Source: UNIVERSITY OF ARIZONA submitted to NRP
NATURAL PRODUCTS FOR AGRICULTURE AND MEDICINE FROM ARID LAND PLANTS AND MICROORGANISMS
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
HATCH
Reporting Frequency
Annual
Accession No.
1005072
Grant No.
(N/A)
Cumulative Award Amt.
(N/A)
Proposal No.
(N/A)
Multistate No.
(N/A)
Project Start Date
Nov 5, 2014
Project End Date
Sep 30, 2019
Grant Year
(N/A)
Program Code
[(N/A)]- (N/A)
Recipient Organization
UNIVERSITY OF ARIZONA
888 N EUCLID AVE
TUCSON,AZ 85719-4824
Performing Department
Natural Resources & the Environment
Non Technical Summary
Natural products are in demand for pharmaceutical and agrochemical use. This project will investigate arid land plants and microorganisms for useful natural products and manipulate the biosynthesis of microbial metabolites for the production of their analogs. It will also investigate chemical and microbial transformation of natural products for the production of their analogues for bioactivity evaluation, and alternate soil-less agricultural systems for the production of plant-based natural products.
Animal Health Component
30%
Research Effort Categories
Basic
60%
Applied
30%
Developmental
10%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
2042299106075%
5114020108025%
Knowledge Area
511 - New and Improved Non-Food Products and Processes; 204 - Plant Product Quality and Utility (Preharvest);

Subject Of Investigation
2299 - Miscellaneous and new crops, general/other; 4020 - Fungi;

Field Of Science
1060 - Biology (whole systems); 1080 - Genetics;
Goals / Objectives
The major goals and objectives of this project are: (a) screen arid-land plants for biological activity, (b) screen arid-land microorganisms for biological activity, (c) bioassay-directed fractionation of extracts with demonstrated biological activity and structure elucidation of bioactive natural products, (d) characterize and manipulate the biosynthesis of promising natural products, (e) further develop alternative agricultural systems, especially aeroponics system for plant cultivation, and production and structural diversification of their secondary metabolites of economic importance, (f) produce analogues of major natural products by chemical transformations and microbial biotransformations, and (g) evaluate promising lead natural products and their analogues with collaborators in other University of Arizona departments and colleges, other academic institutions, government agencies and private industry.
Project Methods
The approach to be taken involves collection and identification of plants and plant-and lichen- associated microorganisms, processing of these to obtain extracts and screening of the resulting extracts in a panel of bioassays to evaluate their potential use in agricultural applications and as agents to treat cancer and neurodegenerative disorders. Extracts active in one or more of these bioassays will be selected for bioactivity-guided fractionation to isolate and characterize compounds responsible for their observed activity. Structures of all new compounds will be elucidated with the help of spectroscopic techniques. The biosynthesis of microbial natural products with interesting and promising biological activities will be characterized and manipulated by the application of cloning, heterologous expression and mutasynthesis. For production of plant-based pharmaceutically and agriculturally useful natural products alternative soil-less agricultural systems, especially aeroponic culture systems, will be investigated.

