University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Synthesis And Characterization Of Photolabile Ruthenium Polypyridyl Crosslinkers With Applications In Soft Materials And Biology Teresa Rapp University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biochemistry Commons, Biomedical Commons, and the Inorganic Chemistry Commons Recommended Citation Rapp, Teresa, "Synthesis And Characterization Of Photolabile Ruthenium Polypyridyl Crosslinkers With Applications In Soft Materials And Biology" (2018). Publicly Accessible Penn Dissertations. 2808. https://repository.upenn.edu/edissertations/2808 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2808 For more information, please contact [email protected]. Synthesis And Characterization Of Photolabile Ruthenium Polypyridyl Crosslinkers With Applications In Soft Materials And Biology Abstract Since its discovery in 1844, ruthenium has solidified its position as the most widely used transition metal in catalysis and excited state chemistry. Its lower toxicity and relatively low price (compared to other platinum group metals) have enabled many applications of ruthenium coordination compounds. In this dissertation I discuss ruthenium polypyridyl complexes that undergo photoinduced ligand exchange, and how this unique property can be harnessed to develop next-generation smart materials and responsive chemical biology tools. Ru(LL)2X22+ complexes, where LL is a bidentate aromatic heterocycle such as 2,2’-bipyridine, 1,10-phenanthroline, or 2,2’-biquinoline, and X is a pyridine-, nitrile-, sulfur-, or imidazole-based monodentate ligand, have the unique capability to undergo ligand exchange under visible light irradiation. We have harnessed this property to develop a series of visible-light-sensitive photodegradable crosslinkers by choosing X ligands that contain reactive moieties such as alkynes (for copper-mediated azide-alkyne cycloaddition (CuAAC)) or aldehydes (for Schiff base reaction with hydrazines). Ru(bpy)2(3-ethynylpyridine)2 (RuBEP) has been used in CuAAC reactions to circularize azide-terminated oligonucleotides important for gene regulation or transcriptome analysis. Ru(bpy)2(3-pyridinaldehyde)2 (RuAldehyde) alternately employed aldehydes to react with hydrazine-modified hyaluronic acid (HA-HYD). The resulting hydrogel was cytocompatible, efficiently degraded with visible light, and well adapted for the storage and delivery of active enzymes via lysine-mediated crosslinking into the hydrogel matrix. Finally, Ru(biq)2(5-hexynenitrile)2 and Ru(bpy)2(5-hexynenitrile)2 were developed as crosslinkers to form PEG- based hydrogel, which was subsequently degraded using two different colors of visible light, orange and blue. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Chemistry First Advisor Ivan J. Dmochowski Second Advisor Donald Berry Keywords Antisense, Biomaterials, Hydrogels, Oligonucleotides, Photochemistry Subject Categories Biochemistry | Biomedical | Inorganic Chemistry This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2808 SYNTHESIS AND CHARACTERIZATION OF PHOTOLABILE RUTHENIUM POLYPYRIDYL CROSSLINKERS WITH APPLICATIONS IN SOFT MATERIALS AND BIOLOGY Teresa Rapp A DISSERTATION in Chemistry Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2018 Supervisor of Dissertation ______________ Ivan J. Dmochowski, Professor of Chemistry Graduate Group Chairperson _________________ Gary A. Molander, Hirschmann-Makineni Professor of Chemistry Dissertation Committee Donald H. Berry, Professor of Chemistry David Christianson, Roy and Diana Vagelos Professor in Chemistry and Chemical Biology Sergei Vinogradov, Associate Professor of Biochemistry and Biophysics SYNTHESIS AND CHARACTERIZATION OF PHOTOLABILE RUTHENIUM POLYPYRIDYL CROSSLINKERS WITH APPLICATIONS IN SOFT MATERIALS AND BIOLOGY COPYRIGHT 2018 Teresa Louise Rapp This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ To Mr. Oliver and Dr. Gragson, the chemistry professors who inspired me to be just like them. iii ACKNOWLEDGMENTS This dissertation would not be possible without my family and friends who have supported me for the last 6 years. Firstly, to my advisor, Ivan. The only reason there are 6 chapters instead of 4 (or fewer) is because you allowed me to branch out and pursue my passion, even when it wasn’t what I signed on to do. For that I am incredibly grateful, and because of that I have a clear idea of what I want to pursue in my career as an independent researcher. Secondly, I’d like to acknowledge my committee, and all the hard work they did working with me