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United States Department of Agriculture

Agricultural Research Service

2010 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 968 plant samples to our inventory this year. Screened over 11,900 natural product crude extracts, semi-purified fractions and purified compounds in 08-09 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 30 species for 08-09. As a result, more than 100 including 50 new natural products were identified from plants, marine sponges, and fungi. They showed potent phytotoxic, antifungal, antibacterial, and/or antimalarial activities. Over 200 of our 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, 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 3 new antimalarial leads in the past year, and 19 new antifungal and antibacterial leads that have been scaled up and progressed to animal testing. Tested the efficacy of several urushiol derivatives [the toxic principle of poison ivy] for desensitization to poison ivy dermatitis in animal models. These have been developed under a Small Business Initiative Research (SBIR) grant from the National Institutes of Health (NIH), in collaboration with ElSohly Laboratories, Inc. A patent application has been filed for these compounds. Demonstration plots of several medicinal herbs are grown each year in our Medicinal Plant Garden. Two medicinal plants Echinacea purpurea and Smallanthus sonchifolius were explored for developing preliminary data on cultivatability in this region.

1. Antifungal Natural Products. The antifungal natural product discovery program at the National Center for Natural Products Research (NCNPR) has been supported by National Institutes of Health (NIH) funding for the past 20 years. The overall goal of this project is to discover novel antifungal compounds for the treatment of life-threatening opportunistic fungal infections. It covers various aspects of drug discovery including screening and isolation of antifungal compounds, determining their mechanism of action, and understanding potential resistance mechanisms. An additional goal of this program is to isolate novel compounds that can restore antifungal activity in clinically used drugs such as fluconazole (FLC) that have become inactive due to drug resistance. In this past year, many important achievements have resulted including: (a) the isolation of new antifungal compounds as well as compounds with FLC-enhancing activity, (b) the identification of new molecular pathways targeted by two new antifungal compounds – these pathways are new in that they are not targeted by current clinically used antifungal drugs, and (c) the identification of new genes previously not implicated in FLC resistance – these genes have the potential for the development of combination therapies to treat fungal infections.

2. Antimalarial Drugs. In the past year, the NCNPR was able to identify and secure external funding from the Department of Defense to support research on developing new and safer antimalarial drugs. Additional funding was obtained through congressionally directed medical research program (CDMRP) for a natural products antileishmanial discovery program. Also, a Grand Challenges Exploration (GCE) award was received from the Bill & Melinda Gates Foundation. Malaria kills more than 2 million people each year world-wide, most of them children. Though most malaria and leishmaniasis 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 diseases. In addition, antimalarial and antileishmanial drugs have important military applications, especially for prophylaxis and treatment in troops deployed in malarious regions. A consortium for discovery of non-hemolytic 8-aminoquinioline antimalarials was established for a UM-WRAIR antimalarial discovery program.

3. Agents for Prevention/treatment of Poison Ivy Dermatitis. Research under an NIH funded project for developing new leads that are effective in animals in the prevention of poison ivy dermatitis has continued. Efforts are now underway to determine the relative safety of 2 compounds at different dose levels in guinea pigs. To this end, we have generated data showing no untoward effect of doses ranging from 20mg/kg up to 100mg/kg on blood chemistry, or hematological parameters.

4. Immunostimulant Product. The patented, standardized extract of Spirulina developed at the NCNPR (Immulina in Europe and Re:Sist in the U.S.) was used by scientists at the NCNPR (pilot study with 10 healthy individuals) and in Denmark (12 healthy subjects, double blind placebo controlled) to determine if ingestion of this extract impacted Natural Killer (NK) cell activity. NK cells play a significant role in the body’s defense against viruses and cancer. Both studies showed that ingestion of this extract for one week resulted in a statistically significant 40% enhancement of NK cell cytotoxicity against cancer cells. The mRNA expression of several NK cell markers also increased in subjects ingesting this extract.

Review Publications
Herath, W., Mikell, J.R., Khan, I.A. 2009. Microbial Metabolism. Part 10. Metabolites of 7,8 Dimethoxyflavone and 5-Methoxyflavone . Natural Product Research. 23(13):1231-1239.

Ding, Y., Li, X., Ferreira, D. 2010. 4-Arylflavan-3-ols as Proanthocyanidin Models: Absolute Configuration via Density Functional Calculation of Electronic Circular Dichroism. Journal of Natural Products. 73:435-440.

Avula, B., Wang, Y., Ali, Z., Smillie, T.J., Filion, V., Cuerrier, A., Arnason, J.T., Khan, I.A. 2009. RP-HPLC Determination of Phenylalkanoids and Monoterpenoids in Rhodiola rosea and Identification by LC-ESI-TOF. Biomedical Chromatography. 23(8):865-872.

