Postdoctoral
As a DoD Breast Cancer Research Postdoctoral Fellow in the Francis group at UC Berkeley, my research has been highly interdisciplinary, with focuses in developing targeted, nanoscale protein-based imaging agents and in advancing highly efficient, chemoselective bioconjugation reactions. In the targeted imaging agent space, I developed, characterized, and validated techniques to attach antibodies to MS2 bacteriophage, a promising drug delivery agent. I optimized a highly streamlined method to prepare targeted viral capsids through an efficient oxidative coupling reaction. In this reaction, aminophenol-labeled antibodies conjugate to virus-like particles bearing a genetically-introduced aniline. With as few as 3 equivalents of antibody with respect to capsid, this reaction reaches completion in minutes. Under these conditions, no free antibodies remain, and >95% of capsids are labeled with at least one antibody. In all the cases we have examined, these conjugates retain both their specificity and affinity for their targets, as determined by both flow cytometry and live cell confocal microscopy. I also demonstrated that capsids labeled with anti-HER2 or anti-EGFR antibodies are rapidly internalized when incubated with cells over-expressing the appropriate receptors on their surfaces. In addition to these studies, I have devoted considerable effort to advancing oxidative coupling strategies for bioconjugation. In this space, I was involved in developing a novel light-triggered “oxidative coupling” reaction of ortho-azidophenols and anilines with application to facile biomolecular photopatterning. In addition, I designed and synthesized a novel ligand that facilitates oxidative coupling to gold nanoparticles while alleviating the formation of dense protein coronas commonly observed on gold nanoparticles. Recently, I developed an alternative oxidative coupling reaction of air stable ortho-methoxyphenols and extended its utility to highly site-selective heterobifunctional cross linkers for the synthesis of well-defined protein-protein conjugates. Currently, my research focuses on improving the selectivity and efficiency of various techniques for selective N-terminal modification.
Graduate
As a member of the Snyder group at Columbia, my research began toward the total synthesis of the complex, polycyclic myrmicarin natural products. The oligomeric members of this family are among the most complex alkaloids ever isolated from an insect. Here, we adopted a diversity-oriented approach to the synthesis of an advanced intermediate that allowed for controlled dimerization of the various stereoisomers. This approach allowed a key C–C bond to be formed with the correct stereochemistry for the first time. Furthermore, these advanced materials could be controllably cyclodehydrated to the monomeric myrmicarin alkaloids in the presence of polar, protic solvents. This general approach facilitated an enantioselective synthesis of the monomeric myrmicarins that is the shortest and most efficient to date. Concurrent with our approaches to oligomeric natural products, our research goals also focused on developing new cascade reactions to access the complex, polycyclic frameworks of the securinega alkaloids. This natural product family consists of structures that are tetracyclic in nature and contain a bridged, conjugated butenolide system. Previous work towards these architectures have generally required multiple steps to install the bridged butenolide system. I addressed this problem by developing an efficient N-heterocyclic carbene (NHC) cascade sequence of an enynal to access the tricyclic core architecture of secu’amamine A from much simpler, acyclic precursors through a formal hetero-Pauson-Khand process. This reaction constitutes the first example of an NHC-catalyzed nucleophilic homoenolate addition of an ynal to any carbonyl electrophile, and a rare example of a homoenolate acting in a nucleophilic capacity on an unactivated ketone. Using this unprecedented reaction, I executed a 9 step synthesis to access 3-deshydroxy secu’amamine A.
Undergraduate and Masters
During my undergraduate and masters research in the Tschumper lab, I developed and utilized computational techniques to study weak, intermolecular interactions, such as hydrogen bonding and pi—pi interactions. I also provided reliable structures and electron affinities of a series of perfluorocycloalkanes. Here, I developed the cyanogen and diacetylene dimers as two new prototypes for pi—pi interactions while anchoring their potential energy surfaces with high level ab initio methods. Furthermore, I developed and implemented a new and efficient 2-body:many body treatment of molecules in clusters under an ONIOM-type formalism that is readily applied to analytic gradients for geometry optimizations. The structures and energetics of a series of hydrogen-bonded clusters are accurately reproduced by this method using a fraction of the computational resources of a high-level calculation on the whole cluster. Finally, a fruitful collaboration with Ffrancon Williams’ laboratory at the University of Tennessee, Knoxville used computational techniques to understand a series of unique hyperfine ESR couplings observed in the negative ions of a series of perfluorocycloalkanes, and reliable electron affinities of these unusual molecular species were also reported.