products. Objective 4: Assess selected medicinal or aromatic plants for cultivation, harvest and processing to optimize yields of biomass and active principles.

1b. Approach (from AD-416):
The approach includes a program of: (1) Using cell-based screening and mechanistic assays to discover new pharmaceutical and agrochemical leads from natural sources; (2) Using secondary assays and animal models to characterize mechanisms of action, selectivity, toxicity and functional activity of the best candidate compounds having anti-infective, anti-cancer, immunomodulatory, or anti-inflammatory properties; (3) Selection, agronomics and analysis of bioactive or medicinally important plants and their derived products.

3. Progress Report:
Researchers at the National Center for Natural Products Research (NCNPR) at the University of MS, Oxford, MS, maintained basic discovery operations, with emphasis on the discovery of antifungals, anticancer, anti-inflammatory agents and immunomodulating agents. Scientists continued to source plant materials for screening from NCNPR plant collections and from numerous collaborators. Over 1,400 plant samples were added to the NCNPR inventory this year. Over 14,000 natural product crude extracts, semi-purified fractions and purified compounds were screened for biological activities against specific molecular targets and whole cell systems. As part of continuing efforts in the search for anti-infective, anticancer, and immunomodulator/anti-inflammatory leads from natural sources, more than 150 compounds (including 15 new natural products) were identified from plants, marine sponges, and fungi. Many of these showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. Over 150 isolated actives or extracts 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 operations, NCNPR has selected a number of these compounds for more advanced study, whether for characterizing mechanisms of action, determining suitability for further pharmaceutical development, evaluation in disease models in preclinical studies, or in field applications. In collaboration with ElSohly Laboratories, Inc., the development of a product shown to be effective in animal models for desensitization to poison ivy dermatitis continues. The lead compound in the poison ivy project is now undergoing advanced toxicology studies. With new facilities of the Medicinal Plant Garden at the University of Mississippi now complete, the outdoor growing sites are being developed and commissioned with plantings of various species. This new facility enhances the capabilities of NCNPR to cultivate and process medicinal plants to be used in the discovery program. Construction of a 97,000 sq. ft. research wing began this year and is expected to be completed by 2015. The new research wing will expand and enhance the research capabilities of NCNPR with a second plant specimen repository, herbarium, and laboratories for plant tissue cultures, cellular cultures, scale-up isolation and synthetic chemistry.

4. Accomplishments
1. Develop agents for prevention/treatment of poison ivy dermatitis. Poison ivy is a widespread plant that causes an itching rash in most people who touch it. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi in collaboration with ElSohly Laboratories, Inc. are developing preventive treatments for poison ivy dermatitis. Of the two lead compounds shown to be effective in animal models for desensitization to poison ivy dermatitis and have undergone bioavailability and preliminary toxicology studies, one product was selected for further development. This product is now being evaluated in advanced toxicology studies which will enable application for investigative new drug status by the U.S. Food and Drug Administration. These accomplishments may lead to a new product for a common but serious condition.

2. New scientific technologies that improve laboratory operations. Many research and testing laboratories use various chromatographic techniques to separate mixture for purification and analysis, but no single technique can be for all types of mixtures. Because different compounds may have significantly different chemical and physical properties, a separation technique compatible with the compounds of interest must be used to achieve proper results. Scientists at the National Center for Natural Products Research (NCNPR) invented a chromatographic device which uses centrifugal force to efficiently separate complex mixtures of organic compounds into their various components. A prototype instrument was built and tested. A patent application has been filed and a research disclosure is pending. This accomplishment may lead to a marketable product that will provide new solutions to chromatographic challenges faced by scientists and laboratory technicians in many fields, including agriculture, pharmaceutics, and food science.

3. Develop treatments for cancer. A cancer research program requires a drug discovery program in order to explore all avenues of treatment. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi operate the Drug Discovery Core of the University of Mississippi Medical Center (UMMC) Cancer Institute. A new cancer-related luciferase based reporter gene assay has been developed and added to the anticancer screening battery. Additionally, the twelve-gene battery of tests developed last year has been improved in order to enhance throughput and reduce cost. Two novel compounds having significant anti-cancer effects were identified using these tests. The most promising anticancer compounds will be produced in quantities required for further development and evaluation by the UMMC Cancer Institute, which may lead to new treatments for cancer.

