Thursday, May 2, 2024
5/2/2024
Project Summary Gasotransmitters, such as H2S and NO, are small molecule bioregulators that are responsible for regulating different aspects of physiological functions and cellular signaling. The crosstalk between these and related biologically active species can lead to the formation of reactive sulfur species (RSS), reactive nitrogen species (RNS), and reactive oxygen species (ROS), which have their own roles in physiological mechanisms. Although often written as a neutral species, H2S and other reactive sulfur, nitrogen and oxygen species are typically anionic under physiological conditions. Anionic reactive sulfur, oxygen, and nitrogen species (ARSONS) are short-lived, small molecule intermediates formed by the crosstalk between gasotransmitters and other physiologically relevant species. Molecular crosstalk between NO and H2S leads to the formation of SNO– and SSNO– which have their own physiological roles in crosstalk and cell-signaling processes. The complexity and reactivity of these small reactive species in biological environments make understanding their interconnectivity and specific involvement in signaling pathways incredibly difficult. My proposed research will investigate methods of molecular recognition to target RSS, RNS, and ARSONS as an understudied class of anionic targets with the more long-term goal of understanding specific molecular environments that stabilize these reactive species. The long-term goal of this research is to develop new tools for the molecular recognition of ARSONS. In a recently submitted manuscript, I have been able to demonstrate through a diverse library of C–H hydrogen bonding based receptors that vary in charge, directionality, and preorganization that HS– and NO2– can be bound and that these receptors exhibit a particular preference for forming strong C–H¿S interactions. We noted that the macrocyclic receptors exhibited much stronger binding affinities compared to non-macrocyclic analogues. Inspired by these strong hydrogen bonding interactions and the driving force of preorganization, we now first focus on using C–H and N–H based macrocycles, cryptands, and cages to further investigate RSS, RNS, and ARSONS. Additionally, I will also investigate how anion-p interactions can stabilize these reactive species. These host compounds are comprised of electron deficient p-systems capable of binding anions and vary in flexibility and complimentary binding motifs. Finally, I will use the insight gained the previous experiments to rationally design novel anion receptors specific for binding ARSONS. The iterative feedback gained from the other hosts will provide new information on how cooperative interactions can target different functional groups present in ARSONS. Completion of this work will aid in the development of new tools to investigate biologically relevant, reactive anions and has the longer-term potential to inform on mechanisms and pathways related to molecular crosstalk and cellular signaling of these under-investigated species.
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