Department of Medicinal and Biological Chemistry

L.M. Viranga Tillekeratne, D.Phil.

  Professor

  Department of Medicinal and Biological Chemistry
  E-mail: liyanaaratchige.tillekeratne@utoledo.edu

 

 

 

AREA OF RESEARCH

My lab is interested in the study of small molecule probes of both synthetic and natural origin to study protein function as a basis for drug design and drug discovery. This involves synthesis of biologically active natural products and their analogues and structural optimization of natural products for improving pharmacological properties. We are also interested in the development of redox-active electrocatalysts to be used in electrochemical sensors to detect thiols.

Study of small molecule probes for drug design

Two bioactive natural products that we are currently focusing on are epothilones and largazole.

Epothilones

Epothilones are a group of anticancer natural products with a mechanism of action similar to that of paclitaxel (taxol). Due to their superior properties over paclitaxel, including resistance to multi-drug resistant cancer cell lines, epothilones have become important target molecules in anticancer research. We are currently investigating a class of structurally and conformationally-constrained epothilone analogues and a class of open-chain epothilones. We believe that the structurally-constrained epothilone analogues we have designed will provide information on the bioactive conformation of epothilone, and also will lead to analogues of improved pharmacological profile. We have already synthesized several of these analogues by a multi-step convergent synthetic strategy. Several other analogues are being synthesized. We are also synthesizing a new class of open-chain epothilone analogues in which a small molecular scaffold holds together key fragments of the molecule necessary for biological activity. We are currently developing a library of these open-chain epothilone analogues for structure-activity (SAR) studies.

Largazole

Largazole is a very potent and selective antiproliferative agent recently isolated from a marine cyanobacterium. It is a histone deacetylase (HDAC) inhibitor. HDACs are a class of metalloenzymes responsible for the hydrolysis of the acetyl group from lysine residues in histone proteins, leading to transcriptionally inactive condensed forms of chromatin. They are being extensively investigated as targets for epigenetic regulation or changing gene expression without changing DNA sequence for treating human disorders. HDACs are linked to cellular events such as proliferation, cell-cycle regulation, differentiation and induction of apoptosis. Aberrant HDAC activity is implicated in a number of human disorders including cancer, inflammation, rheumatoid arthritis, cardiac hypertrophy and neurodegenerative diseases. HDACs also deacetylate non-histone proteins such as hormone receptors, transcription factors, molecular chaperone proteins and cytoskeletal proteins and modify their roles in cellular functions. However, the precise role of individual HDAC isoforms in cell function and pathology of disease is not well understood. A major priority in HDAC research is the development of isoform-selective HDAC inhibitors. Isoform selective HDAC inhibitors will be useful as tools to decipher the role of individual isoforms in biochemical processes and cellular function and also to increase the therapeutic potential of HDAC inhibitors by reducing undesirable side effects.

The recently isolated HDAC inhibitor largazole possesses remarkable selective activity against cancer cells compared to normal cells. We are synthesizing a series of structural analogues of largazole by modifying its depsipeptide core, which interacts with the hydrophobic rim of the active site of histone deacetylase, and its thiol side chain, which constitutes the metal-binding domain, for SAR studies as well as to develop isoform-selective HDAC inhibitors of higher potency. The largazole analogues synthesized are tested for their anticancer, neuroprotective, cardioprotective anti-inflammatory and anti-arthritic properties.

Development of Molecular Probes for Sensors

We are developing redox-active molecular probes to be used as electrocatalysts in sensors to detect thiols and neurotoxins electrochemically. This is a collaborative project with Dr. Jon R. Kirchhoff of the Department of Chemistry, Universityof Toledo. Following on the success of our first generation electrodes with entrapped quinones as electrocatalysts, we are now synthesizing quinone-capped molecular wires to be used in our second generation thiol sensors, in order to overcome some of the drawbacks of the first generation sensors.

