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Medicinal and Biological Chemistry
|B.S., 1969||University of Colombo, Sri Lanka|
|D.Phil., 1975||Oxford University|
|Postdoctoral Research Associate, 1982||University of Oklahoma|
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 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 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.
1. Tillekeratne, L. M. V., Sherette, A., Grossman, P., Hupe, L., Hupe, D., and Hudson, R. A. Simplified catechin-gallate inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2001, 11, 2763-2767.
2. Tillekeratne L. M. V., Sherette A., Fulmer J. A., Hupe L., Hupe D., Gabbara S., Hudson R. A. Differential inhibition of polymerase and strand-transfer activities of HIV-1 reverse transcriptase. Bioorg Med Chem Lett. 2002, 12(4), 525-528.
3. Khobzaoui M., Tillekeratne L. M. V., Hudson R. A. Potent isothiocyanate inhibitors of carbonic anhydrase: synthesis and evaluation. Biochem Biophys Res Commun. 2004, 318(1), 1-3.
4. Fouchard D. M., Tillekeratne L. M. V., Hudson R. A. Synthesis of imidazolo analogues of the oxidation-reduction cofactor pyrroloquinoline quinone (PQQ). J Org Chem. 2004, 69(7), 2626-2629.
5. Liu Q, Viranga Tillekeratne LM, Kim YW, Kirchhoff JR, HudsonRA. Evaluation of chiral discrimination of highly negatively charged enantiomers by quaternary ammonium beta-cyclodextrin using 1H NMR. Chirality. 2005;17(9):570-576.
6. Fouchard D., Tillekeratne L. M. V., and HudsonR. A. An efficient one-pot synthesis of aminobenzimidazoles avoiding a troublesome acetonitrile-mediated reductive ethylation reaction. Synthesis, 2005, 17-18
7. Nacario R., Kotakonda S., Fouchard D. M., Tillekeratne L. M V., Hudson R. A. Reductive monoalkylation of aromatic and aliphatic nitro compounds and the corresponding amines with nitriles. Org Lett. 2005, 7(3), 471-474.
8. Alhamadsheh M., Hudson R. A., Tillekeratne L. M. V. Design, total synthesis, and evaluation of novel open-chain epothilone analogues. Org Lett. 2006, 8(4), 685-688.
9. Cai S., Mukherjee J., Tillekeratne L. M. V., Hudson R. A., Kirchhoff J. R. Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents. Bioorg Med Chem. 2007, 15(22), 7042-7047
10. Gupta, S., Alhamadsheh, M., Rajagopalan, M., Tillekeratne, L. M. V., Hudson, R. A. A total stereospecific synthesis of gonioheptolide A, Synthesis. 2007, 3512-3518
11. Barkhimer T. V., Kirchhoff J. R., Hudson R. A., Messer W. S., Jr., Tillekeratne L. M. V. Electrochemical detection of acetylcholine and choline: application to the quantitative nonradiochemical evaluation of choline transport. Anal Bioanal Chem. 2008, 392(4), 651-662.
12. Alhamadsheh M., Gupta S., Hudson R. A., Perera L., Tillekeratne L. M. V. Total synthesis and selective activity of a new class of conformationally restrained epothilones. Chem. – A Euro. J. 2008, 14(2):570-581.
13. Gupta S., Poeppelman L., Hinman C. L., Bretz J., Hudson R. A., Tillekeratne L. M. V. Apoptotic activities in closely related styryllactone stereoisomers toward human tumor cell lines: Investigation of synergism of styryllactone-induced apoptosis with TRAIL. Bioorg Med Chem. 2010, 18(2), 849-854.
14. WendlandT. R., Muntean B. S., Kaur J., MukherjeeJ., Chen, J., Tan X., Attygalle D., Collins R. W., Kirchhoff J. R., Tillekeratne L. M. V. In situ self assembly of thiolated ortho-quinone capped electrocatalysts for bioanalytical applications. Electroanalysis, 2011, 23(10), 2275-2279.
15. Bhansali, P., Hanigan, C. L., Casero, R. A. Jr. and Tillekeratne, L. M. V. Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation. J. Med. Chem. 2011, 54, 7453-7463.