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Location: Natural Products Utilization Research

2014 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 Mississippi, 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 the NCNPR plant collections and from numerous collaborators. Over 1,100 plant samples were added to the NCNPR inventory this year. NCNPR researchers screened over 17,000 natural product crude extracts, semi-purified fractions and purified compounds 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 120 compounds (including 62 new natural products) were identified from plants, marine sponges, and fungi. Many showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. Over 250 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 scientists have 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., continued development of a product shown to be effective in animal models for desensitization to poison ivy dermatitis. The lead compound in the poison ivy project is now progressing to advanced toxicology studies. The Medicinal Plant Garden at the University of Mississippi, Oxford, MS, continues to expand its renowned collection of living medicinal plants. New demonstration beds and field plots are being developed. Here NCNPR cultivates and processes medicinal plants to be used in the discovery program. NCNPR continued construction this year of a 96,000 sq. ft. research wing 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, Oxford, MS, in collaboration with ElSohly Laboratories, Inc., also in Oxford, MS, are developing preventive treatments for poison ivy dermatitis. Development continued of the compound shown to be effective in animal models for desensitization to poison ivy dermatitis and shown to have desirable bioavailability and toxicological properties. A formulation which maximizes the shelf life of the final product was developed. This product is now being prepared for use 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. 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, Oxford, MS, operate the Drug Discovery Core of the University of Mississippi Medical Center Cancer Institute. Over the last year a new cancer-related luciferase based reporter gene assay has been developed and added to the anticancer screening battery. This assay will detect compounds that act on important targets for cancer therapy. Additionally, this battery of tests has been improved in order to enhance throughput and reduce cost by the purchase of an Agilent Bravo liquid handling system containing a 384 position head. Several lead compounds having significant anti-cancer effects were identified using this battery of assays. The most promising anticancer compounds will be produced in quantities required for further development and evaluation by the University of Mississippi Medical Center (UMMC) Cancer Institute, which may lead to new treatments for cancer.

3. 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, Oxford, MS, aim to discover novel antifungal compounds for treating life-threatening opportunistic fungal infections. In addition, projects are underway for discovering compounds that can improve the activity of current antifungal drugs, especially in drug-resistant fungal pathogens. 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 in the fungal pathogen Cryptococcus neoformans. Scientists also evaluated the mechanism behind the synergistic effects of natural products in combination with the antifungal drug fluconazole, which led to discoveries that demonstrate possible means to enhance the membrane disruption caused by this drug and improving its activity in pathogens that have become resistant to it. This year, a new mechanism-based screen was also initiated to identify compounds that enhance the activity of the antifungal drug caspofungin. This screen identifies compounds that disrupt the repair pathway induced in response to the cell wall damage caused by caspofungin. An initial screen with 880 in-house compounds identified 6 compounds that significantly improved caspofungin activity in fungal pathogens. These accomplishments may lead to new treatments for numerous diseases of plants, animals, and humans.

4. Discovery of new drugs to prevent or treat diseases caused by protozoans. The diseases caused by parasitic protozoa remain to be major global health challenges. New drug leads for treatment of malaria and leishmaniasis will afford development of drugs that reduce risk of treatment failures, overcome the problem of drug resistance and diminish the side effects of the drug now commonly used for treatment. This year scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, identified lead compounds that inhibit essential enzymes of the causative agents for malaria and leishmaniasis. Several compounds have been tested in pre-clinical animal models of the disease. These lead compounds of natural product origin have great potential for further development of new drugs. These accomplishments contribute to efforts to fight these widespread diseases.

Review Publications
Wang, M., Avula, B., Wang, Y., Zhao, J., Avonto, C., Parcher, J., Raman, V., Zweigenbaum, J., Wylie, P., Khan, I. 2014. An integrated approach utilizing chemometrics and GC/MS for classification of chamomile flowers, essential oils and commerical products. Journal of Food Chemistry. 152:391-398.

Zhao, J., Khan, S.I., Wang, M., Vasquez, Y., Yang, M., Avula, B., Yan-Hong, W., Avonto, C., Smillie, T.J., Khan, I.A. 2014. Octulosonic acid derivatives from roman chamomile (Chamaemelum Nobile) with activities against inflammation and metabolic disorder. Journal of Natural Products. 77:509-515.

Yang, M., Kim, J., Khan, I.A., Walker, L., Khan, S.I. 2014. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents. Life Sciences. 100:75-84.

Avula, B., Wang, Y., Wang, M., Ali, Z., Smillie, T.J., Zweigenbaum, J., Khan, K. 2014. Characterization of steroidal saponins from Dioscorea villosa and D Cayennensis using ultrahigh performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Planta Medica. 80:321-329.

Haron, M.H., Khan, I.A., Dasmahapatra, A.K. 2014. Developmental regulation of neuroligin genes in Japanese rice fish (oryzias latipes) embryogenesis maintains the rhythym during ethanol-in. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 159C:62-68.

Ahmed, M.H., Ibrahim, M.A., Zhang, J., Melek, F.R., El-Hawary, S.S., Jacob, M.R., Muhammad, I. 2014. Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium active Dimeric isobutyrylphloroglucinol from Ivesia gordonii. Natural Product Communications. 9(2):221-224.

Ghosh, S., Ozek, T., Tabana, N., Aabas, A., Rehman, J., Khan, I.A., Rangan, L. 2014. Chemical composition and bioactivity studies of Alpinia nigra essential oils. Industrial Crops and Products. 53:111-119.

