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Colchicine Derivatives

Colchicine is a well-known antimitotic agent that binds to the β-monomer of the tubulin heterodimer. Its binding site has been identified to be in close proximity to the intradomain region of the two tubulin monomers. Colchicine has been known as a highly toxic chemotherapeutic agent, and acts as a microtubule destabilizer. While colchicine failed Phase II clinical trials for the treatment of leukemia conducted in the 1980’s, its failure was not due to the lack of efficacy, but rather excessive toxicity, especially renal. There has been renewed interest in colchicine as a potential chemotherapeutic agent, mainly in terms of its anti-angiogenic action.

We have designed, synthesized and tested numerous colchicine derivatives with high specificity and selectivity for tubulin isotypes. We are now preparing to begin animal testing at the Cross Cancer Institute for our best colchicine derivative, in order to gain information about its biodistribution, metabolism, and tumor uptake properties, in addition to efficacy studies. Furthermore, we have initiated a collaboration with the Centre for Drug Research and Development, with the goal of developing antibody-drug conjugates of our colchicine derivatives.


Publications

J.Y. Mane, V. Semenchenko, R. Perez-Pineiro, P. Winter, D. Wishart, and J.A. Tuszynski, Experimental and computational study of the interaction of novel colchicinoids with a recombinant human alpha-I/beta-I-tubulin heterodimer, Chemical Biology & Drug Design 82(1):60-70 (2013). doi:10.1111/cbdd.12132

M. Ashrafuzzaman, M. Duszyk and J.A. Tuszynski, Chemotherapy Drugs Thiocolchicoside and Taxol Permeabilize Lipid Bilayer Membranes by Forming Ion Pores, Journal of Physics: Conference Series 329:012029 (2011). doi:10.1088/1742-6596/329/1/012029

C-Y Tseng, J.Y. Mane, P. Winter, L. Johnson, T. Huzil, E. Izbicka, R.F. Luduena and J.A. Tuszynski, Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives, Molecular Cancer 9:131 (2010) doi:10.1186/1476-4598-9-131

J.T, Huzil, P. Winter, L. Johnson, A.L. Weis, T. Bakos, A. Banerjee, R.F. Luduena, S. Damaraju and J.A. Tuszynski, Computational design and biological testing of highly cytotoxic colchicine ring A modifications, Chemical Biology and Drug Design 75(6):541-550 (2010). doi:10.1111/j.1747-0285.2010.00970.x

D. Bartusik, B. Tomanek, E. Lattová, H. Perreault, J. Tuszynski, and G. Fallone, Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F magnetic resonance ex vivo, Bioorganic Chemistry 38(1):1-6 (2010). doi:10.1016/j.bioorg.2009.10.002

J.T. Huzil, J. Mane, and J.A. Tuszynski, Computer assisted design of second generation colchicine derivatives, Interdisciplinary Sciences- Computational Life Sciences 2(2):169-174 (2010). doi:10.1007/s12539-010-0076-z

D. Bartusik, B. Tomanek, E. Lattová, H. Perreault , J.A. Tuszynski and G. Fallone, The efficacy of new colchicine derivatives and viability of the T-lymphoblastoid cells in three-dimensional culture using 19F MRI and HPLC-UV ex vivo, Bioorganic Chemistry 37(6):193-201 (2009). doi:10.1016/j.bioorg.2009.07.007

J.T. Huzil, K. Barakat and J.A. Tuszynski, Electrostatic Contributions to Colchicine Binding within Tubulin Isotypes, Electromagnetic Biology and Medicine, 28(4): 355-364 (2009). doi:10.3109/15368370903206606

J.Y. Mane, M. Klobukowski, J.T. Huzil and J.A. Tuszynski, Free energy calculations on the binding of colchicine and its derivatives with the alpha/beta-tubulin isoforms, Journal of Chemical Information and Modeling 48(9):1824-1832 (2008). doi:10.1021/ci800054n