4. New antifungal natural products for use in agriculture and medicine. Because many organisms contain inherent protective mechanisms the natural environment is a rich source for compounds to treat fungal diseases. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi aim to discover novel antifungal compounds for treating life-threatening opportunistic fungal infections. This ongoing program covers various aspects of drug discovery including screening and isolation of natural product antifungal compounds, determining their mechanism of action, and understanding potential resistance mechanisms. Two new antifungal pathways were discovered this year. Scientists also evaluated the mechanism behind the synergistic effects of natural products in combination with the antifungal drug caspofungin, which led to discoveries that demonstrate possible means to enhance cell wall damage caused by current antifungal drugs. These accomplishments may lead to new treatments for numerous diseases of plants, animals, and humans.

5. Discovery of new drugs to prevent or treat diseases caused by protozoans. New drugs for malaria and leishmaniasis will reduce risk of treatment failure, reduce risk of developing resistance, and reduce side-effects of the drug now commonly used. This year scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi identified several compounds that inhibit certain enzymes of parasitic protozoans. These novel compounds of natural product origin have great potential as potent agents against leishmaniasis. These accomplishments contribute to efforts to fight these widespread diseases.

Review Publications
Herath, W., Khan, S.I., Khan, I.A. 2012. Microbial metabolism Part 14 Isolation and bioactivity evaluation of microbial metabolites of resveratrol. Natural Product Research. 32:1377-1382.

Wang, M., Avula, B., Zhao, J., Parcher, J.F., Khan, I.A. 2012. Fatty acid analysis of saw palmetto (Serenoa repens) and pygeum (Prunus africanum) in dietary supplements by mass spectrometry in the selected ion monitoring mode. Planta Medica. 77:84-90.

Mikell, J.R., Khan, I.A. 2012. Bioconversion of 7-hydroxyflavanone: isolation, characterization and bioactivity evaluation of twenty-one phase I and phase II microbial metaboites. Chemical and Pharmaceutical Bulletin. 60(9):1139-1145.

Machumi, F., Yenesew, A., Midiwo, J.O., Heydenreich, M., Kleinpeter, E., Tekwani, B.L., Khan, S.I., Walker, L.A., Muhammad, I. 2012. Antiparasitic and anticancer carvotacetone derivatives of Sphaeranthus bullatus. Natural Product Communications. 7(9):1123-1126.

Raman, V., Galal, A.M., Khan, I.A. 2012. An investigation of the vegetative anatomy of Piper sarmentosum, and a comparison with the anatomy of Piper betle (Piperaceae). American Journal of Plant Sciences. 3:1135-1144.

Ilias, M., Samoylenko, V., Machumi, F., Zaki, M.A., Gillum, V. 2013. Preparation and application of reversed phase chromatorotor for the isolation of natural products by centrifugal preparative chromatography. Journal of Chromatography A. 8(3):311-314.

Machumi, F., Midiwo, J.O., Jacob, M.R., Khan, S.I., Tekwani, B.L., Zhang, J., Walker, L.A., Muhammad, I. 2013. Phytochemical, antimicrobial and antiplasmodial investigations of Terminalia brownii. Natural Product Communications. 8(6):761-764.

Peddikotla, P., Khan, I.A., Chittiboyina, A.G. 2013. Synthesis of pterostilbene by Julie Olefination. Synthetic Communications. 78:43-50.

Mohamed, Z., Balachandran, P., Khan, S., Wang, M., Mohammed, R., Hetta, M.H., Pasco, D.S., Muhammad, I. 2013. Cytotoxicity and modulation of cancer-related signaling by (Z)- and (E)- 3,4,3´,5´ tetramethoxystilbene isolated from Eugenia rigida. Journal of Natural Products. 76:679–684.

Pugh, N.D., Jackson, C.R., Pasco, D.S. 2012. Total bacterial load within Echinacea purpurea, determined using a new PCR-based quantification method, is correlated with LPS levels and In vitro macrophage activity. Planta Medica. 79:9-14.