Progress 11/05/14 to 09/30/19

Outputs
Target Audience:The efforts of this project are designed for the target audiences consisting of arid land agriculturists and pharmaceutical company scientists. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project has provided training opportunities and professional development for 9 visiting scholars, 5 postdoctoral researchers, 2 technicians, 3 graduate students, and 2 undergraduate students. How have the results been disseminated to communities of interest?Results obtained in this project have been disseminated in the form of peer-reviewed publications and conference presentations. In addition, outcomes of the project on plant-based antimicrobials was disseminated to 25 academic and industry professionals as well as investors, ca. 15 food science professionals, and over 45 high school students in the form of laboratory tours and demonstrations. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Impact: Our work resulted in: (a) application of an alternate soil-less agricultural system known as aeroponic technology for efficient production and diversification of plant-based natural products; (b) production of bioactive and/or novel fungal metabolites by epigenetic modulation of their biosynthetic pathways; (c) identification of nematicidal metabolites from a mutualistic bacterium of an entomopathogenic nematode and determination of the genome sequence of the bacterium; and (d) demonstration of the potential of plant-based antimicrobials to eliminate or reduce the presence of foodborne pathogens in produce and in the production and processing environments. 1. Evaluation of extracts of arid-land plants and microorganisms for biological activities. 1.1. Major activities: During the life of this project over 50 arid land plants and 100 fungi were subjected to detailed investigation. Active extracts derived from these were subjected to bioactivity-guided fractionation, isolation, and characterization of bioactive NPs some of which were subjected to chemical transformations for the purpose of improving their biological activities. 1.2. Data collected: Yields and bioactivities of extracts, fractions, and pure NPs. Spectroscopic (UV, IR, NMR, high-resolution mass spectroscopic, and X-ray) data of pure NPs. 1.3. Discussion of results: Seven plants and 7 fungi produced NPs with pharmaceutical potential and/or novel structures. From plants (Physalis crassifolia, Physalis peruviana, Physalis philadelphica, Physalis acutifolia, Croton californicus, Eremocarpus sentigerus, Hyptis emoryi) several NPs with potential anticancer and anti-nociceptive activities were characterized. Bioactive and/or novel NPs identified from fungi included oxaspirols (Lecythophora sp.), curvularins (Alternaria sp.), verruculides (Phoma sp.), montagnuphilones (Montagnulaceae sp.), polyketides (Anteaglonium sp.), naphthoquinones (Teratosphaeria sp.), and geopyxins (Geopyxis sp.). 1.4. Key outcomes: All 4 aeroponically-cultivated Physalis sp. investigated produced 17beta-hydroxywithanolides (17-BHWs), some with selective cytotoxicity against prostate cancer cells. Intriguingly, when combined with immune adjuvants these withanolides exhibited apoptotic activity against renal carcinoma and melanomas. 2. Further evaluation of promising lead compounds in collaboration with other scientists. 2.1. Major activities: Promising lead NPs and their analogs were subjected to secondary assays and animal studies at the National Cancer Institute, University of Arizona College of Pharmacy, University of Geneva, and Sun Pharma Advanced Research Center. A total of over 60 natural and semi-synthetic analogs of 17-BHWs were evaluated for their anti-prostate cancer activity and activity against renal carcinoma and melanomas when combined with immune adjuvants. 2.2. Data collected: In vitro activities against the cancer cell lines, LNCaP, 22Rv1, PC-3, ACHN, M14, and SK-MEL-28 with and without an immune adjuvant. In vivo activity of the most active natural withanolide in mice. 2.3. Discussion of results: Confirmation of in vitro cell culture results through in vivo studies in mice. The major withanolide, physachenolide D, obtained from aeroponically-cultivated P. crassifolia was converted into several semi-synthetic analogues. One of these was found to inhibit growth of implanted melanoma in animals when used in combination with an immune adjuvant. 2.4. Key outcomes: The above approach allowed us to identify relatively modest structural modifications that alter the potential anticancer activity of 17-BHWs. 3. Application of an alternate agricultural system, aeroponic system for cultivation of Physalis sp. for production of potential pharmaceuticals of economic importance 3.1. Major activities: A soil-less aeroponic technique was applied for cultivation of four Physalis sp. 3.2. Data collected: Application of this technique to above 4 Physalis species resulted in production of large quantities of active 17-BHWs. 3.3. Discussion of results: Availability of large quantities of 17-BHWs made it possible carryout animal studies and structural modification by chemical transformations. 3.4. Key outcomes: Our findings suggest that the 17-BHW scaffold provides a useful approach to improving the therapeutic potential of this class of NPs as anticancer agents to treat prostate cancer, renal carcinoma, and melanomas. 4. Production of bioactive and/or novel fungal metabolites by epigenetic modulation of their biosynthetic pathways. 4.1. Major activities: Over 100 fungal strains were cultured in potato dextrose broth (PDB) and PDB containing the epigenetic modifiers, 5-azacytidine (5-AZA), suberoylanilide hydroxamic acid (SAHA), and anacardic acid (AA) on small-scale to produce extracts which were investigated by TLC and HPLC for changes in their constituent metabolites. 4.2. Data collected: Three of the fungal strains that showed changes were selected for large-scale work. 4.3. Discussion of Results: Selected large-scale PDB cultures with and without the epigenetic modifier were subjected to fractionation to isolate bioactive and/or new metabolites. 4.4. Key outcomes: Incorporation of SAHA to Phoma sp. nov. LG0217 resulted in the production of (10S)-verruculide B inhibiting protein tyrosine phosphatases important in diabetes. 5. Investigation of the secondary metabolome of the mutualistic endosymbiotic bacterium of the entomopathogenic nematode and determination of the genome sequence of the bacterium. 5.1. Major activities: The secondary metabolites of the bacterium, Photorhabdus luminescens ssp. sonorensis Caborca that had been isolated in Arizona as a mutualistic endosymbiont of the entomopathogenic nematode Heterorhabditis sonorensis, were evaluated for their ability to kill plant parasitic nematodes. The genome sequence of the bacterium was determined. 5.2. Data collected: Bioactivity (nematicidal, cytoxicity); NMR spectra; genome sequence. 5.3. Discussion of results: Three NPs were identified and were shown not to be toxic to human cell lines, free living nematodes, and non-target nematodes. The genome sequence of the bacterium predicted 25 gene clusters that are involved in secondary metabolism. 5.4. Key outcomes: Secondary metabolites that showed selective activity against the root knot nematode were identified. The genome sequence of the producer bacterium was determined, analyzed, and deposited to GenBank. 6. Investigation of the efficacy of plant-based antimicrobials against foodborne pathogens. 6.1. Major activities: The efficacy of plant-based antimicrobials at various concentrations against Salmonella and Listeria on melon rinds was evaluated. 6.2. Data collected: Compared to the control wash, the plant-based antimicrobial treatments caused significant reductions in populations of these pathogens. 6.3. Discussion of results: The reduction in bacterial biofilm formation by natural sanitizers was tested by treating with various concentrations of plant-based antimicrobial solutions. 6.4. Key outcomes: The results indicated that the plant-based antimicrobial micro-emulsions can prevent biofilm formation by the two pathogens.

