Research in the Alexanian Group focuses on the general areas of reaction development and chemical synthesis. Our studies are ultimately driven by the discovery of new and useful forms of chemical reactivity. A theme of these studies is an emphasis on catalytic transformations employing easily accessed substrates and common molecular functionality. We also use the wide array of unique architectures found in nature to challenge and inspire ourselves to develop creative solutions to current problems in complex molecule synthesis.
One current area of investigation is the utilization of simple hydroxamic acids to develop general, radical-mediated approaches to the metal-free difunctionalization of alkenes. We are also exploring novel approaches to the catalytic activation of alkyl electrophiles for the development of new carbon-carbon bond-forming processes, and the development of new complexity-generating multi-component cycloadditions for synthesis. Ultimately, we strive to apply these new processes to the efficient syntheses of bioactive natural and un-natural products.
The Forbes Group seeks to understand the structure, reactivity and dynamics of free radicals in a variety of media. We are especially interested in how radicals behave in confined environments such as micelles, nanocrystals polymers, and host-guest complexes. Using timeâ€“resolved and steady-state magnetic resonance spectroscopies (EPR and NMR), our current projects include investigation of the role of spin in proton-coupled electron transfer reactions, the spectroscopic signatures of free radicals trapped in organic nanocrystals, the degradation of novel polymers in solution, the location of singlet oxygen in photodynamic therapy for cancer treatment, and the adhesion of polymers to each other via grafting reactions. Previous projects have included the elucidation of the mechanism of formation of "skunky" beer by sunlight, and the formation of free radicals upon UV exposure to commercial sunless tanning lotions.
Congratulations to Professor Joseph DeSimone, winner of the 2014 Dickson Prize in Science, awarded annually to the person judged by Carnegie Mellon University to have made the most progress in the scientific field in the United States for the year in question. DeSimone was formally presented with the award during a February 16, 2015 ceremony where he delivered his Dickson Prize Lecture titled "Breakthroughs in Imprint Lithography and 3-D Additive Fabrication."
Protein quinary interactions organize the cellular interior and its metabolism. Although the interactions stabilizing secondary, tertiary, and quaternary protein structure are well defined, details about the protein–matrix contacts that compose quinary structure remain elusive. This gap exists because proteins function in the crowded cellular environment, but are traditionally studied in simple buffered solutions.
Researchers in the Pielak Group use NMR-detected H/D exchange to quantify quinary interactions between the B1 domain of protein G and the cytosol of Escherichia coli. In their work, published in PNAS, the group demonstrates that a surface mutation in this protein is 10-fold more destabilizing in cells than in buffer, a surprising result that firmly establishes the significance of quinary interactions. Remarkably, the energy involved in these interactions can be as large as the energies that stabilize specific protein complexes. These results will drive the critical task of implementing quinary structure into models for understanding the proteome.
Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, researchers in the DeSimone Group, in a broadly collaborative work, have developed modalities for the localized iontophoretic delivery of cytotoxic agents. As described in Science Translational Medicine, these iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow.
Device therapy Compared to a control (left), mice treated with a chemotherapy drug using the device experienced significant growth reduction as confirmed by the lack of brown staining for a marker of tumor growth.
"Surgery to remove a tumor currently provides the best chance to cure pancreatic cancer," said DeSimone, Chancellor's Eminent Professor of Chemistry here at UNC, and William R. Kenan, Jr. Distinguished Professor of Chemical Engineering at NC State University. "However, often a diagnosis comes too late for a patient to be eligible for surgery due to the tendency of the tumors to become intertwined with major organs and blood vessels." James Byrne, a member of the DeSimone Group, led the research by constructing the device and examining its ability to deliver chemotherapeutic drugs effectively to pancreatic cancer tumors, as well as two types of breast cancer tumors. Depending on the tumor type, the new device can be used either internally after a minimally invasive surgery to implant the device's electrodes directly on a tumor, or externally to deliver drugs through the skin. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors.
Professor James Cahoon has had some very rewarding months. First, he was chosen as one of eighteen national recipients of a David and Lucile Packard Foundation Fellowship. He was elected as one of the nation's most innovative early-career scientists and engineers receiving a Packard Fellowships for Science and Engineering. Each Fellow will receive a grant of $875,000 over five years to pursue their research. "The Packard Fellowships are an investment in an elite group of scientists and engineers who have demonstrated vision for the future of their fields and for the betterment of our society," said Lynn Orr, Keleen and Carlton Beal Professor at Stanford University, and Chairman of the Packard Fellowships Advisory Panel.
As if that was not enough, he was then awarded a Sloan Research Fellowship by the Alfred P. Sloan Foundation. Given annually since 1955, the fellowships go to early career scientists and scholars whose achievements and potential identify them as rising stars, the next generation of scientific leaders. "These fellowship provide a well-deserved recognition of Jim's accomplishments and will help him continue his active research program," said Valerie Ashby, Professor and Chair of the Chemistry Department. "I have no doubt that his research efforts will be the source of major breakthroughs in the field of semiconductor nanomaterials and their exciting applications."
Just the other day, we also learned that James is one of 48 recipients of an Award from the Research Corporation for Science Advancement, RCSA, which supports "innovative research projects proposed by early career scientists at American colleges and universities." The awards cover a wide range of research in astronomy, chemistry, and physics.
“RCSA has always been about finding and supporting the next big scientific paradigm, the theory or discovery that will revolutionize and advance an entire field of study,” said RCSA President Robert N. Shelton. And noted all RCSA awards are subject to a critical peer-review process, which tends ensure that funding goes to the best and brightest among America's young academic scientists, the men and women who are likely to be leaders in their fields in the coming decades. Over the past century, 40 scientists receiving RCSA support have also earned the Nobel Prize, and many others have received significant honors in the physical sciences.
Light-activatable drugs offer the promise of controlled release with exquisite temporal and spatial resolution. However, light-sensitive prodrugs are typically converted to their active forms using short-wavelength irradiation, which displays poor tissue penetrance. Researchers in the David Lawrence Group report in Angewandte Chemie, International Edition, on erythrocyte-mediated assembly of long-wavelength-sensitive phototherapeutics.
The activating wavelength of the constructs is readily preassigned by using fluorophores with the desired excitation wavelength λex. Drug release from the erythrocyte carrier was confirmed by standard analytical tools and by the expected biological consequences of the liberated drugs in cell culture: methotrexate, binding to intracellular dihydrofolate reductase; colchicine, inhibition of microtubule polymerization; dexamethasone, induced nuclear migration of the glucocorticoid receptor.
Researchers at the University of North Carolina at Chapel Hill and North Carolina State University have uncovered a novel approach to creating inhalable vaccines using nanoparticles that shows promise for targeting lung-specific diseases, such as influenza, pneumonia and tuberculosis.
The work, led by Cathy Fromen and Gregory Robbins, members of the DeSimone and Ting labs, reveals that a particle's surface charge plays a key role in eliciting immune responses in the lung. Using the Particle Replication in Nonwetting Templates, PRINT, technology invented in the DeSimone lab, Fromen and Robbins were able to specifically modify the surface charge of protein-loaded particles while avoiding disruption of other particle features, demonstrating PRINT's unique ability to modify particle attributes independently from one another.
At the Department of Chemistry, we feel strongly that diversity is crucial to our pursuit of academic excellence, and we are deeply committed to creating a diverse and inclusive community. We support UNC's policy, which states that "the University of North Carolina at Chapel Hill is committed to equality of opportunity and pledges that it will not practice or permit discrimination in employment on the basis of race, color, gender, national origin, age, religion, creed, disability, veteran's status, sexual orientation, gender identity or gender expression."