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

Primary Department

School of Natural Resources and the Environment

Department Affiliations

School of Natural Resources and the Environment

BIO5 Institute

Contact

(520) 621-9932

leslieg@ag.arizona.edu

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

Structure-activity relationships for withanolides as inducers of the cellular heat-shock response

Wijeratne, E. M., Xu, Y., Scherz-Shouval, R., Marron, M. T., Rocha, D. D., Liu, M. X., Costa-Lotufo, L. V., Santagata, S., Lindquist, S., Whitesell, L., & Gunatilaka, A. A. (2014). Structure-activity relationships for withanolides as inducers of the cellular heat-shock response. Journal of medicinal chemistry, 57(7), 2851-63.

To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure-activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of β-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of β-OAc to 4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms.

An analog of withaferin a activates the MAPK and glutathione "stress" pathways and inhibits pancreatic cancer cell proliferation

Liu, X., Wenqing, Q. i., Cooke, L. S., Wijeratne, E. K., Xu, Y., Marron, M. T., Gunatilaka, A. L., & Mahadevan, D. (2011). An analog of withaferin a activates the MAPK and glutathione "stress" pathways and inhibits pancreatic cancer cell proliferation. Cancer Investigation, 29(10), 668-675.

PMID: 22085270;Abstract:

Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC50 for 1, 2, and 3 were 0.87, 0.45, and 0.29 μM (BxPC-3); 1.28, 1.53, and 0.52 μM (MIAPaCa-2); and 0.59, 2.25, and 0.56 μM (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose-and time-dependent apoptosis, activates MAPK and glutathione "stress" pathways, and inhibits proliferation. © 2011 Informa Healthcare USA, Inc.

Terpenoid and biflavonoid constituents of Calophyllum calaba and Garcinia spicata from Sri Lanka

Gunatilaka, A., Silva, A. D., Sotheeswaran, S., Balasubramaniam, S., & Wazeer, M. I. (1984). Terpenoid and biflavonoid constituents of Calophyllum calaba and Garcinia spicata from Sri Lanka. Phytochemistry, 23(2), 323-328.

Abstract:

A new bark acid, isochapelieric acid (cis-chapelieric acid), chapelieric acid, friedelin, friedelan-3β-ol, canophyllal, canophyllol, friedelan-3β,28-diol, canophyllic acid and amentoflavone have been isolated and characterized from leaf extractives of Calophyllum calaba. ¹³CNMR spectra of methyl chapelierate and methyl isochapelierate have been recorded and interpreted. Leaf extractives of Garcinia spicata afforded an unidentified long chain carboxylic acid, friedelin, friedelan-3β-ol, sitosterol and the biflavanones GB-1, GB-1a, GB-2a and morelloflavone. Chemotaxonomic significance of the occurrence of some of the above foliar constituents in Calophyllum and Garcinia species is discussed. © 1984.

Heptaketides from Corynespora sp. inhabiting the cavern beard lichen, Usnea cavernosa: First report of metabolites of an endolichenic fungus

Paranagama, P. A., M., E., Burns, A. M., Marron, M. T., Gunatilaka, M. K., Arnold, A. E., & A., A. (2007). Heptaketides from Corynespora sp. inhabiting the cavern beard lichen, Usnea cavernosa: First report of metabolites of an endolichenic fungus. Journal of Natural Products, 70(11), 1700-1705.

PMID: 17988097;Abstract:

Two new heptaketides, corynesporol (1) and 1-hydroxydehydroherbarin (2), along with herbarin (3) were isolated from an endolichenic fungal strain, Corynespora sp. BA-10763, occurring in the cavern beard lichen Usnea cavernosa. The structures of 1-3 were elucidated from their spectroscopic data. Aerial oxidation of corynesporol (1) yielded herbarin (3). Acetylation of 1 afforded the naphthalene derivative 4, whereas acetylation of 3 gave the corresponding naphthoquinone 6 and dehydroherbarin (5). All compounds were evaluated for their cytotoxicity and ability to inhibit migration of human metastatic breast and prostate cancer cell lines MDA-MB-231 and PC-3M, respectively. Dehydroherbarin (5) inhibited migration of both cell lines at concentrations not toxic to these cell lines. This is the first report of metabolites from an endolichenic fungus. © 2007 American Chemical Society and American Society of Pharmacognosy.

A rhizosphere fungus enhances Arabidopsis thermotolerance through production of an HSP90 inhibitor

McLellan, C. A., Turbyville, T. J., Wijeratne, E. K., Kerschen, A., Vierling, E., Queitsch, C., Whitesell, L., & Gunatilaka, A. L. (2007). A rhizosphere fungus enhances Arabidopsis thermotolerance through production of an HSP90 inhibitor. Plant Physiology, 145(1), 174-182.

PMID: 17631526;PMCID: PMC1976574;Abstract:

The molecular chaperone HEAT SHOCK PROTEIN90 (HSP90) is essential for the maturation of key regulatory proteins in eukaryotes and for the response to temperature stress. Earlier, we have reported that fungi living in association with plants of the Sonoran desert produce small molecule inhibitors of mammalian HSP90. Here, we address whether elaboration of the HSP90 inhibitor monocillin I (MON) by the rhizosphere fungus Paraphaeosphaeria quadriseptata affects plant HSP90 and plant environmental responsiveness. We demonstrate that MON binds Arabidopsis (Arabidopsis thaliana) HSP90 and can inhibit the function of HSP90 in lysates of wheat (Triticum aestivum) germ. MON treatment of Arabidopsis seedlings induced HSP101 and HSP70, conserved components of the stress response. Application of MON, or growth in the presence of MON, allowed Arabidopsis wild type but not AtHSP101 knockout mutant seedlings to survive otherwise lethal temperature stress. Finally, cocultivation of P. quadriseptata with Arabidopsis enhanced plant heat stress tolerance. These data demonstrate that HSP90-inhibitory compounds produced by fungi can influence plant growth and responses to the environment. © 2007 American Society of Plant Biologists.

Leslie Gunatilaka