A programmable chemical switch based on triggerable Michael acceptors

Zhuang, Jiaming; Zhao, Bo; Meng, Xiangxi; Schiffman, Jessica D.; Perry, Sarah L.; Vachet, Richard W.; Thayumanavan, S.

doi:10.1039/c9sc05841a

Cited by 44 publications

(56 citation statements)

References 55 publications

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“…These compounds form a covalent bond with the nucleophile, which may be followed by the concomitant release of a leaving group that was present at the β-position ( Figure 1 ). Similar chemistry has been reported in the context of bioconjugation 19 , 20 of lysines and cysteines in proteins, but not in the context of targeted inhibitors. Here we show it can be used to modulate the reactivity of selective covalent inhibitors.…”

Section: Introductionsupporting

confidence: 62%

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

et al. 2021

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Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful covalent inhibitor design. Here we describe α-substituted methacrylamides as a new class of electrophiles suitable for targeted covalent inhibitors. While typically α-substitutions inactivate acrylamides, we show that hetero α-substituted methacrylamides have higher thiol reactivity and undergo a conjugated addition–elimination reaction ultimately releasing the substituent. Their reactivity toward thiols is tunable and correlates with the p K a /p K b of the leaving group. In the context of the BTK inhibitor ibrutinib, these electrophiles showed lower intrinsic thiol reactivity than the unsubstituted ibrutinib acrylamide. This translated to comparable potency in protein labeling, in vitro kinase assays, and functional cellular assays, with improved selectivity. The conjugate addition–elimination reaction upon covalent binding to their target cysteine allows functionalizing α-substituted methacrylamides as turn-on probes. To demonstrate this, we prepared covalent ligand directed release (CoLDR) turn-on fluorescent probes for BTK, EGFR, and K-Ras G12C . We further demonstrate a BTK CoLDR chemiluminescent probe that enabled a high-throughput screen for BTK inhibitors. Altogether we show that α-substituted methacrylamides represent a new and versatile addition to the toolbox of targeted covalent inhibitor design.

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Section: Introductionsupporting

confidence: 62%

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

et al. 2021

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“…The reactivity of PYR vs DMAP leaving groups is greatly dependent on contributions from bases. 24 Our emulsion systems likely display different reactivity as a result of the biphasic solvent contributions, wherein the basic leaving groups partition partially into the oil phase, diminishing their contribution to overall reactivity; we, therefore, expect trends more similar to those based on structure alone. We also note that all emulsion studies are conducted starting at neutral conditions.…”

Section: Small Molecule Nucleophile Studiesmentioning

confidence: 84%

Programmable Emulsions via Nucleophile-Induced Covalent Surfactant Modifications

et al. 2020

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Responsive surfactants designed with kinetic control to triggers are rare and offer new opportunities in generating tunable reactive assemblies. In this work, we discuss the design of novel molecular assemblies based on covalently triggerable surfactants programmed to respond exclusively to nucleophilic triggers to cause interfacial alterations. Through a formal SN2' type Michael addition chemistry, these induced alterations at the interface of single and dynamic double emulsions can be kinetically tuned and brought about by various small molecule nucleophiles and functionalized nanoassemblies to cause macroscopic responses -bursting or morphology changes. In addition, separate responsive modalities can be used to further control the emulsion systems to impart cascade trigger behavior and programmed release applications.

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“…To operate the reaction cycle we studied two different allyl acetate fuel molecules; diethyl(αacetoxymethyl) vinylphosphonate (DVP) 35 and methyl 2-(acetoxymethyl)acrylate (ME), 36 the latter of which we found to be more reactive due to its stronger electron withdrawing R group.…”

Section: Resultsmentioning

confidence: 99%

“…35 The allyl acetate fuel is essentially an activated Michael acceptor, which have been shown to have reactivities spanning many orders of magnitude for triggered release of good leaving groups (such as tertiary amines). 36 In this work, we demonstrate the utility of the allyl acetate CRN to achieve reversible unimer to C3M transitions by transient quaternization of tertiary amine functionalised polymers mixed with a polyanion. By tuning the rates of the ionization and deionization reactions, both signal induced and transient fuel-driven micelle (dis)assemblies are accessible (Scheme 1).…”

Section: Introductionmentioning

confidence: 92%

Signal responsive transient coacervation in complex coacervate core micelles

Lewis

Klemm

Macchione

et al. 2021

Preprint

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Triggered coacervate phase (de)stabilisation in complex coacervate core micelles (C3Ms) has traditionally been limited to changes in pH and salt concentration, limiting options in responsive C3M material design. To expand this toolbox, we have developed C3Ms, that, at constant physiological pH, assemble and disassemble by coupling to a chemical reaction network (CRN) driven by the conversion of electron deficient allyl acetates and thiol or amine nucleophiles. This CRN produces transient quaternization of tertiary amine-functionalised block copolymers, which can then form the complex coacervate phase. We demonstrate triggered C3M assembly using two different allyl acetates, resulting in dramatically different assembly rates from hours to days. These are applied in various combinations with selected nucleophiles, demonstrating sequential signal induced C3M formation and deformation, as well as transient non-equilibrium (de)formation. We expect that timed and signal-responsive control over coacervate phase formation at physiological pH will find application in nucleic acid delivery, nano reactors and protocell research.

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A programmable chemical switch based on triggerable Michael acceptors

Abstract: A triggerable Michael acceptor (TMAc) with programmable reactivity and reversibility for simultaneous coupling and decoupling has been developed for selective protein modification, self-immolative linker and orthogonally addressable hydrogel.

Cited by 44 publications

References 55 publications

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

Programmable Emulsions via Nucleophile-Induced Covalent Surfactant Modifications

Signal responsive transient coacervation in complex coacervate core micelles

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