Edith (Phoebe) Glazer
Ph.D. University of California, San Diego, 2003
Control of biological and chemical processes with light.
Understanding dynamic biological processes, such as the discrete steps involved in enzyme-ligand recognition and catalysis, requires the development of novel synthetic compounds that can act as reporters to identify these changes. We are interested in creating small molecule photoactive probes to target key medically relevant biological targets. This will enable us to address complex in vitro and in vivo biological problems, providing information about intricate, complex processes at the molecular level. We also want to develop the ability to control biological processes, using photoswitchable molecules. This research requires a multi-disciplinary approach, using chemistry to design probes with tailored features, biochemical techniques, and biophysics approaches to interrogate biomolecules.
Ruthenium complexes as DNA binding cytotoxins
Cancer is the second leading causes of death in the United States, and there is a pressing need for new drugs to address this disease. One of the greatest drawbacks of current treatments is their debilitating side effects, due to non-specific cytotoxicity. In contrast, “pro-drugs” are non-toxic until activated, allowing for both spatial and temporal control of their activity, facilitating selective targeting of cancerous tissues. Ruthenium complexes have been used for decades as nucleic acid binders and probes, due to their fortuitous combination of structural, electrochemical, and photophysical features. Since they are electro- and photo-active, there is the potential to develop these types of molecules as targeted chemotherapies that are less toxic than the classical drugs available. We are interested in developing photo-activated Ruthenium complexes which should act as inert “pro-drugs” until triggered by light, whereupon they can crosslink DNA. In addition, due to their mechanism of action, there is potential for their use as hypoxia-selective agents, allowing us to target these drug- and radiation-resistant types of tumors.
Dynamics of ligand binding: Heme containing enzymes as a model system
How is it that ligands find their way to their binding sites in proteins? In the cytochrome P450 family of enzymes the active site is located deep inside the protein, and is often not accessible by the surrounding solvent. What kinds of dynamic motions does the protein go through to open up and bind the ligand, and what triggers these structural motions? Are there specific, key contact points on the protein that the ligand interacts with that act as the latch on a door? Are there multiple binding sites? What controls the protein dynamics and the ligand's pathway to the active site? We are interested in the where, how and why of protein binding events. We must first develop chemical tools so that we can chart the protein landscape from a ligand’s perspective so we can “see” the protein from a small molecule’s perspective. Photoaffinity labeled ligand analogues will allow us to identify the key interactions of the small molecule with the protein. With these probes, we can explore the complex, fundamental process of molecular recognition. Understanding this process will facilitate the development of effectors of protein function.
Dual emission from coordination complexes
A few years ago, we discovered a specific type of Ruthenium complexes that break the most fundamental rule of photophysics: instead of a single emissive excited state, they possess multiple excited states that can emit simultaneously, producing dual emission. The structural and electronic features that lead to this extraordinary behavior will be explored through the synthesis of substituted, highly conjugated ligands, and incorporation of other types of metal centers. The goal is to produce a full library of systems that show dual emission, with tunable energies, efficiencies, and the potential for selectively accessing each excited state. We will investigate if the selective population of excited states on different ligands could be used to develop simple “molecular switches”, ratiometric emissive probes, and systems for improved solar energy conversion.
- Magde, D.,* Magde, M.D., Glazer, E.C., “So-called “Dual Emission” for 3MLCT luminescence in ruthenium complex ions: What is really happening?” Coord. Chem. Rev. 2015, ASAP (to be included in a special issue dedicated to Peter Ford).
- Heidary, D.K., Howerton, B.S., Glazer, E.C., “Coordination of quinolines to ruthenium bis-dimethyl-phenanthroline improves potency for potential antineoplastic agents”, J. Med. Chem. 2014, 57, 8936-8946.
- Dickerson, M., Sun, Y., Glazer, E.C., “Modifying charge and hydrophilicity of simple Ru(II) polypyridyl complexes radically alters biological activities: old complexes, surprising new tricks”, Inorg. Chem. 2014, 53, 10370-10377.
- Hidayatullah, A.N., Wachter, E., Heidary, D.K., Parkin, S., Glazer, E.C., “Photoactive Ru(II) complexes with dioxinophenanthroline ligands are potent cytotoxic agents”, Inorg. Chem. 2014, 53, 10030-10032.
- Wachter, E., Glazer, E.C., “Mechanistic study on the photochemical “light-switch” behavior of [Ru(bpy)2dmdppz]2+”, included in the special issue “Current Topics in Photochemistry” in J. Phys. Chem. A 2014, 45, 10474-10486.
- Heidary, D. K., Glazer, E. C., “A light-activated metal complex targets both DNA and RNA in a fluorescent in vitro transcription and translation assay", ChemBioChem 2014, 15, 507-511.** Highlighted on the Thermo Fisher website as an application of the Pierce Human In Vitro Protein Expression system.
- Wachter, E., Howerton, B. S., Hall, E. C., Parkin, S. Glazer, E. C., “A new type of DNA “light-switch”: a dual photochemical sensor and metalating agent for duplex and G-quadruplex DNA”, ChemComm 2014, 50, 311-313.
- Glazer, E. C. “Light-activated metal complexes that covalently modify DNA”, invited review, Israel Journal of Chemistry special issue on “Contemporary Topics in Nucleic Acids”; 2013, 53, 391-400.
- Wachter, E., Heidary, D. K., Howerton, B. S., Glazer, E. C., “Light-activated ruthenium complexes photobind DNA and are cytotoxic in the photodynamic therapy window”, ChemComm 2012, 48, 9649-9651.
- Howerton, B. S., Heidary, D. K., Glazer, E. C. “Strained ruthenium complexes are potent light-activated anticancer agents”, J. Am. Chem. Soc. 2012, 134, 8324-8327.** Highlighted in Chemical and Engineering News, “Turning on ruthenium to kill cancer cells”, Science and Technology, Latest News, May 9, 2012; “Ruthenium switches on to kill cancer cells”, Science and Technology, Concentrates, May 21, 2012; highlighted on several medical websites.**
Selected publications prior to UK:
- Lee, Y. T.*, Glazer, E. C.*, Wilson, R. F., Stout, C. D., and Goodin, D. B. “Three clusters of conformational states in P450cam reveals a multi-step pathway for opening of the substrate access channel”, Biochemistry 2011, 50, 693-703. * Equal contribution.
- Glazer, E. C., Nguyen, Y. H., Goodin, D. B., Gray, H.B. "Probing inducible nitric oxide synthase with a pterin-Ru(II) sensitizer wire", Angew. Chem. Int. Ed. 2008, 47, 898-901.
- Glazer, E. C., Magde, D., Tor, Y. "Ru(II) complexes that break the rules: structural features regulating dual emission", J. Am. Chem. Soc. 2007, 129, 8544-8551.
- Jouvenot, D., Glazer, E. C., Tor, Y. "Photodimerizable ditopic ligand", Org. Lett. 2006, 8, 1987-1990.
- Glazer, E. C., Magde, D., Tor, Y. "Dual emission from a family of conjugated dinuclear RuII complexes", J. Am. Chem. Soc. 2005, 127, 4190-4192.
- Aldrich-Wright, J., Brodie, C., Glazer, E. C., Luedtke, N. W., Elson-Schwab, L., Tor, Y. "Symmetrical bisintercalating complexes based on [Ru(dpq)2(phen)]2+ with high DNA affinity", Chem. Comm. 2004, 8, 1018-1019.
- Glazer, E. C., Tor, Y. "Ru(II) complexes of "large-surface" ligands", Angew. Chem., Int. Ed. 2002, 41, 4022-4026.