Leslie Gunatilaka
Director, Natural Products Center
Professor, Arid Lands Resources Sciences - GIDP
Professor, BIO5 Institute
Professor, Cancer Biology - GIDP
Professor, Natural Resources and the Environment
Professor, Pharmacology and Toxicology
Primary Department
Department Affiliations
(520) 621-9932
Work Summary
Discovery of natural products from plants and their associated microorganisms as potential drugs to treat cancer. Application of medicinal chemistry approach for structure-activity relationship studies and to obtain compounds for preclinical evaluation. Development of alternative agricultural systems for sustainable utilization of natural resources.
Research Interest
Despite many therapeutic successes, cancer remains a major cause of mortality in the US. Natural products (NPs) represent the best source and inspiration for the discovery of drugs and molecular targets. Our aim is to discover effective and non-toxic NP-based anticancer drugs. Working with NCI we have recently discovered a class of plant-derived NPs useful in cancer immunotherapy. The main focus of our current research is to utilize medicinal chemistry approach to obtain their analogues for preclinical evaluation. Leslie Gunatilaka is Professor at the School of Natural Resources and the Environment and Director of the Natural Products Center. He is also Adjunct Professor of Department of Nutritional Sciences, and a member of the Arizona Cancer Center. He is a member of several professional societies, editorial boards, and pharmaceutical company advisory groups. He is a Fellow of the Academy of Sciences for the Developing World (TWAS), Italy, and the National Academy of Sciences, Sri Lanka. Dr. Gunatilaka has over 200 peer-reviewed publications and book chapters and over 150 communications in natural product science to his credit. He is the recipient of the Sri Lankan Presidents’ gold medal for “creating a center of excellence in natural products research at the University of Peradeniya, Sri Lanka” (1987), CaPCURE award for “dedication to ending prostate cancer as a risk for all men and their families” (2000), Research Faculty of the Year Award of the UA College of Agriculture and Life Sciences (2003), the UA Asian American Faculty, Staff and Alumni Association Outstanding Faculty Award (2005), and the UA Leading Edge Researcher Award for Innovative Research (2012). He has delivered over 100 invited lectures worldwide and was the Chief Guest and Plenary Lecturer at the International Herbal Medicine Conference held in Sri Lanka (2005), and the Keynote Speaker and the Guest of Honor at Chemtech-2007, an International Conference organized by the Institute of Chemistry, Ceylon. His current research interests include discovery, identification of protein targets, and structure-activity relationship (SAR) studies of natural product-based drugs to treat cancer, neurodegenerative, and other diseases from plants, and plant- and lichen-associated microorganisms, maximization of chemistry diversity and production of microbial and plant secondary metabolites, and scientific investigation of medicinal plants and herbal supplements. Keywords: Natural Product-Based Drug Discovery, Medicinal Chemistry, Cancer Immunotherapeutic Agents

Publications

Bashyal, B. P., Wellensiek, B. P., Ramakrishnan, R., Faeth, S. H., Ahmad, N., & Gunatilaka, A. A. (2014). Altertoxins with potent anti-HIV activity from Alternaria tenuissima QUE1Se, a fungal endophyte of Quercus emoryi. Bioorganic & medicinal chemistry, 22(21), 6112-6.
BIO5 Collaborators
Nafees Ahmad, Leslie Gunatilaka

Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3-5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM, respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics.

