Small platinum-based anticancer therapeutics including cisplatin, oxaliplatin, and carboplatin have been used in the treatment of various cancers since the 1970’s. Despite extensive research on the mechanism of action of these compounds, a precise molecular assignment of Pt-bound species in the cell has not been performed.
In the DeRose lab we are developing novel functionalized Pt(II) reagents that mimic the activity of native Pt compounds while allowing for post-labeling, purification, and identification of Pt-bound biomolecules. Our group has synthesized multiple clickable derivatives including picazoplatin, scorpioplatin and azidoplatin. We have used these compounds in addition to 1,3 platin and 1,2 platin for a variety of purposes. By adding an azide functional group to scaffolds that resemble those of FDA approved platinum drugs, we can visualize our compounds through fluorophores or pull down platinum interactions that were previously unknown. Our lab has used many clickable platinum derivatives to probe in vitro and in vivo interactions with platinum. In particular Azidoplatin, developed and used in our lab, has been used to identify 153 novel proteins that interact with platinum in yeast, it has been used to pull down DNA as well as fluorescently label DNA, and it has been used to for cellular imaging.
Here are some of our currently published papers on this work:
Tracking the cellular targets of platinum anticancer drugs: Current tools and emergent methods
Emily Sutton, Christine McDevitt, Matthew Yglesias, Rachael Cunningham, Victoria J. DeRose Inorganica chim. acta, 2019 available online Link
Platinum Binds Proteins in the Endoplasmic Reticulum of S. cerevisiae and Induces Endoplasmic Reticulum Stress
Rachael M. Cunningham and Victoria J. DeRose ACS Chem. Biol., 2017 12(11), 2737-2745 Link
Multifunctional Pt(II) Reagents: Covalent Modifications of Pt Complexes Enable Diverse Structural Variation and In-Cell Detection
Jonathan D. White, Michael M. Haley, and Victoria J. DeRose Acc. Chem. Res., 2016 49(1), 56-66Link
Azide vs Alkyne Functionalization in Pt(II) Complexes for Post-treatment Click Modification: Solid-State Structure, Fluorescent Labeling, and Cellular Fate
Regina Wirth*, Jonathan D. White*, Alan D. Moghaddam*, Aurora L. Ginzburg, Lev N. Zakharov, Michael M. Haley, and Victoria J. DeRose J. Am. Chem. Soc., 2015 137(48), 15169-15175 Link
An Alkyne-Appended, Click-Ready Pt(II) Complex with an Unusual Arrangement in the Solid State
Jonathan D. White, Lindsay E. Guzman, Dr. Lev N. Zakharov, Prof. Michael M. Haley and Prof. Victoria J. DeRose, Angew. Chem. Int. Ed. 2015 54 (3), 1032-1035 Link
Picazoplatin, an Azide-Containing Platinum(II) Derivative for Target Analysis by Click Chemistry
White, Jonathan D.; Osborn, Maire F; Moghaddam, Alan D; Guzman, Lindsay E; Haley, Michael M; DeRose, Victoria J J. Am. Chem. Soc. 2013, 135 (32), pp 11680–11683 Link
(1) Kelland, L. Nature reviews. Cancer 2007, 7, 573–84.
(2) Hannon, M. J. Pure and Applied Chemistry 2007, 79, 2243–2261.
(3) Fricker, S. P. Dalton transactions (Cambridge, England : 2003) 2007, 4903–17.
(4) Wang, X.; Guo, Z. Dalton transactions (Cambridge, England : 2003) 2008, 1521–32.
(5) Hostetter, A.; Osborn, M.; DeRose, V. ACS Chemical Biology 2012, 7(1), 218-225.
(6) Chapman, E.; DeRose, V. JACS 2012, 134(1), 256-262.