Publications

  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Ozonized Water with Plant Antimicrobials: An Effective Method to Inactivate Salmonella enterica on Iceberg Lettuce in Produce Wash Water. Dev Kumar, G. and Ravishankar, S. 2019. Poster presented at the Annual Meeting of the International Association for Food Protection. Louisville, KY, July 2019.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Green sanitizers: Improved safety and shelf-life of iceberg lettuce washed with plant-based antimicrobial microemulsions. Arellano, S., Law, B. and Ravishankar, S. Poster presented at the Annual Food Safety Conference. Tucson, AZ, October 2019.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Green Sanitizers: Improved Safety and Shelf-life of Iceberg Lettuce Washed with Plant-based Antimicrobial Microemulsions. Arellano, S. Law, B. and Ravishankar, S. Poster presented at the Annual GIDP Student Research Showcase. Tucson, AZ, December 2019.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: NRF2 Activation by Geopyxins Protects Cells from Toxicants, S. Tao, W. Tian, J. Tillotson, E.M.K. Wijeratne, A.A.L. Gunatilaka, D.D. Zhang, and E. Chapman, Cell Chem. Biol., 2019, 26, 1-9.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom 2 Augmentation of Radicicol, T. Shi, E.M.K. Wijeratne, C. Solano, A.J. Ambrose, A.B. Ross, C. Norwood, C. K. Orido, T. Grigoryan, J. Tillotson, M. Kang, G. Luo, B.M. Keegan, W. Hu, B.S.J. Blagg, D.D. Zhang, A.A.L. Gunatilaka, and E. Chapman, Biochemistry, 2019, 58, 3225-3231.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Reversal of peripheral neuropathic pain by the small-molecule natural product physalin F via block of CaV2.3 (R-type) and Cav2.2 (N-type) voltage-gated calcium channels, Z. Shan, S. Cai, J. Yu, Z. Zhang, T.G.M. Vallecillo, M.J. Sera?ni, A.M. Thomas, N.Y.N. Pham, S.S. Bellampalli, A. Moutal, Y. Zhou, G.-B. Xu, Y.-M. Xu, S. Luo, M. Patek, J.M. Streicher, A.A.L. Gunatilaka, and R. Khanna, ACS Chem. Neurosci., 2019, 10, 2939-2955.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Draft genome assembly of the entomopathogenic bacterium Photorhabdus luminescens subsp. sonorensis Caborca. Duong, D.A., Espinosa-Artiles, P., Orozco, R.A., Moln�r, I., Stock, S.P.: Microbiol. Resour. Announc. 8, e00692-19, 2019. DOI: 10.1128/MRA.00692-19, PMID: 31488529 PMCID: PMC6728639.
  • Type: Journal Articles Status: Published Year Published: 2020 Citation: Edible films containing carvacrol and cinnamaldehyde inactivate Escherichia coli O157:H7 on organic leafy greens in sealed plastic bags. Zhu, L., Olsen, C., McHugh, T., Friedman, M. Jaroni, D. and Ravishankar, S. 2020. J. Food Safety. 2020;e12758 https://doi.org/10.1111/jfs.12758.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Antimicrobial Efficacy of Plant Essential Oils and Extracts Against Escherichia coli. Gilling, D. H., Ravishankar, S. and Bright, K.R 2019. J. Environ. Sci. and Health, Part A, DOI: 10.1080/10934529.2019.1574153.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Antimicrobial Activities of Essential Oils, Plant Extracts and their Applications in Foods- A Review. Cordery, A., Rao, A. P. and Ravishankar, S. 2019. J. Agric. and Environ. Sci., 7(2): 76-89.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Rational reprogramming O-methylation regioselectivity for combinatorial biosynthetic tailoring of benzenediol lactone scaffolds, X. Wang, C. Wang, L. Duan, L. Zhang, H. Liu, Y.