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

The structure of celastranhydride: A novel triterpene anhydride of celastraceae

Gamlath, C. B., Gunatilaka, A. L., Tezuka, Y., & Kikuchi, T. (1988). The structure of celastranhydride: A novel triterpene anhydride of celastraceae. Tetrahedron Letters, 29(1), 109-112.

Abstract:

The structure of celastranhydride, a novel triterpene anhydride isolated from Kokoona zeylanica and present in Cassine balae and Reissantia indica, all of the family Celastraceae, has been deduced as 1 from its spectral data including 2-D heteronuclear ¹H¹³C shift correlated NMR spectra. © 1988.

2,3-Dimethoxyxanthone from Hypericum mysorense

Gunatilaka, A., Balasubramaniam, S., & Kumar, V. (1979). 2,3-Dimethoxyxanthone from Hypericum mysorense. Phytochemistry, 18(1), 182-183.

Abstract:

Different parts of Hypericum mysorense have been examined for the presence of2,3-dimethoxyxanthone which comprised the major constituent of the timber. Presence of simple xanthones in this genus supports the classification of Hypericum in the subfamily Hypericoideae in Guttiferae. © 1979.

PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90

Lafayette, S. L., Collins, C., Zaas, A. K., Schell, W. A., Betancourt-Quiroz, M., Gunatilaka, A. L., Perfect, J. R., & Cowen, L. E. (2010). PKC signaling regulates drug resistance of the fungal pathogen candida albicans via circuitry comprised of mkc1, calcineurin, and hsp90. PLoS Pathogens, 6(8), 79-80.

PMID: 20865172;PMCID: PMC2928802;Abstract:

Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to lifethreatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections. © 2010 LaFayette et al.

Biogenetically important quinonemethides and other triterpenoid constituents of Salacia reticulata

Dhanabalasingham, B., Karunaratne, V., Tezuka, Y., Kikuchi, T., & A., A. (1996). Biogenetically important quinonemethides and other triterpenoid constituents of Salacia reticulata. Phytochemistry, 42(5), 1377-1385.

Abstract:

Phytochemical investigation of the outer root bark of Salacia reticulata var. β-diandra (Celastraceae) has resulted in the isolation of two novel quinonemethide triterpenoids (celastroloids), isoiguesterinol and 30- hydroxypristimerin, along with salacenonal, several known celastroloids and friedo-oleanane triterpenoids. Details of the structural elucidation and ¹H and ¹³C NMR spectral assignments of these compounds are presented and their biogenetic significance is discussed.

Quinone-methide, phenolic and related triterpenoids of plants of Celastraceae: further evidence for the structure ofCelastranhydride

Gamlath, C. B., Gunatilaka, A. L., Tezuka, Y., Kikuchi, T., & Balasubramaniam, S. (1990). Quinone-methide, phenolic and related triterpenoids of plants of Celastraceae: further evidence for the structure ofCelastranhydride. Phytochemistry, 29(10), 3189-3192.

Abstract:

Quinone-methide and phenolic triterpenoids of the root outer bark ofCelastrus paniculatus have been identified as celastrol, pristimerin, zeylasterone and zeylasteral whereas those ofKokoona reflexa root outer bark were pristimerin, zeylasterone and zeylasteral. Celastranhydride, an unusual triterpene anhydride isolated fromK. zeylanica was shown to be present inK. reflexa, Cassine balae andReissantia indica. Details of the isolation and structure elucidation of celastranhydride are presented along with the analysis of¹H-detected heteronuclear multiple-bond multi-quantum correlation (HMBC) NMR spectrum which aided the confirmation of its structure. Extracts ofC. balae, Gymnosporia emarginata, Pleurostylia opposita andR. indica were found to contain quinone-methides but were devoid of phenolic triterpenoids. The biosynthetic and chemotaxonomic significance of the co-occurrence of these triterpenoids in Celastraceae is discussed. © 1990 Pergamon Press plc.

Leslie Gunatilaka