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

New norcucurbitacin and heptanorcucurbitacin glucosides from Fevillea trilobata

M., L., A., A., Glass, T. E., G., D., & Pinto, A. C. (1993). New norcucurbitacin and heptanorcucurbitacin glucosides from Fevillea trilobata. Journal of Natural Products, 56(10), 1772-1778.

PMID: 8277315;Abstract:

From the MeOH extract of the seeds of Fevillea trilobata (Cucurbitaceae) were isolated fevicordin A glucoside [1], cayaponoside B [2], cayaponoside D [3], a new norcucurbitacin glucoside, and a new heptanorcucurbitacin glucoside. The structure of the new norcucurbitacin glucoside, andirobicin A glucoside, was established as 29-nor-1,2,3,4,5,10-dehydro-25-methoxy-2-O-β-D-glucopyranosyl-3,16α, 20R,22ξ-tetrahydroxy-11-oxocucurbit-23-ene [4], and that of the novel heptanorcucurbitacin glucoside, andirobicin B glucoside, as 22,23,24,25,26,27,29-heptanor-1,2,3,4,5,10-dehydro-2-O-β-D-glucopyranosyl- 3,16α-dihydroxycucurbita-11,20-dione [5].

The structure of zeylasterone - the first of a new series of phenolic 24-nor-D:A-friedo-oleanan triterpenes

Kamal, G. M., Gunaherath, B., Gunatilaka, A. L., Uvais, M., Sultanbawa, S., & Wazeer, M. I. (1980). The structure of zeylasterone - the first of a new series of phenolic 24-nor-D:A-friedo-oleanan triterpenes. Tetrahedron Letters, 21(49), 4749-4752.

Abstract:

Zeylasterone, a new triterpene from Kokoona zeylanica, is shown to be 2,3-dihydroxy-6-oxo-24-nor-D:A-friedo-oleana-1,3,5(10),7-tetraen-23,29-d ioic acid-29-methyl ester (20 α) (1), the first member of a new series of phenolic 24-nor-D:A-friedo-oleanans. © 1980.

Studies on medicinal and related plants of Sri Lanka. Part 18. Structure of a new naphthoquinone from Plumbago zeylanica

M., G., A., A., & Thomson, R. H. (1988). Studies on medicinal and related plants of Sri Lanka. Part 18. Structure of a new naphthoquinone from Plumbago zeylanica. Journal of the Chemical Society, Perkin Transactions 1, 407-410.

Abstract:

The isolation of chitranone (3), zeylanone (4), maritinone (5), 2-methylnaphthazarin (6), plumbazeylanone, and a new naphthoquinone, methylene-3,3′-diplumbagin (7) from the phenolic fraction of the light petroleum extract of the roots of Plumbago zeylanica (Plumbaginaceae) is reported. The dimethyl ether of the new quinone has been synthesized from plumbagin methyl ether.

Differential control of growth, cell cycle progression, and expression of NF-κB in human breast cancer cells MCF-7, MCF-10A, and MDA-MB-231 by ponicidin and oridonin, diterpenoids from the Chinese herb Rabdosia rubescens

Hsieh, T., Wijeratne, E. K., Liang, J., Gunatilaka, A. L., & Wu, J. M. (2005). Differential control of growth, cell cycle progression, and expression of NF-κB in human breast cancer cells MCF-7, MCF-10A, and MDA-MB-231 by ponicidin and oridonin, diterpenoids from the Chinese herb Rabdosia rubescens. Biochemical and Biophysical Research Communications, 337(1), 224-231.

PMID: 16176802;Abstract:

Ponicidin and oridonin are novel diterpenoids isolated from Rabdosia rubescens. We tested their effects in MCF-7 and MDA-MB-231 cells, as representing low and high invasive breast carcinoma, with normal MCF-10A cells. Clonogenicity and proliferation in MCF-7 cells were inhibited more significantly by ponicidin than oridonin, while the reverse was observed in MCF-10A cells. Ponicidin and oridonin induced S/G2M arrest and G1/S block in MCF-7 cells. In MCF-10A cells treated with either diterpenoid, induction of apoptosis was observed. Moreover, oridonin almost completely blocked MCF-10A progression from S to G2/M phase; in contrast, ponicidin-treated MCF-10A cells showed no discernable changes in cell cycle phase distribution. Neither diterpenoid affected growth of MDA-MB-231 cells, at the dose range effective for MCF-7 or MCF-10A cells. Ponicidin-treated MCF-7 cells expressed reduced levels of cyclin B1, cdc2, transcription factor E2F, and Rb including phosphorylation at S780. Less pronounced effects were found in cells treated with oridonin. Neither compound altered cyclin D1 and cdk4 in MCF-7 cells. In MCF-10A cells, oridonin was more active than ponicidin in inhibiting the expression of cyclin B1, cdc2, S780-phosphorylated Rb, and E2F. To further investigate induction of apoptosis in MCF-10A cells, we measured changes in NF-κB. Decreases in p65 or p50 forms of NF-κB and its upstream regulator I-κB were found in oridonin-treated MCF-10A and not MCF-7 cells. Taken together, these results provide a mechanistic framework for the cellular effects of ponicidin and oridonin in different stage breast cancer cells. © 2005 Elsevier Inc. All rights reserved.

Withaferin A targets heat shock protein 90 in pancreatic cancer cells

Yanke, Y. u., Hamza, A., Zhang, T., Mancang, G. u., Zou, P., Newman, B., Yanyan, L. i., Gunatilaka, A. L., Zhan, C., & Sun, D. (2010). Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochemical Pharmacology, 79(4), 542-551.

PMID: 19769945;PMCID: PMC2794909;Abstract:

The purpose of this study is to investigate the efficacy and the mechanism of Hsp90 inhibition of Withaferin A (WA), a steroidal lactone occurring in Withania somnifera, in pancreatic cancer in vitro and in vivo. Withaferin A exhibited potent antiproliferative activity against pancreatic cancer cells in vitro (with IC50s of 1.24, 2.93 and 2.78 μM) in pancreatic cancer cell lines Panc-1, MiaPaCa2 and BxPc3, respectively. Annexin V staining showed that WA induced significant apoptosis in Panc-1 cells in a dose-dependent manner. Western blotting demonstrated that WA inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins (Akt, Cdk4 and glucocorticoid receptor), which was reversed by the proteasomal inhibitor, MG132. WA-biotin pull down assay of Hsp90 using Panc-1 cancer cell lysates and purified Hsp90 showed that WA-biotin binds to C-terminus of Hsp90 which was competitively blocked by unlabeled WA. Co-immunoprecipitation exhibited that WA (10 μM) disrupted Hsp90-Cdc37 complexes from 1 to 24 h post-treatment, while it neither blocked ATP binding to Hsp90, nor changed Hsp90-P23 association. WA (3, 6 mg/kg) inhibited tumor growth in pancreatic Panc-1 xenografts by 30% and 58%, respectively. These data demonstrate that Withaferin A binds Hsp90, inhibits Hsp90 chaperone activity through an ATP-independent mechanism, results in Hsp90 client protein degradation, and exhibits in vivo anticancer activity against pancreatic cancer.

Leslie Gunatilaka