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

Wijeratne, E. K., Xu, Y., Arnold, A. E., & Gunatilaka, A. L. (2015). Pulvinulin A, Graminin C, and cis-Gregatin B – New Natural Furanones from Pulvinula sp. 11120, a Fungal Endophyte of Cupressus arizonica. Natural Product Communications, 10(1), 107-111.
Wijeratne, E. M., Gunaherath, G. M., Chapla, V. M., Tillotson, J., de la Cruz, F., Kang, M., U Ren, J. M., Araujo, A. R., Arnold, A. E., Chapman, E., & Gunatilaka, A. A. (2016). Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii. Journal of natural products, 79, 340-352.

A new metabolite, oxaspirol D (4), together with oxaspirols B (2) and C (3) were isolated from Lecythophora sp. FL1375, an endolichenic fungus isolated from Parmotrema tinctorum, whereas Lecythophora sp. FL1031 inhabiting the lichen Cladonia evansii afforded oxaspirols A (1), B (2), and C (3). Of these, oxaspirol B (2) showed moderate p97 ATPase inhibitory activity. A detailed characterization of all oxaspirols was undertaken because structures proposed for known oxaspirols have involved incomplete assignments of NMR spectroscopic data leading only to their planar structures. Thus, the naturally occurring isomeric mixture (2a and 2b) of oxaspirol B was separated as their diacetates (5a and 5b) and the structures and absolute configurations of 1, 2a, 2b, 3, and 4 were determined by the application of spectroscopic techniques including two-dimensional NMR and the modified Mosher's ester method. Oxaspirol B (2) and its diacetates 5a and 5b were evaluated for their ATPase inhibitory activities of p97, p97 mutants, and other ATP-utilizing enzymes, and only 2 was found to be active, indicating the requirement of some structural features in oxaspirols for their activity. Additional biochemical and cellular assays suggested that 2 was a reversible, non-ATP competitive, and specific inhibitor of p97.

Harrigan, G. G., Ahmad, A., Baj, N., Glass, T. E., Gunatilaka, A. A., & Kingston, D. G. (1993). Bioactive and other sesquiterpenoids from Porella cordeana. Journal of Natural Products, 56(6), 921-925.

PMID: 8350093;Abstract:

Bioassay-directed fractionation of the MeCOEt extract of Porella cordeana yielded drimenin [1] and aristolone [4], which were moderately toxic towards DNA-repair-deficient mutants of Saccharomyces cerevisiae. Three inactive sesquiterpenes, 7-ketoisodrimenin [2], 7-ketoisodrimenin-5-ene [3], and norpinguisanolide, were also obtained. Compounds 2 and 3 are new.

Yuquan, X. u., Orozco, R., Wijeratne, E. K., Espinosa-Artiles, P., Gunatilaka, A. L., Stock, S. P., & Molnár, I. (2009). Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana. Fungal Genetics and Biology, 46(5), 353-364.

PMID: 19285149;Abstract:

Beauveria bassiana is a facultative entomopathogen with an extremely broad host range that is used as a commercial biopesticide for the control of insects of agricultural, veterinary and medical significance. B. bassiana produces bassianolide, a cyclooligomer depsipeptide secondary metabolite. We have cloned the bbBsls gene of B. bassiana encoding a nonribosomal peptide synthetase (NRPS). Targeted inactivation of the B. bassiana genomic copy of bbBsls abolished bassianolide production, but did not affect the biosynthesis of beauvericin, another cyclodepsipeptide produced by the strain. Comparative sequence analysis of the BbBSLS bassianolide synthetase revealed enzymatic domains for the iterative synthesis of an enzyme-bound dipeptidol monomer intermediate from d-2-hydroxyisovalerate and l-leucine. Further BbBSLS domains are predicted to catalyze the formation of the cyclic tetrameric ester bassianolide by recursive condensations of this monomer. Comparative infection assays against three selected insect hosts established bassianolide as a highly significant virulence factor of B. bassiana. © 2009 Elsevier Inc. All rights reserved.

Xu, Y., Gao, S., Bunting, D. P., & Gunatilaka, A. A. (2011). Unusual withanolides from aeroponically grown Withania somnifera. Phytochemistry, 72(6).

In an attempt to maximize production and the structural diversity of plant metabolites, the effect of growing the medicinal plant Withania somnifera under soil-less aeroponic conditions on its ability to produce withaferin A and withanolides was investigated. It resulted in the isolation and characterization of two compounds, 3α-(uracil-1-yl)-2,3-dihydrowithaferin A (1) and 3β-(adenin-9-yl)-2,3-dihydrowithaferin A (2), in addition to 10 known withanolides including 2,3-dihydrowithaferin A-3β-O-sulfate. 3β-O-Butyl-2,3-dihydrowithaferin A (3), presumably an artifact formed from withaferin A during the isolation process was also encountered. Reaction of withaferin A with uracil afforded 1 and its epimer, 3β-(uracil-1-yl)-2,3-dihydrowithaferin A (4). The structures of these compounds were elucidated on the basis of their high resolution mass and NMR spectroscopic data.