Click Chemistry

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 reagents that mimic the activity of native Pt compounds while allowing for post-labeling, purification, and identification of Pt-bound biomolecules.Our current progress has centered on derivitization of picoplatin, a cancer therapeutic in phase 2 clinical trials for lung cancer. By adding an azide functional group to the picoline ring, this compound, termed picazoplatin, is ready for use in a 1,3 Huisgen cycloaddition reaction to any alkyne-containing fluorophore or bead.

To pursue different applications both in vitro and in vivo we have explored a variety of different clickable reagents to pair with our platinum analogues. We have explored the use of a variety of different fluorophores as well as the use of a clickable biotin derivative to aid in cell pull down studies.

 

 

 

Here are some of our currently published papers on this work:

Convenient Detection of Metal-DNA, Metal-RNA, and Metal-Protein Adducts With a Click-Modified Pt(II) Complex
Alan D. Moghaddam, Jonathan D. White, Rachael M Cunningham, Andrea N Loes, Michael M Haley and Victoria J. DeRose Dalton Transactions 2014 ASAP Link

Platinum-RNA Modifications Following Drug Treatment in S. cerevisiae Identified by Click Chemistry and Enzymatic Mapping
Maire F. Osborn , Jonathan D. White , Michael M. Haley , and Victoria J. DeRose ACS Chem. Biol. 2014 ASAP 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

References

(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.

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