Dynamic Signaling Cascades:Reversible Covalent Reaction-Coupled Molecular Switches

Signal transduction plays a vital role in many biological processes,which relies on receptors that respond to specific inputs in the environment,and then uses a chain of biochemical reactions to amplify the signal.Recently,there has been significantinterest in designing multicomponent systems as a means of mimicking the complexity of biological processes,and a new research field of systems chemistry has been burgeoning.The construction of dynamic multistep cascade systems,which are difficult to control due to many components and signals involved,are among the most challenging.The development of hydrazone-based rotary switches that undergo configurational switching through the strategy of photoacid or metal-mediated coordination-coupled deprotonation has been reported.Yet,dynamic covalent chemistry,which has been flourishing in the past decade,was rarely introduced into the signaling cascade system.Given their reversibility and stimuli responsiveness,the formation and exchange of dynamic covalent bonds can lead to structural and functional diversity as well as complexity with unparalleled efficiency,and as a result,dynamic covalent chemistry has been becoming a powerful tool for the research of systems chemistry.This article reports the discovery and modulation.of a novel dynamic covalent reaction(DCR)as well as the coupling of this DCR with molecular switches to create chemical cascades,thus closely mimicking a biological signaling system.The main contents are as follows:1.We chose protonation-induced switches because acid-base equilibrium is one of the most fundamental reactions in nature,and thus require a DCR which is pH sensitive under mild conditions.A novel Michael type DCR of 10-methylacridinium perchlorate and monothiols exhibiting excellent regioselectivity and tunable affinity was discovered through rational design.This dynamic covalent reaction was fully characterized by 'H-NMR,ESI-MS,and UV-vis.The unique reactivity of 10-methylacridinium perchlorate(an analog of iminium ion)in conjunction with the structural feature of the adduct results in the formation of strong acids in the equilibrium mixture.The acidity of products increased by about 10 orders of magnitude compared with reactant.The dynamic nature of the system was furthered verified.Moreover,the equilibrium of the DCR creating protons described herein was altered by simply adjusting pH,changing components,or adding oxidants.2.The dynamic cascades were then created through a proton relay.First,the coupling of the aforementioned DCR and a protonation-induced configurational switch(E/Z isomerization)was achieved.The analysis of interdependence of the equilibrium allowed us to rationally optimize the cascade and also shed light on the potential intermediate of the switching process.Furthermore,relative independence of the coupled reactions was proved by the identification of stimuli that are able to facilitate one reaction but suppress the other.To further enhance systematic complexity,a second DCR of electrophilic aldehydes and thiols to form thiohemiacetals was used for the reversible inhibition of the binary system.Finally,a fluorescence switch was turned on through coupling with the DCR,demonstrating the versatility of our strategy.groups on aromatic amines.