Oxanorbordienes and Azanorbordienes as thiol cleavable linkers
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De Pascalis, Lucrezia
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Abstract
Oxa/ Azanorbornadienes (ONDs/ ZNDs) are potent electrophiles that undergo Michael addition with thiols, and then fragment by retro-Diels-Alder (rDA) reaction, a unique two-step sequence among thiol-reactive linkages. Modifications can be made which change adduct stability toward rDA over a very wide range. The structure-activity of rDA rates to substituents was explored. The rDA reaction rate was found to be highly sensitive to the substitution pattern, with half-lives spanning a large range. Since the cleavage mechanism is not traceless, leaving a furan unit behind, the consequences of this were tested. A series of furan conjugates of metabolically stable drugs was synthesized. The microsomal stability of the furan derivatives was tested to explore the potential for adverse metabolic processing. Lastly, ONDs were used as cleavable linkers for delivery and stimuli responsive release of cargo using a virus-like particle (VLP). The work described in this dissertation will aid the development of this linker technology for future applications in drug delivery and biomaterials, which is widely useful to applications requiring controlled release over hours or months.
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Date
2021-05-06
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Dissertation