Drug-Targeting Methods
Biochemistry Research at UCF
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This group is interested in developing new drug-targeting methods to fight cancer. In particular, we are synthesizing a series of multi-functional drugs, which append a polyamine vector to a DNA intercalator. The strategy involves using the polyamine portion of the drug to carry the lethal intercalator into the cell (e.g., a Trojan Horse approach). What makes our system unique, is that once the drug conjugate enters the cell, both portions of the drug act synergistically to bind to supercoiled DNA. Once bound, the drug interferes with the untwisting of supercoiled DNA by topoisomerase II, thereby killing the cancer cell.
Figures 1 and 2. Polyamine-Conjugates: Deconvolution microscopy images of detached A375 melanoma cells treated with 1 (Panels 1-3). Panel 1 (3 min), Panel 2 (10 min), and Panel 3 (60 min) represent cells incubated with 1 at 10 μM, for the respective time period, then washed with buffer and fixed with paraformaldehyde. Conjugate 1 readily enters and is dispersed throughout the cell.
Publications
In general the polyamine scaffold has been shown to alter the action of several drug classes. Our plan is to develop a vectored delivery system to specifically target cancer cells.
Refs: "Synthesis and Biological Evaluation of N1-(anthracen-9-ylmethyl)triamines as Molecular Recognition Elements for the Polyamine Transporter," Wang, C.; Delcros, J-G.; Biggerstaff, J.; Phanstiel IV, O. J. Med. Chem. 2003, 46, 2663-2671.
"Molecular Requirements for Targeting the Polyamine Transport System; Synthesis and Biological Evaluation of Polyamine-Anthracene Conjugates," Wang, C.; Delcros, J-G.; Biggerstaff, J.; Phanstiel IV, O. J. Med. Chem. 2003, 46, 2672-2682.
"Defining the Molecular Requirements for the Selective Delivery of Polyamine-Conjugates into Cells Containing Active Polyamine Transporters," Wang, C.; Delcros, J-G.; Cannon, L.; Konate, F.; Carias, H.; Biggerstaff, J.; Gardner, R.A.; Phanstiel IV, O. J. Med. Chem. 2003, 46, 5129-5138.
For More Information
Otto Phanstiel
Department of Chemistry, CH 117
University of Central Florida
Orlando, FL 32816
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