-m. Xu, T. Mao, W. Zhang, M. Lin, A.A.L. Gunatilaka, Y. Xu, and I. Moln�r, J. Am. Chem. Soc. 2019, 141, 4355-4364.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: (-)-Hardwickiic acid and Hautriwaic acid induce antinociception via blockade of tetrodotoxin-sensitive voltage-dependent sodium channels, S. Cai, S. Bellampalli, J. Yu, W. Li, Y. Ji, E.M.K. Wijeratne, A. Dorame, S. Luo, Z. Shan, M. Khanna, A. Moutal, J. Streicher, A.A.L. Gunatilaka, R. Khanna. ACS Chem. Neurosci., 2019, 10, 1716-1728.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: Betulinic acid, a constituent of the desert lavender Hyptis emoryi, attenuates paclitaxel- and HIV-associated peripheral sensory neuropathy via block of Cav3.2 and Cav3.3 T-type calcium channels, S. S. Bellampalli, Y. Ji, A. Moutal, S. Cai, E.M.K. Wijeratne, M.A. Gandini, J. Yu, A. Dorame, L.A. Chew, S. Luo, G. Molnar, J.M. Streicher, G.W. Zamponi, A.A.L. Gunatilaka, and R. Khanna, Pain, 2019, 160, 117-135.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2018 Citation: Natural Products-Based Induction of Cancer Cell Death Combined with Immunotherapy for Melanoma Treatment. Gunatilaka, A.A.L.; Sayers, T.J.; Xu, Y.M.; Wijeratne, E.M.K.; Brooks, A. and Tewary, P. Poster Presentation at the 3rd Annual Arizona Biomedical Research Center Research Conference, Phoenix, AZ, March 2018.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Discovery of Anticancer Drugs from Plants Used in Traditional Medicines. Gunatilaka, A.A.L. Oral Presentation at the 10th International Conference on TCM Pharmaceutical Analysis, Shanghai, P.R. China, June 2019.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: 17beta-Hydroxywithanolides and Their Semi-Synthetic Analogues Potentiate Immunotherapy of Melanoma by Reducing cFLIPs and Promoting Caspase-8-Dependent Cell Death. Gunatilaka, A.A.L.; Sayers, T.J.; Tewary, P.; Wijeratne, E.M.K.; Xu, Y.M.; and Brooks, A. Poster Presentation at the 4th Annual Arizona Biomedical Research Center Research Conference, Phoenix, AZ, May 2019.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: An epigenetic modifier induces the production of new metabolites by Aspergillus terreus AST0006. Amorim, M.R. de; Wijeratne, E.M.K.; Batista, J.; Santos, L. dos; Gunatilaka, A.A.L. Poster presentation at the 67th International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research, Innsbruck, Austria, Sept 2019.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Validation of the paspalitrem gene cluster of Claviceps paspali by Agrobacterium tumefaciens-mediated gene replacement approach. L. Koz�k, Z. Szil�gyi, L. T�th, B. V�g�, I. Molnar and I. P�csi: Semi-Plenary Lecture presented at the Eighteenth International Congress of the Hungarian Society for Microbiology, Budapest, Hungary, July 2019.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2019 Citation: Isolation, Identification and Nematicidal Activity of Secondary Metabolites from the Entomopathogenic Bacterium Photorhabdus luminescens sonorensis against the Root Knot Nematode, Meloidogyne incognita. Kusakabe, A., Molnar, I., Stock, S.P. Oral Presentation at the Fifty-second Annual Meeting of the Society of Invertebrate Pathology, Valencia, Spain, July 2019.


