Progress 10/01/10 to 11/05/12
Outputs
Progress Report Objectives (from AD-416): The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharamceuticals or agrichemicals and to identify, characterize and develop medicinal plants for production of pharmaceuticals as potential alternative crops. 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 [NP301, C4, PS 4B]; (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 [NP301, C4, PS 4B]; and (3)Selection, agronomics and analysis of medicinally important plants and their derived products [NP301, C4, PS 4B]. This is a final report for this project. 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. Plant materials from the NPURU plant collections, as well as from numerous collaborators continue to be sourced for screening. NPURU continues to add plant samples to the inventory and screen natural product crude extracts, semi-purified fractions and purified compounds for biological activities against specific molecular targets and whole cell systems. As part of the continuing effort in the search for anti-infective, anticancer, and immunomodulator/anti- inflammatory leads from natural sources, many new natural products were identified from plants, marine sponges, and fungi. Many of these showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. A number of the 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, a number of these compounds have been selected 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 lead compounds are shown to be effective for treatment of poison ivy dermatitis. New facilities in progress include a new medicinal plant garden and a new research wing. Accomplishments 01 Develop antifungal natural products. 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. A number of promising agents were identified by screening natural product samples for antifungal activity against different fungal pathogens. Important achievements include the isolation and identification of new antifungal compounds, and the identification of new molecular pathways. These accomplishments may lead to new treatments for numerous diseases of plants, animals, and humans. 02 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 are developing preventive treatments for poison ivy dermatitis. Two lead compounds shown to be effective in animal models for desensitization to poison ivy dermatitis are being advanced toward upcoming clinical studies. These accomplishments may lead to new products for a common but serious condition. 03 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 number of plant extracts and pure compounds were screened for anticancer activity. 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. 04 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. Scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi have discovered a number of novel anti-protozoal compounds. These accomplishments contribute to efforts to fight these widespread diseases.
Impacts
(N/A)
Publications
- Muhammad, I., Ibrahim, M.A., Khan, S.I., Jacob, M.R., Tekwani, B.L., Walker, L.A., Sameylenko, V. 2012. Pentacyclic ingamine-type alkaloids, a new antiplasmodial pharmacophore from the marine sponge petrosid Ng5 Sp5. Planta Medica. 78(15):1690-1697.
- Avula, B., Wang, Y., Wang, M., Smillie, T.L., Khan, I.A. 2012. Simultaneous determination of sesquiterpenes and pyrrolizidine alkaloids from the rhizomes of petasites hybridus (L.) G.M. et Sch. and dietary supplements using UPLC-UV and LC-TOF methods. Journal of Pharmaceutical and Biomedical Analysis. 70:53-63.
- Avula, B., Wang, Y., Wang, M., Shen, Y., Khan, I.A. 2013. Simultaneous determination and characterization of tannins and triterpene saponins from the fruits of various species of terminalia and phyllantus emblica using UPLC-UV-MS method: application to triphala. Planta Medica. 79(20:181-188.
- Galal, A.M., Raman, V., Avula, B., Wang, Y., Rumalla, C.S., Weerasooriya, A.D., Khan, I.A. 2012. Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC�UV and HPTLC analyses. Journal of Natural Medicine. 67:554-661.
- Bharathi, A., Tekwani, B.L., Chauarasiya, N.D., Nanayakkara, D.N., Wang, Y. , Khan, S.I., Adelli, V.R., Sahu, R.K., Elsohly, M.A., Mcchesney, J.D., Khan, I., Walker, L.A. 2013. Profiling primaquine metabolites in primary human hepatocytes by UPLC-QTOF-MS with 13c stable isotope labeling. Journal of Mass Spectrometry. 48(2):276-285.
