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

Microbial biotransformation of 16a,17-epoxy-ent-kaurane-19-oic acid by beauveria sulfurescens ATCC 7159-F

Furtado, R. A., M., G., Bastos, J. K., & A., A. (2013). Microbial biotransformation of 16a,17-epoxy-ent-kaurane-19-oic acid by beauveria sulfurescens ATCC 7159-F. Natural Product Communications, 8(8), 1041-1044.

PMID: 24079162;Abstract:

Biotransformation of 16α,17-epoxy-ent-kaurane-19-oic acid (1) by Beauveria sulfurescens ATCC 7159-F led to the production of a new ent-kaurane diterpenoid, 7β,17-dihydroxy-ent-kaur-15-en-19-oic acid (7), and four other ent-kauranes (8 - 11), all of which were identified as their methyl esters. Compounds 9 and 10 were found to be new stereoisomers. Structures of these were established by the extensive usage of their spectroscopic characteristics.

The anticancer activity of the fungal metabolite terrecyclic acid A is associated with modulation of multiple cellular stress response pathways

Turbyville, T. J., Wijeratne, E. K., Whitesell, L., & Gunatilaka, A. L. (2005). The anticancer activity of the fungal metabolite terrecyclic acid A is associated with modulation of multiple cellular stress response pathways. Molecular Cancer Therapeutics, 4(10), 1569-1576.

PMID: 16227407;Abstract:

Tumors are dependent on cellular stress responses, in particular the heat shock response, for survival in their hypoxic, acidotic, and nutrient-deprived microenvironments. Using cell-based reporter assays, we have identified terrecyclic acid A (TCA) from Aspergillus terreus, a fungus inhabiting the rhizosphere of Opuntia versicolor of the Sonoran desert, as a small-molecule inducer of the heat shock response that shows anticancer activity. Further characterization suggested that TCA also affects oxidative and inflammatory cellular stress response pathways. The presence of an α-methylene ketone moiety suggested that TCA may form adducts with sulfhydryl groups of proteins. Reaction with labile intracellular cysteines was supported by our finding that the glutathione precursor N-acetyl-cysteine protected tumor cells from the cytotoxic effects of TCA whereas the glutathione-depleting agent buthionine sulfoximine enhanced its activity. Related sesquiterpenes have been shown to increase levels of reactive oxygen species (ROS) and to inhibit nuclear factor κB (NF-κB) transcriptional activity. To assess whether TCA could have similar activities, we used a ROS-sensitive dye and flow cytometry to show that TCA does indeed increase ROS levels in 3LL cells. When tested in cells carrying NF-κB reporter constructs, TCA also exhibited concentration-dependent inhibition of cytokine-induced NF-κB transcriptional activity. These findings suggest that TCA modulates multiple stress pathways - the oxidative, heat shock, and inflammatory responses - in tumor cells that promote their survival. Small-molecule natural products such as TCA may serve as useful probes for understanding the relationships between these pathways, potentially providing leads for the design of novel and effective anti-cancer drugs. Copyright © 2005 American Association for Cancer Research.

Chemical constituents of three rutaceae species from Sri Lanka

M., E., M., B., A., A., Tezuka, Y., & Kikuchi, T. (1992). Chemical constituents of three rutaceae species from Sri Lanka. Journal of Natural Products, 55(9), 1261-1269.

Abstract:

The stem bark of Luvunga angustifolia yielded a new acridone alkaloid, 5-methoxyarborinine [1], and several known compounds. Several known compounds were also isolated from Limonia acidissima. Pleiospermium alatum afforded a rare coumarin glycoside, apiosylskimmin [5], and two known limonoids 6 and 7. Nmr studies of 6 demonstrated strong nOe effects due to "through-space" coupling and led to revision of some previous carbon signal assignments. A probable biosynthetic relationship between some limonoids of the Rutaceae is suggested.

A dioxoaporphine and other alkaloids of two annonaceous plants of sri lanka

Wijeratne, E. K., Hatanaka, Y., Kikuchi, T., Tezuka, Y., & Gunatilaka, A. L. (1996). A dioxoaporphine and other alkaloids of two annonaceous plants of sri lanka. Phytochemistry, 42(6), 1703-1706.

Abstract:

A new 4.5-dioxoaporphine alkaloid, 8-methoxyyouregidione, along with artabotrine, ouregidione, liriodenine, oxocrebanine, oxobuxifoline, atherospermidine and lanuginosine have been isolated from Artobotrys zeylanicus. Investigation of Xylopia championii afforded O-methylmoschatoline and dicentrinone.

Leslie Gunatilaka