Progress 10/01/17 to 09/30/18

Outputs
Target Audience:Target audiences include stakeholders in anticancer, agricultural, food and microbiological research. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The project provided training for four postdoctoral associates and two graduate students. How have the results been disseminated to communities of interest?Some results obtained during the reporting period have been disseminated to communities of interest in the form of journal publications and research seminar presentations. Demonstrations on use of plant antimicrobials were conducted for produce industry professionals and local high school students throughout the year. What do you plan to do during the next reporting period to accomplish the goals?Prepare additional analogues of withanolides for evaluation in target-oriented anticancer assays for prostate cancer and melanoma and in melanoma animal models at the National Cancer Institute. Work will be continued to determine the efficacy of plant antimicrobials in reducing Salmonella and Listeria monocytogenes populations on melons during washing and via edible films. The role of plant antimicrobials in increasing the re-usability of produce wash water will be evaluated. These studies will have an impact on water costs and the environment.

Impacts
What was accomplished under these goals? The major withanolide, physachenolide D, obtained from aeroponically-cultivated Physalis crassifolia was converted into several semi-synthetic analogues. One of these was found to inhibit growth of implanted melanoma in animals when used in combination with the immune adjuvant, poly (I:C). A new methodology was developed to eliminate the production of toxic metabolites by Claviceps paspali, a fungal parasite of wild grasses. Plant-derived antimicrobials when used in combination with ozone was found to be effective in killing Salmonella on leafy greens.

Publications

  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Annonalide and derivatives: Semisynthesis, cytotoxic activities and studies on interaction of annonalide with DNA, R. A. Marques, A. O. C. V. Gomes, M. V. de Brito, L. B. de Lima, F. M. Nunes, M. C. de Mattos, F. C. E. de Oliveira, C. do O Pessoa, M. O. de Moraes, A. de Fatima, L. L. Franco, M. de M. Silva, M. D. de A. Dantas, J. C. C. Santos, I. M. Figueiredo, E. F. da Silva-Junior, T. M. de Aquino, J. X. de Araujo-Junior, M. C. F. de Oliveira, and A. A. L Gunatilaka, J. Photochem. Photobiol. B, 2018, 179, 156-166.
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Cytotoxic and Non-Cytotoxic Metabolites from Teratosphaeria sp. FL2137, a Fungus Associated with Pinus clausa, C. Padumadasa, Y.-M. Xu, E. M. K. Wijeratne, P. Espinosa-Artiles, J. M. URen, A. E. Arnold, and A. A. L. Gunatilaka, J. Nat. Prod., 2018, 81, 616-624.
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Cytotoxic and other withanolides from aeroponically grown Physalis philadelphica, Y.-M. Xu, E. M. K. Wijeratne, A. D. Brooks, P. Tewary, L.-J. Xuan, W.-Q. Wang, T. J. Sayers, and A. A. L. Gunatilaka, Phytochemistry, 2018, 152, 174-181.
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Inactivation of the indole-diterpene biosynthetic gene cluster of Claviceps paspali by Agrobacterium-mediated gene replacement, L. Kozak, Z. Szilagyi, B. Vago, A. Kakuk, L. Toth, I. Molnar and I. Pocsi, Appl. Mirobiol. Biotechnol., 10,3255-3266, 2018.
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Modulation of polyketide biosynthetic pathway of the endophytic fungus, Anteaglonium sp. FL0768, by copper (II) and anacardic acid, J. Mafezoli, Y.M. Xu, F. Hilario, B. Freidhof, P. Espinosa-Artiles, L.C. dos Santos, M.C.F. de Oliveira, and A.A.L. Gunatilaka, Phytochem. Lett., 2018, 28, 157-163.
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Ozonized water with plant antimicrobials: An effective method to inactivate Salmonella enterica on iceberg lettuce in the produce wash water, G. Dev Kumar and S. Ravishankar, Environmental Research, 2018, 171, 213-217.
  • Type: Journal Articles Status: Published Year Published: 2018 Citation: Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation, E. M. K. Wijeratne, M. C. F. Oliveira, J. Mafezoli, Y.-M. Xu, S. Minguzzi, P. H. J. Batista, O. D. L. Pessoa, L. Whitesell, and A. A. L. Gunatilaka, J. Nat. Prod., 2018, 81, 825-837.