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Progress 10/01/11 to 09/30/12
Outputs
Progress Report Objectives (from AD-416): The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharamceuticals or agrichemicals and to identify, characterize and develop medicinal plants for production of pharmaceuticals as potential alternative crops. 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 [NP301, C4, PS 4B]; (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 [NP301, C4, PS 4B]; and (3)Selection, agronomics and analysis of medicinally important plants and their derived products [NP301, C4, PS 4B]. 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. University scientists continued to source plant materials for screening from our own plant collections and from numerous collaborators. Added 700 plant samples to our inventory this year. Screened over 4,000 natural product crude extracts, semi-purified fractions and purified compounds for biological activities against specific molecular targets and whole cell systems. As part of our continuing effort in the search for anti- infective, anticancer, and immunomodulator/anti-inflammatory leads from natural sources, more than 130 compounds (including 13 new natural products) were identified from plants, marine sponges, and fungi. Many showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. Over 800 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, evaluation in disease models in preclinical studies, or in field applications. In collaboration with ElSohly Laboratories, Inc., continued development of lead compounds shown to be effective in animal models for desensitization to poison ivy dermatitis. Two leads in the poison ivy project are now undergoing formulation development, and bioavailability and toxicology studies. Construction of new facilities of the Medicinal Plant Garden at the University of Mississippi was completed this year, and work has begun to develop the outdoor growing sites. Completed facilities include a laboratory building, horticulture building, greenhouse, shade house, and equipment building. These facilities will enhance the capabilities of NCNPR to cultivate and process medicinal plants to be used in the discovery program. NCNPR continued planning a major construction project this year to complete its major research building with a 90,000 sq. ft. research wing. Construction documents were reviewed and approved by the funding agencies (Health Resources and Services Administration; National Institutes of Health) and a construction contract has been awarded for the project which will be completed in March, 2014. 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. Accomplishments 01 Develop antifungal natural products. Because many organisms contain inherent protective mechanisms the natural environment is a rich source for compounds to treat fungal diseases. Scientists at the National Cent for Natural Products Research (NCNPR) at the University of Mississippi i Oxford, MS, aim to discover novel antifungal compounds for treating life threatening opportunistic fungal infections. This ongoing program cover various aspects of drug discovery including screening and isolation of natural product antifungal compounds, determining their mechanism of action, and understanding potential resistance mechanisms. In this past year, over 4,000 natural product samples were screened for antifungal activity against 5 different fungal pathogens, and over 50 �hits� were identified. The mechanism of action of 8 antifungal compounds was analyzed by genomic and genetic approaches, and 2 potentially novel antifungal pathways were identified. Several important achievements hav resulted in the past year including: (a) the isolation and identificatio of new antifungal compounds, and (b) the identification of new molecular pathways (heme synthesis and fatty acid metabolism) targeted by two different antifungal compounds. These pathways are new in that they are not targeted by current antifungal drugs used clinically. These accomplishments may lead to new treatments for numerous diseases of plan animals, and humans. 02 Develop agents for prevention/treatment of poison ivy dermatitis. Poiso ivy is a widespread plant that causes an itching rash in most people who touch it. Scientists at the National Center for Natural Products Researc (NCNPR) at the University of Mississippi in Oxford, MS, are developing preventive treatments for poison ivy dermititus. Two lead compounds sho to be effective in animal models for desensitization to poison ivy dermatitis are now undergoing bioavailability and toxicology studies expected to be completed in August, 2012. These compounds are also now undergoing formulation development studies. A batch of pharmaceutical- grade ingredient of one of the lead compounds has been manufactured in anticipation of upcoming clinical studies. These accomplishments may le to new products for a common but serious condition. 03 Develop treatments for cancer. A cancer research program requires a dru discovery program in order to explore all avenues of treatment. Scientists at the National Center for Natural Products Research (NCNPR) the University of Mississippi in Oxford, MS, operate the Drug Discovery Core of the University of Mississippi Medical Center (UMMC) Cancer Institute. Because the NCNPR core group accelerated the development of screening assays that target signal-transduction pathways known to be involved in the expression of cancers, this new screening program is one year ahead of its original development plan. Over 500 crude plant extracts and 50 pure compounds have now been screened for anticancer activity. 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. 04 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 o the drug now commonly used. This year scientists at the National Center for Natural Products Research (NCNPR) at the University of Mississippi i Oxford, MS, screened hundreds of natural products and synthetic analogs natural products for activity against malarial and leishmaniasis. A number of novel anti-protozoal compounds were discovered. These accomplishments contribute to efforts to fight these widespread diseases
Impacts
(N/A)
Publications
- Dai, L., Jacob, M.R., Khan, S.I., Khan, I.A., Clark, A.M., Li, X. 2011. Synthesis and antifungal activity of natural product-based 6-alkyl-2 3 4 5- tetrahydropyridines. Journal of Natural Products. 74(9):2023-2026.