Wellensiek, B. P., Ramakrishnan, R., Bashyal, B. P., Eason, Y., Gunatilaka, A. A., & Ahmad, N. (2013). Inhibition of HIV-1 Replication by Secondary Metabolites From Endophytic Fungi of Desert Plants. The open virology journal, 7, 72-80.
BIO5 Collaborators
Nafees Ahmad, Leslie Gunatilaka

Most antiretroviral drugs currently in use to treat an HIV-1 infection are chemically synthesized and lead to the development of viral resistance, as well as cause severe toxicities. However, a largely unexplored source for HIV-1 drug discovery is endophytic fungi that live in a symbiotic relationship with plants. These fungi produce biologically active secondary metabolites, which are natural products that are beneficial to the host. We prepared several hundred extracts from endophytic fungi of desert plants and evaluated the inhibitory effects on HIV-1 replication of those extracts that showed less than 30% cytotoxicity in T-lymphocytes. Those extracts that inhibited viral replication were fractionated in order to isolate the compounds responsible for activity. Multiple rounds of fractionation and antiviral evaluation lead to the identification of four compounds, which almost completely impede HIV-1 replication. These studies demonstrate that metabolites from endophytic fungi of desert plants can serve as a viable source for identifying potent inhibitors of HIV-1 replication.

Gunatilaka, A., Sotheeswaran, S., Sriyani, H., & Waight, E. S. (1982). A revised structure for hermonionic acid. Tetrahedron Letters, 23(29), 2987-2990.

Abstract:

Hermonionic acid and its decarboxylated product have been isolated from Garcinia quaesita. 13C NMR spectral and chemical evidence indicate that hermonionic acid is 2-0-[2-(3-methylbut-2-enyl)-3-methoxy- 4-hydroxy-5-(3,7-dimethylocta-2,6-dienyl]-4-methoxy-5-(3-methylbut-2-enyl-6-hydroxybenzoic acid. The previously assigned dienone structure for this acid is incorrect. © 1982.

Yuquan, X. u., Orozco, R., Wijeratne, E. K., Gunatilaka, A. L., Stock, S. P., & Molnár, I. (2008). Biosynthesis of the Cyclooligomer Depsipeptide Beauvericin, a Virulence Factor of the Entomopathogenic Fungus Beauveria bassiana. Chemistry and Biology, 15(9), 898-907.
BIO5 Collaborators
Leslie Gunatilaka, Istvan Molnar

PMID: 18804027;Abstract:

Beauvericin, a cyclohexadepsipeptide ionophore from the entomopathogen Beauveria bassiana, shows antibiotic, antifungal, insecticidal, and cancer cell antiproliferative and antihaptotactic (cell motility inhibitory) activity in vitro. The bbBeas gene encoding the BbBEAS nonribosomal peptide synthetase was isolated from B. bassiana and confirmed to be responsible for beauvericin biosynthesis by targeted disruption. BbBEAS utilizes D-2-hydroxyisovalerate (D-Hiv) and L-phenylalanine (Phe) for the iterative synthesis of a predicted N-methyl-dipeptidol intermediate, and forms the cyclic trimeric ester beauvericin from this intermediate in an unusual recursive process. Heterologous expression of the bbBeas gene in Escherichia coli to produce the 3189 amino acid, 351.9 kDa BbBEAS enzyme provided a strain proficient in beauvericin biosynthesis. Comparative infection assays with a BbBEAS knockout B. bassiana strain against three insect hosts revealed that beauvericin plays a highly significant but not indispensable role in virulence. © 2008 Elsevier Ltd. All rights reserved.

Gunatilaka, A., Nanayakkara, N., Uvais, M., & Sultanbawa, S. (1981). Structures of kokzeylanol and kokzeylanonol two new natural tri- and tetra- oxygenated D:A-friedo-oleananes. Tetrahedron Letters, 22(15), 1425-1428.

Abstract:

Kokzeylanol and kokzeylanonol obtained from Kokoona zeylanica have been shown to be 6β,27-dihydroxy-D:A-friedo-olean-3-one (1) and 6β,27-dihydroxy-D:A-friedo-oleana-3,21-dione (2), respectively by the deoxygenatlon of their 27-acetoxy derivatives using Lithium-ethylene diamine reduction coupled with spectroscopic and irradiation methods. Kokzeylanonol represents the first tetraoxygenated D:A-friedo-oleanane isolated from a natural source. © 1981.