The Crimmins Group focuses on new methods development for the stereoselective construction of complex biologically active natural products. Most specifically, titanium enolates of acyloxazolidinethiones and acylthiazolidinethiones can be utilized in the enantio- and diastereoselective formation of beta-hydroxy acid derivatives and alpha, beta-hydroxy acid derivatives through chiral auxiliary-controlled aldol additions. All possible diastereomers can be accessed through slight modifications of reaction conditions. These diastereoselective aldol reactions can be applied to the construction of polyketide natural products such as apoptolidin, sorangicin A, irciniastatin A, and iriomoteolide A. Additionally, incorporation of a terminal alkene into the aldehyde and acyloxazolidinethione allows for the ultimate construction of medium ring ethers by means of ring-closing metathesis. Utilization of this strategy recently culminated in the enantioselective synthesis of the complex ladder toxin Brevetoxin A.
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.
As reported in Biomaterials, secondary amine-functionalized chitosan oligosaccharides of different molecular weights have been synthesized by the Schoenfisch Group. The process involved grafting 2-methyl aziridine from the primary amines on chitosan oligosaccharides, followed by reaction with nitric oxide, NO, gas under basic conditions to yield N-diazeniumdiolate NO donors. The total NO storage, maximum NO flux, and half-life of the resulting NO-releasing chitosan oligosaccharides were controlled by the molar ratio of 2-methyl aziridine to primary amines and the functional group surrounding the N-diazeniumdiolates respectively.
The secondary amine-modified chitosan oligosaccharides greatly increased the NO payload over existing biodegradable macromolecular NO donors. In addition, the water-solubility of the chitosan oligosaccharides enabled their penetration across the extracellular polysaccharides matrix of Pseudomonas aeruginosa biofilms and association with embedded bacteria. The effectiveness of these chitosan oligosaccharides at biofilm eradication was shown to depend on both the molecular weight and ionic characteristics. Low molecular weight and cationic chitosan oligosaccharides exhibited rapid association with bacteria throughout the entire biofilm, leading to enhanced biofilm killing. At concentrations resulting in 5-log killing of bacteria in Pseudomonas aeruginosa (P. aeruginosa) biofilms, the NO-releasing and control chitosan oligosaccharides elicited no significant cytotoxicity to mouse fibroblast L929 cells in vitro.
Published in Molecular Pharmaceutics, scientists in the DeSimone Group report on the development of a nonviral lipid-complexed PRINT, Particle Replication in Nonwetting Templates, protein particle system, LPP particle, for RNA replicon delivery with a view toward RNA replicon-based vaccination. Cylindrical bovine serum albumin, BSA, particles with a diameter, d, of 1 μm, height, h, 1 μm, loaded with RNA replicon and stabilized with a fully reversible disulfide cross-linker were fabricated using PRINT technology.
Highly efficient delivery of the particles to Vero cells was achieved by complexing particles with a mixture of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) lipids. Our data suggest that (1) this lipid-complexed protein particle is a promising system for delivery of RNA replicon-based vaccines and (2) it is necessary to use a degradable cross-linker for successful delivery of RNA replicon via protein-based particles.
The cell cytoplasm contains a complex array of macromolecules at concentrations exceeding 300 g/L. The natural, most relevant state of a biological macromolecule is thus a "crowded" one. Moving quantitative protein chemistry from dilute solution to the inside of living cells represents a major frontier that will affect not only our fundamental biological knowledge, but also efforts to produce and stabilize protein-based pharmaceuticals.
Published in PNAS, researchers in the Pielak Group show that the bacterial cytosol actually destabilizes a test protein, contradicting most theoretical predictions, but in agreement with a novel Escherichia coli model.
Nitric oxide, NO, a reactive free radical, has proven effective in eradicating bacterial biofilms with reduced risk of fostering antibacterial resistance. Published in ACS Applied Materials & Interfaces, researchers in the Schoenfisch Group have evaluated the efficacy of NO-releasing silica nanoparticles against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus biofilms as a function of particle size and shape.
Three sizes of NO-releasing silica nanoparticles with identical total NO release were utilized to study antibiofilm eradication as a function of size. To observe the role of particle shape on biofilm killing, the group varied the aspect ratio of the NO-releasing silica particles from 1 to 8 while maintaining constant particle volume and NO-release totals. Nitric oxide-releasing particles with decreased size and increased aspect ratio were more effective against both P. aeruginosa and S. aureus biofilms, with the Gram-negative species exhibiting the greatest susceptibility to NO.
To further understand the influence of these nanoparticle properties on NO-mediated antibacterial activity, the group visualized intracellular NO concentrations and cell death with confocal microscopy. Smaller NO-releasing particles exhibited better NO delivery and enhanced bacteria killing compared to the larger particles. Likewise, the rod-like NO-releasing particles proved more effective than spherical particles in delivering NO and inducing greater antibacterial action throughout the biofilm.
A new $4.47 million project in the DeSimone Group at Carolina Chemistry, funded by the Defense Threat Reduction Agency, will help lay the groundwork for developing potentially better ways to deliver antidotes against exposure to chemical weapons. The work could ultimately help both civilian and military populations through the design of precisely engineered particles and microneedle patches that are loaded with a nerve gas antidote that can be easily administered in the event of an attack.
Researchers in the DeSimone Group will use the PRINT® technology, also known as Particle Replication In Non-wetting Templates, to design and optimize the size, shape and composition of particles and microscopic needles that can carry life-saving antidotes to chemical nerve gas. If successful, the application of this technology could make it easier to deliver drugs faster to counteract severe reactions to chemical agents.
Congratulations to Professor Joseph DeSimone and former lab members, Jason Rolland and Ben Maynor, winners of the 2014 Kathryn C. Hach Award for Entrepreneurial Success from the American Chemical Society!
The winners will be formally presented with the award during a March 2014 National Awards Ceremony at the ACS National Meeting in Dallas. The award recognizes the team's successful efforts to commercialize the PRINT® technology after it was invented in the DeSimone lab in 2004.
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."