- Avula, B., Wang, Y., Khan, I.A. 2012. Quantitative determination of curcuminoids from the Roots of Curcuma longa, Curcuma species and dietary supplements using an UPLC-UV-MS method. Journal of Chromatography. 3(1):1- 6.
- Wang, M., Avula, B., Parcher, J.F., Khan, I.A. 2011. Comparison of concentration pulse and tracer pulse chromatography: experimental determination of eluent uptake by bridged-ethylene hybrid ultra high performance liquid chromatography packings. Journal of Chromatography A. 1220:75-81.
- Wang, Y., Avula, B., Fu, X., Khan, I.A. 2012. Simultaneous determination of the absolute configuration of twelve monosaccharide enantiomers from natural products in a single injection by UPLC-UV/MS method. Planta Medica. 78:834-837.
- Khan, S.I., Aumsuwan, P., Khan, I.A., Walker, L.A., Dasmahapatra, A.K. 2011. Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome. Chemical Research in Toxicology. 25:61-73.
- Raman, V., Avula, B., Galal, A.M., Wang, Y., Khan, I. 2012. Microscopic and UPLC-UV-MS analyses of authentic and commercial yohimbe (Pausinystalia johimbe) bark samples. Journal of Natural Medicine. 249-252.
- Avula, B., Wang, Y., Ali, Z., Smillie, T.J., Khan, I.A. 2011. Quantitative determination of triperpene saponins and alkenated-phenolics from Labisia pumila using LC-UV/ELSD method and confirmation by LC-ESI-TOF. Planta Medica. 77:1742-1748.
- Avula, B., Wang, Y., Moraes, R.M., Khan, I.A. 2011. Rapid analysis of lignans from leaves of Podophyllum peltatum l. samples using UPLC-UV-MS. Biomedical Chromatography. 25:1230-1236.
- Avula, B., Shukla, Y.J., Wang, Y., Khan, I.A. 2011. Chemical fingerprint analysis and quantitative determination of pregnanes from aerial parts of caralluma species using HPLC-UV and identification by LC-ESI-TOF. Official Methods of Analysis of AOAC International. 94(5):1383-1390.
- Xu, W., Li, X. 2011. Antifungal compounds from Piper species. Current Bioactive Compounds. 7(4):262-267.
- Huang, Z., Chen, K., Xu, T., Zhang, J., Li, Y., Li, W., Agarwal, A.K., Clark, A.M., Phillips, J.D., Pan, X. 2011. Sampangine inhibits heme biosynthesis in both yeast and human. Eukaryotic Cell. 10(11):1536-1544.
- Agarwal, A.K., Tripathi, S.K., Xu, T., Jacob, M.R., Li, X., Clark, A.M. 2012. Exploring the molecular basis of antifungal synergies using genome- wide approaches. Frontiers in Microbiology. (3)15:1-6.
- Zhang, X., Jacob, M.R., Rao, R.R., Wang, Y., Agarwal, A.K., Newman, D.J., Khan, I.A., Clark, A.M., Li, X. 2012. Antifungal cyclic peptides from the marine sponge Microscleroderma herdmani. Journal of Medicinal Chemistry. 2:7-14.