Madgula, V.L., Avula, B., Pawar, R.S., Shukla, Y.J., Khan, I.A., Walker, L.A., Khan, S.I. 2010. Characterization of in Vitro Pharmacokinetic Properties of Hoodigogenin A from Hoodia gordonii. Planta Medica. 76:62-69.

Xu, W., Jacob, M.R., Agarwal, A.K., Clark, A.M., Liang, Z., Li, X. 2009. Verbesinosides A-F, Novel 15,27-Cyclooleanane Saponins from the American Native Plant Verbesina virginica . Journal of Natural Products. 72:1022-1027.

Manly, S.P., Smillie, T., Hester, J.P., Khan, I., Coudurier, L. 2010. Unique Discovery Aspects of Utilizing Botanical Sources in Practical Guide to Assay Development and High-Throughput Screening in Drug Discovery. Taosheng Chen, Ed., CRC Press, Boca Raton, FL. PP 213-232.

Xu, W., Jacob, M.R., Agarwal, A.K., Clark, A.M., Liang, Z., Li, X. 2009. Flavonol Glycosides from Gaura Biennis. Heterocycles. 78:2541-2548.

Madgula, V.L., Yu, Y., Avula, B., Wang, Y.H., Tchantchou, F., Fisher, S., Luo, Y., Khan, I.A., Khan, S.I. 2010. Intestinal and Blood-Brain Barrier Permeability of Ginkgolides and Bilobalide: In Vitro and In Vivo Approaches. Planta Medica. 76:599-606.

Ma, G., Bavadekar, S.A., Schaneberg, B.T., Khan, I.A., Feller, D.R. 2010. Effects of Synephrine and B-Phenethylamine on Human a-Adrenoceptor Subtypes. Planta Medica. 76(10):981-986.

Rumalla, C.S., Ali, Z., Weerasooriyaa, A.D., Smillie, T., Khan, I.A. 2010. Two New Triterpene Glycosides from Centella asiatica. Planta Medica. 76:1018-1021.

Xu, W., Ding, Y., Jacob, M.R., Agarwal, A.K., Clark, A.M., Ferreira, D., Liang, Z., Li, X. 2009. Puupehanol, a Sesquiterpene-Dihydroquinone Derivative from the Marine Sponge Hyrtios sp. Bioorganic and Medicinal Chemistry Letters. 19:6140-6143.

Wang, W., Zhao, J., Wang, Y., Smillie, T.A., Li, X., Khan, I.A. 2009. Diterpenoids from Casearia sylvestris. Planta Medica. 75(13):1436-1441.

Wang, W., Ali, Z., Li, X., Khan, I.A. 2009. Clerodane and Ent-kaurane Diterpene Glycosyl and Glycoside Derivatives from the Leaves of Casearia sylvestris. Helvetica Chimica Acta. 92:1829-1839.

Wang, W., Ali, Z., Li, X., Khan, I.A. 2009. Neolignans from the Leaves of Casearia sylvestris Swartz. Helvetica Chimica Acta. 93(1):139-146.

Wang, W., Ali, Z., Shen, Y., Li, X., Khan, I.A. 2010. Ursane Triterpenoids from the Bark of Terminalia arjuna. Fitoterapia. 81:480-484.

Xu, W., Jacob, M.R., Agarwal, A.K., Clark, A.M., Liang, Z., Li, X. 2009. ent-Kaurane Glycosides from Tricalysia okelensis. Chemical and Pharmaceutical Bulletin. 58:261-264.

Heratch, W., Khan, I.A. 2010. Microbial Metabolism. Part 11. Metabolites of Flutamide. Chemical and Pharmaceutical Bulletin. 58(4):562-564.

Wang, W., Ali, Z., Li, X., Khan, I.A. 2010. A New ent-Labdane Diterpene Glycoside form the Leaves of Casearia sylvestris. Natural Product Communications. 5(5):771-774.

Pradhan, A., Tripathi, A.K., Desai, P.V., Mukherjee, P.K., Avery, M.A., Walker, L.A., Tekwani, B.L. 2009. Structure and Function of Plasmodium falciparum malate dehydrogenase: Role of Critical Amino Acids in C-substrate Binding Procket. Biochimie. 91:1509-1517.

Bialonska, D., Kasimsetty, S.G., Khan, S.I., Ferreira, D. 2009. Urolithins, Intestinal Microbial Metabolites of Pomegranate Ellagitannins, Exhibit Potent Antioxidant Activity in Cell-Based Assay. Journal of Agricultural and Food Chemistry. 57(21):10181-10186.

Wang, W., Ali, Z., Li, X., Shen, Y., Khan, I.A. 2010. 18, 19-Secooleanane Type Triterpene Glycosyl Esters from the Bark of Terminalia arjuna. Planta Medica. 76:903-908.

Last Modified: 8/4/2015
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