Progress 10/01/16 to 09/30/17

Outputs
Target Audience:Target audiences include stakeholders in anticancer and agricultural research. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The project provided training for five postdoctoral associates, one graduate student and one undergraduate student. How have the results been disseminated to communities of interest?Some results obtained during the reporting period have been disseminated to communities of interest in the form of journal publications and research seminar presentations. What do you plan to do during the next reporting period to accomplish the goals?Prepare additional analogues of withanolides for evaluation in target-oriented anticancer assays for prostate cancer and melanoma and in melanoma animal models at the National Cancer Institute.

Impacts
What was accomplished under these goals? Aeroponically cultivated plants of Physalis crassifolia, Physalis peruviana, and Physalis philadelphica were processed to obtain large quantities of withanolides. These and their semi-synthetic analogues were evaluated for their activity against prostate cancer and melanoma cells in collaboration with the U.S. National Cancer Institute. Several active analogues of the most potent withanolide, physachenolide C (PCC), were prepared on large-scale and submitted for animal studies using mice bearing implanted melanomas in combination with the immune adjuvant, poly (I:C).

Publications

  • Type: Journal Articles Status: Published Year Published: 2017 Citation: Withanolide D exhibits similar cytostatic effect in drug-resistant and drug-sensitive multiple myoloma cells, M.E. Issa, E.M.K. Wijeratne, A.A.L. Gunatilaka, and M. Cuendet, Frontiers Pharmacol., 2017, 8, Article 610.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: Withanolides from Aeroponically Grown Physalis peruviana and Their Selective Cytotoxicity to Prostate Cancer and Renal Carcinoma Cells, Y. Xu, E.M.K. Wijeratne, A.L. Babyak, H.R. Marks, A.D. Brooks, P. Tewary, L.-J. Xuan, W.-q. Wang, T.J. Sayers, and A.A.L. Gunatilaka, J. Nat. Prod., 2017, 80, 19811991.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: 17beta-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-a Related Apoptosis Inducing Lignad (TRAIL)Induced Apoptosis: StructureActivity Relationships. Y. Xu, E.M.K. Wijeratne, A.D. Brooks, C.J. Henrich, P. Tewary, T.J. Sayers, and A.A.L. Gunatilaka, J. Med. Chem., 2017, 60, 30393051.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: Using natural products to promote caspase-8-dependent cell death. P. Tewary, P., A.A.L. Gunatilaka, and T.J. Sayers, Cancer Immunol. Immunother. 2017, 66, 223231.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: An epigenetic modifier induces production of (10S)-verruculide B, an inhibitor of protein tyrosine phosphatases by Phoma sp. nov. LG0217, a fungal endophyte of Parkinsonia microphylla, J.R. Gubiani, E.M.K. Wijeratne, T. Shi, A.R. Aruajo, A.E. Arnold, E. Chapman, and A.A.L Gunatilaka, Bioorg. Med. Chem., 2017, 25, 18601866.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: Chlorinated Dehydrocurvularins and Alterperylenepoxide A from Alternaria sp. AST0039, a Fungal Endophyte of Astragalus lentiginosus. B.P. Bashyal, E.M.K. Wijeratne, J. Tillotson, A.E. Arnold, E. Chapman, and A.A.L. Gunatilaka, J. Nat. Prod., 2017, 80, 427433.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: Montagnuphilones AG, Azaphilones from Montagnulaceae sp. DM0194, a Fungal Endophyte of Submerged Roots of Persicaria amphibian, J. Luo, Y, Xu, D.C. Sandberg, A.E. Arnold, and A.A.L. Gunatilaka, J. Nat. Prod., 2017, 80, 7681.
  • Type: Journal Articles Status: Published Year Published: 2017 Citation: Efficacy of roselle (Hibiscus sabdariffa) calyx formulations against Escherichia coli O157:H7 during flume washing of organic leafy greens, D. Jaroni, R. Kakani, S. Ravishankar, and R. Jadeja, R. Quality Assurance and Safety of Crops & Foods, 2017, 9, 115-121.


Progress 10/01/15 to 09/30/16

Outputs
Target Audience:Target audiences include stakeholders in anticancer and agricultural research. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The project provided training for two graduate students and three undergraduate students. How have the results been disseminated to communities of interest?Some results obtained during the reporting period have been disseminated to communities of interest in the form of journal publications and research seminar presentations. What do you plan to do during the next reporting period to accomplish the goals?Prepare additional analogues of withanolides for evaluation in target-oriented anticancer assays and in animal models at the National Cancer Institute.