Metwaly, A.M., Fronczek, F.R., Ma, G., Kadry, H.A., El-Hela, A.A., Mohammad, A.I., Cutler, S.J., Ross, S. 2014. Antileukemic alpha-pyrone derivatives from the endophytic fungus Alternaria phragmospora. Tetrahedron Letters. 55:3478-3481.

Yang, M., Avula, B., Smillie, T., Khan, I.A., Khan, S.I. 2013. Screening of medicinal plants for PPPAR-alpha and PPAR-gamma activation and evaluation of their effects on glucose uptake and 3T3-L1 adipogenesis. Planta Medica. 79:1084-1095.

Ravu, R., Chen, Y., Jacob, M.R., Pan, X., Agarwal, A.K., Khan, S.I., Heitman, J., Clark, A.M., Li, X. 2013. Synthesis and antifungal activities of miltefosine analogs. Bioorganic and Medicinal Chemistry Letters. 23:4828-4831.

Yang, M., Vasquez, Y., Ali, Z., Khan, I.A., Khan, S.I. 2013. Constituents from Terminalia species increase PPAR-Alpha and PPAR-Gamma levels and stimulate glucose uptake without enhancing adipocyte differentiation. Journal of Ethnopharmacology. 149:490-498.

Manda, V.K., Bharathi, A., Ali, Z., Wang, Y., Smillie, T.J., Khan, I.A., Khan, S.I. 2013. Characterization of in vitro ADME properties of diosgenin and dioscin from dioscorea villosa. Planta Medica. 79:1421-1428.

Avula, B., Wang, Y., Wang, M., Avonto, C., Zhao, J., Smillie, T.J., Khan, I. 2014. Quantitative determination of phenolic compounds by UHPLC-UV-MS and use of principal component analysis to differentiate chemo-types of chamomile/chrysanthemum flowerheads. Journal of Pharmaceutical and Biomedical Analysis. 88:278-288.

Avonto, C., Wang, M., Chittiboyina, A.G., Avula, B., Zhao, J., Khan, I.A. 2013. Hydroxylated bisabolol oxides: evidence for secondary oxidative metabolism in Matricaria chamomilla. Journal of Natural Products. 76:1848-1853.

Rotte, S.K., Chittiboyina, A.G., Khan, I.A. 2013. Asymmetric synthesis of Crispine A: constructing tetrahydroisoquinoline scaffolds using pummerer cyclizations. European Journal of Organic Chemistry. 28:6355-6360.

Ghoneim, M.M., Elokely, K.M., El-Hela, A.A., Mohammad, A.I., Jacob, M., Cutler, S.J., Doerksen, R.J., Ross, S. 2014. Isolation and characterization of secondary metabolites from Asphodelus microcarpus. Medicnal Chemistry Research. 23:3510-3515.

Ghoneim, M.M., Ma, G., El-Hela, A.A., Mohammad, A., Kottob, S., El-Ghaly, S., Cutler, S.J., Ross, S.A. 2013. Biologically active secondary metabolites from Asphodelus microcarpus. Natural Product Communications. 8(8):1117-1119.

Metwaly, A.M., Kadry, H.A., El-Hela, A.A., Mohammad, A.I., Ma, G., Culter, S.J., Ross, S.A. 2014. Nigrosphaerin A., a new isachromene derivative from the endophytic fungus Nigrospora sphaerica. Phytochemistry Letters. 7:1-5.

Mostafa, A.E., El-Hela, A.A., Mohammad, A.I., Jacob, M., Cutler, S., Ross, S. 2014. New secondary metabolites isolated from dondonae viscosa. Phytochemistry Letters. 8:10-15.

Ali, A., Tabanca, N., Kurkcuglu, M.K., Duran, A., Blythe, E., Khan, I.A., Can Baser, K. 2014. Chemical composition, larvicidal, and biting deterrent activity of essential oils of two subspecies of Tanacetum argenteum (Asterales: Asteraceae) and individual constituents against Aedes aegypti (Diptera: Culicidae). Journal of Medical Entomology. 51(4):824-830.

Yang, J., Liang, Q., Wang, M., Jeffries, C., Smithson, D., Tu, Y., Boulos, N., Jacob, M.R., Shelat, A.A., Wu, Y., Gilbertson, R., Avery, M.A., Khan, I.A., Walker, L.A., Guy, R., Li, X. 2014. UPLC-MS-ELSD-PDA as a powerful dereplication tool to facilitate compound identification from small molecule natural product libraries. Journal of Natural Products. 77:902-909.

Manda, V.K., Avula, B., Ali, Z., Khan, I.A., Walker, L., Khan, S.I. 2014. Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline. Planta Medica. 80:568-576.

Wang, M., Carrell, E., Ali, Z., Avonto, C., Parcher, J., Khan, I. 2014. Comparison of three chromatographic techniques for the detection of mitragynine and other indole and oxindole alkaloids in mitragyna speciosa (Kratom) plants. Journal of Separation Science. 37(12):1411-1418.

Tabanca, N., Avonto, C., Wang, M., Parcher, J.F., Ali, A., Demirci, B., Raman, V., Khan, I.A. 2013. Comparative investigation of Umbellularia californica and Laurus nobilis Leaf essential oils and identification of constituents active against Aedes aegypti. Journal of Agricultural and Food Chemistry. 61:12283-12291.