In this project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, M. G. Finn of The Scripps Research Institute will design and prepare dynamic polymers based upon reversible covalent bonding. The approach is to develop rapid and quantitative nucleophilic substitution reactions based upon reversible intramolecular anchimeric assistance, to apply these methods to dynamic polymer synthesis and dynamic polymer crosslinking, and to adapt the reactions to building dynamic surfaces. The broader impacts involve training undergraduate students and graduate students, enhancing infrastructure for research and education through collaboration between groups at The Scripps Research Institute and UC Santa Barbara, and hosting a local high school or teacher for summer research in each year of the project.
This work will enhance our fundamental understanding about dynamic polymers: long chain molecules that have an average length at any given moment but constantly break apart and reform over time. Polymer chains are the fundamental units of many materials, including plastics, and the development of new types of polymers could lead to new applications in biomedical materials, coatings, and composites.
This project explores the fundamental chemistry and applications to materials development of a new series of cleavable linkages based on anchimeric assistance reaction mechanisms. The key building block is the thia- or aza-bicyclo[3.3.1]nonane skeleton with leaving groups in the 2- and 6-positions; for convenience and to pay homage to the original discoverers of this motif, we term them "WCL" (Weil, Corey, Lautenschlager) electrophiles. We have accomplished the following goals: - Characterization of reaction rates for the making of key bonds to representative WCL electrophiles. - Syntheiszed and tested a series of nucleophiles designed to add to WCL electrophiles to make cleavable linkages. We discovered that linkages based on imidazole nucleophiles are too stable for our intended applications, but that pyridines provide a tunable family of nucleophiles with useful stabilities. - Rate constants for the cleavage of pyridine-WCL adducts have been measured, showing an informative correlation of stability with pyridine basicity. Pyridine derivatives allowing for half-lives of 1-2 days at 37C were identified. - Oligocationic and polycationic adducts of WCL electrophiles with pyridine-based bis(nucleophiles) were prepared and characterized. These polymers were shown to bind DNA and RNA tightly, and to mediate transfection of active polynucleotide into mammalian cells. The toxicity of the polycations was assessed and a useful therapeutic window allowing for transfection without cytotoxicity was identified. - Oxanorbornadienes (ONDs) were introduced as an alternative cleavable linkage, allowing for rapid bond formation by the addition of thiols and subsequent fragmentation by retro-Diels-Alder reaction. The cleavage rates for this family of connectors is generally faster than for WCL adducts, providing a good combination to cover a wide range of stabilities. - The retro-Diels-Alder rates of various OND adducts were measured and found to vary over three orders of magnitude, depending on the structures involved. - OND linkers were used to attach and release model drugs from bovine serum albumin, and shown to allow control of such release in vivo. - OND linkers were used to create novel fragmentable hydrogel materials. Preliminary experiments show that these materials can be programmed to release attached or entrained cargo (small molecules, proteins) at well-defined rates from hours to weeks. Overall, a new family of linkages and materials based on cleavable covalent bonds has been created and their properties defined. Our published reports have allowed several research groups in academia and industry to make use of these technologies.
