1. The Development of Cytotoxic Ruthenium (II) Arene Cyclometalates With Varying pH
Erin E. Braker, Alyssa Bangrazi, Drew Verrier, Janie Berger
University of New Hampshire, Department of Chemistry
Background:
Cytotoxic Complexes in Cancer Research
Cytotoxic ruthenium complexes have recently shown potential for being anticancer agents. These complexes have also have shown they’re tolerable in vivo. The complexes are easily altered and offer a lot of variability from different oxidation states and ligands1.
Click Chemistry
Click chemistry refers to a type of chemistry that is fast, gives high yields, and has easily separated components2. The most common type of click chemistry is copper-catalyzed alkyne-azide cyclo-addition (CuAAC) which has a fast rate and utilizes Cu(I) as a catalyst with sodium ascorbate as a reducing agent.
Aquation-anation
Aquation-anation is the replacement of a ligand present in a complex with a water. In this synthesis, chlorine was replaced with water3.
Results & Discussion:
1-acetanilide-phenyl-1,2,3-triazole
Scheme 2 The synthesis of the R-4-phenyl-1,2,3-triazole ligand using 4-bromoacetanilide
It cannot be concluded that the synthesis of this R-4-phenyl-1,2,3-triazole ligand was truly successful. Visible cues suggest that a reaction had occurred as a precipitate formed along with a color change. The substance recovered from this reaction was a yellow powder.
Ruthenium II Complex
Scheme 3 The synthesis of ruthenium (II) arene complex
No conclusive data was received as to whether or not this complex was made. A reaction is suspected to have occurred as there was a color change to a reddish brown residue.
IR Spectra
Figure 1 The IR spectrum found Figure 2 The IR spectrum found
for the triazole ligand for the final ruthenium complex.
Proton NMR Spectra and Aquation-anation
Figure 4 The proton NMR for the final Figure 5 The proton NMR for the final
complex in the aquation-anation solvent complex in the aquation-anation solvent with
without salt present salt present.
Future Work:
In order to get a better understanding of the effectiveness of each different ligand, dialysis could be used as a way to view how these complexes may react with healthy human tissue. This method would involve tracking the ability of the complexes to go through a semi-permeable membrane.
Less polar starting materials would be used in the next round of experimentation as the synthesis proved to be more difficult as the polarity of the R group increased. This may have been responsible for why these complexes were not heavily soluble in the aquation-anation solvent. A new solvent for this method should be found.
Conclusion:
The triazole ligands that had 4-bromoacetanalide and 1-bromo-2-methylpropane had NMR data that suggested something had been synthesized, but no conclusions could be made. The aquation-anation is thought to have not been successful because the three final ruthenium complexes were not soluble in the heavy water/DMF solution used for the process. Smaller, less polar groups seemed to work better in these complexes.
Synthesis of Ru (II) Complexes Based on pH
Scheme 1 The synthesis of ruthenium (II) arene complex
Cytotoxic Ru(II) complexes were tested as to whether or not the pH of ligands had a response on the effectiveness at targeting cancer cells. This synthesis was done through both CuAAC click chemistry and a substitution reaction. This synthesis used an R group of 4-bromoacetanilide on the R-4-phenyl-1,2,3-triazole ligand4. Other members used R groups of 1-bromo-2-methylpropane, 2,3-dichlorophenol, and 2-bromo-acetophenone. It was hypothesized that ligands of pH ~7.5 and above would be ideal for targeting tumor tissue rather than healthy tissue. This is because healthy tissue has a pH of roughly 7 whereas cancer cells are more acidic5. The ligand proposed for synthesis, 1-acetanilide-4-phenyl-1,2,3-triazole, had an expected pH of roughly 7.5 and is slightly more polar than others tested in the group.
References:
[1] Motswainyana, W.M.; Ajibade, P.A. Advances in Chemistry
[2] Hein, C.D.; Liu, X.; Wang, D. Pharm Res , 2216
[3] Berger, D. Defining the Word Anation. MadSci Network
[4] Riedl, C. A.; Flocke, L. S.; Hejl, M.; Roller, A.; Klose, M. H. M.; Jakupec, M. A.; Kandioller, W.; Keppler, B. K. Inorg. Chem. 2017, 56 (1),
[5] Tannock, I.F.; Rotin, D.; Perspectives in Cancer Research ,
Acknowledgements:
Dr. Roy Planalp
UNH Department of Chemistry
Zane Relethford
Luke Fulton
Fellow group members