- Zhang, J., Rahman, A.A., Jain, S., Jacob, M.R., Khan, S.I., Tekwani, B.L., Muhammad, L. 2012. Antimicrobial and antiparastic abietane diterpenoids from Cupressus sempervirens. Research and Reports in Medicinal Chemistry. 2:1-6.
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Progress 10/01/10 to 09/30/11
Outputs
Progress Report Objectives (from AD-416) The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharamceuticals or agrichemicals and to identify, characterize and develop medicinal plants for production of pharmaceuticals as potential alternative crops. 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 [NP301, C4, PS 4B]; (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 [NP301, C4, PS 4B]; and (3)Selection, agronomics and analysis of medicinally important plants and their derived products [NP301, C4, PS 4B]. 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. Continued to source plant materials for screening from our own plant collections and from numerous collaborators. Added 3,000 plant samples to our inventory this year. Screened over 8,000 natural product crude extracts, semi-purified fractions and purified compounds for biological activities against specific molecular targets and whole cell systems. As part of our continuing effort in the search for anti-infective, anti-cancer, and immunomodulator/anti-inflammatory leads from natural sources, more than 200 compounds (including 50 new natural products) were identified from plants, marine sponges, and fungi. Many showed potent phytotoxic, antifungal, antibacterial, or antimalarial activities. Over 600 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, evaluation in disease models in preclinical studies, or in field applications. Advanced 7 new leads this year 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 grant from the National Institutes of Health, in collaboration with ElSohly Laboratories, Inc. A patent application has been filed for these compounds. The Medicinal Plant Garden at the University of Mississippi has undergone relocation this year with the construction of new facilities begun in September, 2009 and expected to be completed in August, 2011. The new facilities include a laboratory building, horticulture building, greenhouse, shade house, equipment building, and several acres of outdoor growing sites, including a pond for aquatic species. These facilities will enhance the capabilities of NCNPR to cultivate and process medicinal plants to be used in the discovery program. NCNPR began a major construction project this year to complete its major research building with a 90,000 sq. ft. research wing. Construction documents are presently under review by the funding agencies (Health Resources and Services Administration; National Institutes of Health), and groundbreaking will occur in 2011. 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. Accomplishments 01 Develop antifungal natural products. Because many organisms contain inherent protective mechanisms the natural environment is a rich source for compounds to treat fungal diseases. The antifungal drug discovery program at the National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, aims to discover novel antifungal compounds for treating life-threatening opportunistic fungal infections. It 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. In this past year, over 4,000 natural product samples were screened for antifungal activity against 5 different fungal pathogens, and over 100 �hits� were identified. A variety of molecular and genetic mechanistic studies were conducted on 8 different antifungal compounds, and 3 potentially novel antifungal pathways were identified. Several important achievements have resulted in the past year including: (a) the isolation and identification of new antifungal compounds, and (b the identification of a new molecular pathway (calcium signaling) target by a marine-derived antifungal compound � this pathway is new in that it is not targeted by current clinically used antifungal drugs. These accomplishments may lead to new treatments for numerous diseases of plan animals, and humans. 02 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. The National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, continued screening for antimalarial and antileishmanial activities of natural products and synthetic analogs. We have also added new assays for the intracellular stages of leishmania and for anti-trypanosomal activity. Several additional publications and isolations of novel anti-protozoal natural products have resulted from these. These accomplishments contribute to efforts to fight these widespread diseases. 03 Develop agents for prevention/treatment of poison ivy dermatitis. Poiso ivy is a widespread plant that causes an itching rash in most people who touch it. Research for developing new leads that are effective in anima in the prevention of poison ivy dermatitis has continued under a project funded by the National Institutes of Health. Two lead compounds have bee licensed by Hapten Technology. These accomplishments may lead to new products for a common, but serious condition. 04 Develop treatments for cancer. A cancer research program requires a dru discovery program in order to explore all avenues of treatment. This ye NCNPR established the Drug Discovery Core of the University of Mississip Medical Center (UMMC) Cancer Institute. The National Center for Natural Products Research (NCNPR) at the University of Mississippi, Oxford, MS, core group has developed new screening assays that target signal- transduction pathways known to be involved in the expression of cancers, and has begun screening plant extracts for anti-cancer activity. The mos promising anti-cancer compounds will be produced in quantities required for further development and evaluation by the UMMC Cancer Institute.
