Leslie Gunatilaka

Leslie Gunatilaka

Professor, Natural Resources and the Environment
Director, Natural Products Center
Professor, Pharmacology and Toxicology
Professor, Cancer Biology - GIDP
Professor, Arid Lands Resources Sciences - GIDP
Professor, BIO5 Institute
Contact
(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.

H., D., A., A., Nakanishi, T., Patin, H., Widdowson, D. A., & Worth, B. R. (1976). Synthetic uses of steroidal ring B diene protection: 22,23- dihydroergosterol. Journal of the Chemical Society, Perkin Transactions 1, 821-826.

PMID: 944709;Abstract:

Protection of the ring B diene system of ergosterol by (i) a two-step addition of the elements of water across the 5,6-double bond, (ii) formation of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct, or (iii) formation of the iron tricarbonyl adduct by treatment with p-methoxybenzylideneacetonetricarbonyliron, allowed selective reduction of the 22,23-double bond by catalytic or, as appropriate, ionic hydrogenation. Regeneration of the 5,7-diene system in each case gave a high yield of 22,23-dihydroergosterol.

A., A., P., N., & Uvais, M. (1983). Studies on terpenoids and steroids. Part 1. Structures of six novel 27-hydroxy and 6β-hydroxy di- and tri-oxygenated D : A-friedo-oleanane triterpenes from Kokoona zeylanica. Journal of the Chemical Society, Perkin Transactions 1, 2459-2469.

Abstract:

The benzene extract of the inner stem bark of Kokoona zeylanica Thwaites (Celastraceae) contains twelve D : A-friedo-oleananes of which nine are new. The new triterpenes have been classified under three series; kokoonol (3,27-dioxy and 3,21,27-trioxy), zeylanol (3,6-dioxy and 3,6,21 -trioxy), and kokzeylanol (3,6,27-trioxy and 3,6,21,27-tetraoxy). Six of these triterpenes belonging to the kokoonol and zeylanol series have been identified as 27-hydroxy-D : A-friedo-oleanan-3-one (4) (kokoonol), 27-hydroxy-D : A-friedo-oleanane-3,21 -dione (5) (kokoononol), 21 α,27-dihydroxy-D : A-friedo-oleanan-3-one (6) (kokoondiol), 6β-hydroxy-D : A-friedo-oleanan-3-one (21) (zeylanol), 6β-hydroxy-D : A-friedo-oleanane-3,21-dione (22) (zeylanonol) and 6β,21 β-dihydroxy-D : A-friedo-oleanan-3-one (23) (zeylandiol), by spectroscopic methods and chemical interconversions. The biosynthetic significance of 6-hydroxy-D : A-friedo-oleananes is discussed.

H., D., Bracho, R. D., Gunatilaka, A. L., & Widdowson, D. A. (1975). Phenol oxidation and biosynthesis. Part XXV. New syntheses of bis-(2-arylethyl)amines of biosynthetic importance. Journal of the Chemical Society, Perkin Transactions 1, 579-588.

Abstract:

Two efficient routes to bis-(2-arylethyl)amines have been developed by using regiospecific alkylation of dialkylnitrosamine anions and homologation of aromatic aldehydes with methoxyacetonitrile anion as the respective key steps. The hitherto uncharacterised 1,3-diaryl-2-azonia-allene ions have been prepared in isolable form. Attempted insertion of C1 fragments into these systems as a third route to the title compounds failed.