Educational Background

Postdoctoral Research Associate	University of Oklahoma, 1982
D.Phil.	Oxford University, 1975
B.S.	University of Colombo, Sri Lanka, 1969

 PUBLICATIONS AND JOURNALS

1. Riddhidev Banerjee, Endri Karaj, Sabitri Lamichhane, Lauren N Kotsull, Nishanth Kuganesan, Dragan Isailovic, Mary Kay H Pflum, James Slama, William Taylor and L. M. VirangaTillekeratne. Rational Design of Metabolically Stable HDAC Inhibitors: An Overhaul of Trifluoromethyl Ketones, J. Med. Chem. 2022, 244, 114807. https://doi.org/10.1016/j.ejmech.2022.114807
2. Endri Karaj, Shaimaa H. Sindi, Nishanth Kuganesan, Lalith Perera, William R. Taylor and L. M. Viranga Tillekeratne. Tunable Cysteine-Targeting Electrophilic Hetero-Aromatic Warheads Induce Ferroptosis, Med. Chem. 2022, 65, 11788-11817. doi.org/10.1021/acs.jmedchem.2c00909
3. Endri Karaj, Shaimaa H. Sindi, Nishanth Kuganesan, Lalith Perera, William R. Taylor and L. M. Viranga Tillekeratne. Tunable Cysteine-Targeting Electrophilic Hetero-Aromatic Warheads Induce Ferroptosis, 2022. doi.10.26434/chemrxiv-2022-h9t07
4. Endri Karaj, Shaimaa H. Sindi, Nishanth Kuganesan, Radhika Koranne, Joesph R. Knoff, Antonisamy W. James, Yu Fu, Mary Kay H. Pflum, Zahoor Shah, William R. Taylor and L. M. Viranga Tillekeratne. First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids. Med. Chem. 2022, 65, 14764−14791 doi.org/10.1021/acs.jmedchem.2c01276
5. Endri Karaj, Samkeliso Dlamini, Radhika Koranne, Shaimaa H. Sindi, Lalith Perera, William R. Taylor and L. M. Viranga Tillekeratne. Pharmacophore Optimization of Imidazole Chalcones to Modulate Microtubule Dynamics. Chem. 2022. https://doi.org/10.1016/j.bioorg.2022.105700
6. Endri Karaj, Shaimaa H. Sindi and L. M. Viranga Tillekeratne. Photoaffinity Labeling and Biorthogonal ligation: Two Critical Tools for Designing “Fish Hooks” to Scout for Target Proteins. Med. Chem. 2022. https://doi.org/10.1016/j.bmc.2022.116721
7. Saleh I. Alaqel, Samkeliso Dlamini, Daniyah A. Almarghalani, Arjun Shettigar, Qasim Alhadidi, Sinali H. Kodithuwakku, Creed Stary, L. M. Viranga Tillekeratne and Zahoor A. Shah. Synthesis and Development of a Novel First-in-Class Cofilin Inhibitor for Neuroinflammation in Hemorrhagic Brain Injury, ACS Chem. Neurosci. 2022, DOI: 10.1021/acschemneuro.2c0001
8. Nishanth Kuganesan, Viranga L. M. V. Tillekeratne and William R Taylor. Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, Rb and E2F. Biol. Chem. 2021, 297(6) 101365. doi: 10.1016/j.jbc.2021.101365
9. Ayad A. Al-Hamashi, Radhika Koranne, Samkeliso Dlamini. Abdulateef Alqahtani, Endri Karaj, Maisha Rashid, Joseph R. Knoff, Matthew Dunworth, Mary Kay H. Pflum, Robert A. Casero, Jr, Lalith Perera,William R. Taylor and L. M. Viranga Tillekeratne. A New Class of Cytotoxic Agents Targets Tubulin and Disrupts Microtubule Dynamics. Chem. 2021, 116, 105297,  doi.org/10.1016/j.bioorg.2021.105297)
10. Nishanth Kuganesan, Samkeliso Dlamini, Jade McDaniel, Viranga LM Tillekeratne and William R Taylor, Identification and initial characterization of a potent inhibitor of ferroptosis, Cell. Biochem. 2021, 122, 413-424 (doi.org/10.1002/jcb.29870)

UToledo Scholars