Impacts
(N/A)
Publications
- Xu, T., Feng, Q., Jacob, M.R., Avula, B., Mask, M.M., Baerson, S.R., Tripathi, S.K., Mohammed, R., Hamann, M.T., Khan, I.A., Walker, L.A., Clark, A.M., Agarwal, A.K. 2011. The marine sponge-derived polyketide endoperoxide plakortide F acid mediates its antifungal activity by interfering with calcium homeostasis. Antimicrobial Agents and Chemotherapy. 55(4):1611-1621.
- Li, J., Jadhav, A.N., Khan, I.A. 2009. Triterpenoids from Brazilian Ginseng, Pfaffia paniculata. Planta Medica. 75:1-5.
- Avula, B., Wang, Y., Duzgoren-Aydin, N.S., Khan, I.A. 2010. Inorganic elemental compositions of commercial multivitamin/mineral dietary supplements: application of collision/reaction cell inductively coupled- mass spectroscopy. Food Chemistry. 127:54-62.
- Mikell, J.R., Herath, W., Khan, I.A. 2011. Microbial metabolism Part 12 isolation characterization and bioactivity evaluation of eighteen microbial metabolites of 4'-hydroxyflavanone. Chemical and Pharmaceutical Bulletin. 59(6):692-697.
- Kumarihamy, M., Fronczek, F.R., Ferreira, D., Jacob, M., Khan, S.I., Nanayakkara, D. 2010. Bioactive 1, 4-Dihydroxy-5-phenyl-2-pyridinone alkaloids from Septoria pistaciarum. Journal of Natural Products. 73:1250- 1253.
- Li, X., Babu, K., Jacob, M.R., Khan, S.I., Agarwal, A.K., Clark, A.M. 2011. Natural product-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2- a]pyrimidinium scaffold as a new antifungal template. ACS Medicinal Chemistry Letters. 2:391-395.
- Xu, M., Zhang, Y., Li, X., Jacob, M.R., Yang, C. 2010. Steroidal saponins from fresh stems of Dracaena angustifolia. Journal of Natural Products. 73:1524-1528.
- Liu, H., Walker, L.A., Nanayakkara, N., Doerksen, R.J. 2011. Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase. Journal of the American Chemical Society. 133:1172-1175.
- Khan, S.I., Zhao, J., Khan, I.A., Walker, L.A., Dasmahapatra, A.K. 2011. Potential utility of natural products as regulators of breast cancer- assoicated aromatase promoters. Reproductive Biology and Endocrinology. 9:91-101.
- Moraes, R.M., Lata, H., Sumyanto, J., Pereira, A.M., Bertoni, B.W., Joshi, V.C., Pugh, N.D., Khan, I.A., Pasco, D.S. 2011. Characterization and pharmacological properties of in vitro propagated clones of Echinacea tennesseensis (Beadle) small. Plant Cell Tissue And Organ Culture. 106:309- 315.
- Rahman, A., Samoylenko, V., Jacob, M.R., Sahu, R., Jain, S.K., Khan, S.I., Tekwani, B.L., Muhammad, I. 2011. Antiparasitic and antimicrobial indolizidines from the leaves of Prosopis glandulosa var glandulosa from Nevada and Texas USA. Planta Medica. doi.org/10.1055/s-0030-127096.
- Li, X., Ferreria, D., Ding, Y. 2010. Determination of absolute configuration of natural products: theoretical calculation of electronic circular dichroism as a tool. Current Organic Chemistry. 14:1678-1697.
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