Impacts
What was accomplished under these goals? Aeroponically cultivated plants of Physalis crassifolia and Physalis peruviana were processed to obtain large quantities of withanolides, which were evaluated in target-oriented anticancer bioassays in collaboration with the National Cancer Institute. In addition, two withanolide analogues were prepared on large-scale and submitted to the National Cancer Institute for evaluation in animal models.

Publications

  • Type: Journal Articles Status: Accepted Year Published: 2016 Citation: 17beta-Hydroxy-18-acetoxywithanolides from aeroponically grown Physalis crassifolia and their potent and selective cytotoxicity for prostate cancer cells, Y. Xu, D.P. Bunting, M.X. Liu, H.A. Bandaranayake, and A.A.L. Gunatilaka, J. Nat. Prod., 2016, 79, 821830.
  • Type: Journal Articles Status: Accepted Year Published: 2016 Citation: Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii, Wijeratne, E. M. K; Gunaherath, G. M. K. B.; Chapla, V. M.; Tillotoson, J.; Cruz, F de la; Kang, M. J.; URen, J. M.; Araujo, A. R.; Arnold, A. E.; Chapman, E.; Gunatilaka, A. A. L, J. Nat. Prod., 2016, 79, 340352.
  • Type: Journal Articles Status: Accepted Year Published: 2016 Citation: Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin, J. Tollitson, B.P. Bashyal, M. Kang, T. Shi, F. De La Cruz, A.A.L. Gunatilaka, and E. Chapman, Org. Biomol. Chem., 2016, 14, 59185921.
  • Type: Journal Articles Status: Accepted Year Published: 2016 Citation: Bioprospecting for secondary metabolites in the entomopathogenic bacterium Photorhabdus luminescens subsp. sonorensis. Orozco, R.A., Molnar, I., Bode, H., Stock, S.P., J. Invert. Pathol. 141: 45-52, 2016. DOI: 10.1016/j.jip.2016.09.008, PMID: 27702563


Progress 11/05/14 to 09/30/15

Outputs
Target Audience:Target audiences include stakeholders in anticancer and agricultural research. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The project provided training for three graduate students and three undergraduate students. How have the results been disseminated to communities of interest?Yes, some results obtained during the reporting period have been disseminated to communities of interest in the form of journal publications. What do you plan to do during the next reporting period to accomplish the goals?Two withanolide analogues that were found to have potential anticancer activity in National Cancer Institute target-oriented assays will be prepared on large-scale for their evaluation in animal models.

Impacts
What was accomplished under these goals? Soil-less aeroponic technique was applied to cultivate the plants, Physalis crassifolia and Physalis peruviana, resulting in large quantities of biomass. These were processed to obtain several withanolides which have been used to synthesize over 30 of their structural analogues. These were submitted to our collaborator at the National Cancer Institute for evaluation of their anticancer activity in target-oriented assays several fungal metabolites were isolated, characterized and evaluated for their potential biological activities.

Publications

  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Xu, Y., Mafezoli, J., Oliveira, M. C. F., URen, J. M., Arnold, A. E., and Gunatilaka, A. A. L. (2015). Anteaglonialides AF and Palmarumycins CE1CE3 from Anteaglonium sp. FL0768, a Fungal Endophyte of the Spikemoss Selaginella arenicola. Journal of Natural Products 78 (11), 2738-2747.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Xu, Y., Liu, M. X., Grunow, N., Wijeratne, E. M. K., Paine-Murrieta, G., Felder, S., Kris, R. M., and Gunatilaka, A. A. L. (2015). Discovery of Potent 17?-Hydroxywithanolides for Castration-Resistant Prostate Cancer by High-Throughput Screening of a Natural Products Library for Androgen-Induced Gene Expression Inhibitors. Journal of Medicinal Chemistry 58 (17), 6984-6993.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Tao, S., Tillotson, J., Wijeratne, E. M. K., Xu, Y., Kang, M.-J., Wu, T., Lau, E. C., Mesa, C., Mason, D. J., Brown, R. V., La Clair, J. J., Gunatilaka, A. A. L., Zhang, D. D., and Chapman, E. (2015). Withaferin A Analogs That Target the AAA+ Chaperone p97. ACS Chemical Biology 10 (8), 1916-1924.