throughout this process. From conversations about ruthenium chemistry, to manufacturing the LEDs that enabled much of this work, to discussions about the variety of possibilities in biological applications, your time has been invaluable to me in our annual meetings and all the other times I’ve stopped by for advice. Thank you for being available, for reading so many reports, and for taking the time to mentor me throughout my PhD. Also, to the amazing people in my lab and the Chemistry Department who always kept my head on straight. My fellow cohorts Sean and Ben, those who come after us, Linlin, Serge, Yannan, Zhuangyu, Josh, and Kelsey our fabulous undergrad, you all are what make the Dmochowski lab the best lab in the department. Thank you for Waffles and Science, for eating up my less-than- perfect baked goods, and for listening to all my practice talks over the years. I couldn’t mention the people in the Chemistry Department who have supported me without thanking Katie Pulsipher, the first person I met in grad school outside my cohort. Katie, when I first saw you on one of the welcome panels at Open House, I thought you were quiet and meek, and a little … weird. Well, I was 100% wrong. You quickly became my best friend in the department, and one of the closest friends in my life. You saved my sanity while I worked through failure after failure, you rejoiced with me when an experiment actually worked out, and you regularly were the voice of reason when I was anxious about my future. iv There were many others in the department who have supported me, taught me, and encouraged me over the years. Kristen, our grad coordinator, has been a huge blessing; her door is always open. Judith Currano, our librarian, has been more than helpful over the years with anything I’ve struggled with. The late George Furst helped me take my first 2D NMR, and figure out the initial problems I was having with my compounds, and Jun has followed in his footsteps. Dr. Ross has been beyond helpful as I struggle to figure out structures and identify products by mass spectrometry, he is a true asset to the department. Chris Jeffries is great as always, supportive and helpful with anything I need. Outside the Chemistry Department I stumbled into the greatest church family I could have asked for at Freedom Church. To my pastor, Dr. Gabe Bouch, the fact that you have a PhD in mathematic physics yet you pastor this amazing church has inspired me to consider all aspects of life, educational, scientific, and spiritual. To Jen Bouch, you adopted me as your 7th kid, and let me teach science to your other 6. I’m not sure what I did to deserve that honor, but I am truly honored. To everyone else in my Freedom Family who has welcomed me with open arms, Micah and Tiffany, Jeremy Moore, Pannan, Andy, Jeremy Jester, Eugene, Katie Hess, Elisa, Brittanie, Tovah, Denise (my cheering squad!), Ryan, Laurel, Stephanie Lauren, and especially Shannon and Isaac Richardson, you all know I couldn’t have done this without you. I am amazed at what God has done through you in my life. Thank you. For everything. For my friends Emily, Heather, Vieen, and Rachel who have stood by me through the worst and celebrated the best, I am truly grateful. And finally, my loving family. You’ve supported me as I made my way through this 6-year-long journey, and you’ve always been there for me when I needed to talk. Especially my Mom and Dad, who have listened, offered suggestions, and encouraged me when it seemed like nothing was going to work out. This is for you. v ABSTRACT SYNTHESIS AND CHARACTERIZATION OF PHOTOLABILE RUTHENIUM POLYPYRIDYL CROSSLINKERS WITH APPLICATIONS IN SOFT MATERIALS AND BIOLOGY Teresa L. Rapp Ivan J. Dmochowski Since its discovery in 1844, ruthenium has solidified its position as the most widely used transition metal in catalysis and excited state chemistry. Its lower toxicity and relatively low price (compared to other platinum group metals) have enabled many applications of ruthenium coordination compounds. In this dissertation I discuss ruthenium polypyridyl complexes that undergo photoinduced ligand exchange, and how this unique property can be harnessed to develop next- generation smart materials and responsive chemical biology tools. 2+ Ru(LL)2X2 complexes, where LL is a bidentate aromatic heterocycle such as 2,2’-bipyridine, 1,10-phenanthroline, or 2,2’-biquinoline, and X is a pyridine-, nitrile-, sulfur-, or imidazole-based monodentate ligand, have the unique capability to undergo ligand exchange under visible light irradiation. We have