Catalysis of imido group hydrolysis in a maleimide conjugate

Kalia, Jeet; Raines, Ronald T.

doi:10.1016/j.bmcl.2007.09.002

Cited by 75 publications

(67 citation statements)

References 31 publications

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“…An undesirable and underappreciated aspect of maleimide conjugates is the susceptibility of their imido groups to undergo spontaneous hydrolysis, resulting in undesirable heterogeneity. Both molybdate and chromate have been shown to catalyze the hydrolysis of an imido group near neutral pH [76], providing a means to decrease the heterogeneity of bioconjugates derived from maleimides.…”

Section: Bioconjugation Linkagesmentioning

confidence: 99%

Advances in Bioconjugation

Kalia

Raines

2010

COC

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332

252

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Bioconjugation is a burgeoning field of research. Novel methods for the mild and site-specific derivatization of proteins, DNA, RNA, and carbohydrates have been developed for applications such as ligand discovery, disease diagnosis, and high-throughput screening. These powerful methods owe their existence to the discovery of chemoselective reactions that enable bioconjugation under physiological conditions—a tremendous achievement of modern organic chemistry. Here, we review recent advances in bioconjugation chemistry. Additionally, we discuss the stability of bioconjugation linkages—an important but often overlooked aspect of the field. We anticipate that this information will help investigators choose optimal linkages for their applications. Moreover, we hope that the noted limitations of existing bioconjugation methods will provide inspiration to modern organic chemists.

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Section: Bioconjugation Linkagesmentioning

confidence: 99%

Advances in Bioconjugation

Kalia

Raines

2010

COC

Self Cite

332

252

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“…6 Maleimide synthesis can be challenging in some cases, 7–10 and the deactivation of haloacetamides and maleimides by water (giving α-hydroxyamides and ring-opened amic acids, respectively) can compete significantly with thiol modification, particularly above pH 8. 11–13 …”

Section: Introductionmentioning

confidence: 99%

Thiol-Selective Fluorogenic Probes for Labeling and Release

2009

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Thiol alkylation is a powerful technique for the labeling of proteins. We report a new class of highly reactive, selective, and fluorogenic probes for thiols in aqueous solution at neutral pH, based on the 7-oxanorbornadiene (OND) framework. The maleate moiety in 7-oxabicyclo[2.2.1]hept-2,5-diene-2,3-dicarboxylic acid esters serves as both a tunable electrophile and an intramolecular quencher of an attached dansyl fluorophore. Thiols have been found to add with high rates (second-order rate constants of 40–200 M−1s−1) to give adducts that exhibit enhancements of fluorescence intensity up to 180-fold. The resulting adducts are also versatile with respect to cleavage (release) reactions by two different mechanisms. First, retro-Diels–Alder fragmentation occurs with half lives from days to weeks at room temperature, and an epoxide derivative is also reported that is incapable of cycloreversion cleavage. Second, monoamide OND derivatives undergo rapid closure to succinimide derivatives upon thiol addition, providing a thiol-triggered mechanism for immediate alcohol release. Peptides and proteins containing free thiol groups were labeled with OND electrophiles with high chemoselectivity. Since the system is so easily assembled from readily accessible modules, various functional groups can be added to OND linkers to allow the attachment of other molecules of interest.

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“…Figure 4S in the Supporting Information). [41,42] In the gel state the hydrolysis of the imide groups is markedly slower, which is important for the stability and potential application of the hydrogelators as explained in the following sections.…”

Section: Resultsmentioning

confidence: 98%

Versatile Low‐Molecular‐Weight Hydrogelators: Achieving Multiresponsiveness through a Modular Design

Milanesi

Hunter

Tzokova

et al. 2011

Chemistry A European J

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Multiresponsive low-molecular-weight hydrogelators (LMWHs) are ideal candidates for the development of smart, soft, nanotechnology materials. The synthesis is however very challenging. On the one hand, de novo design is hampered by our limited ability to predict the assembly of small molecules in water. On the other hand, modification of pre-existing LMWHs is limited by the number of different stimuli-sensitive chemical moieties that can be introduced into a small molecule without seriously disrupting the ability to gelate water. Herein we report the synthesis and characterization of multistimuli LMWHs, based on a modular design, composed of a hydrophobic, disulfide, aromatic moiety, a maleimide linker, and a hydrophilic section based on an amino acid, here N-acetyl-L-cysteine (NAC). As most LMWHs, these gelators experience reversible gel-to-sol transition following temperature changes. Additionally, the NAC moiety allows reversible control of the assembly of the gel by pH changes. The reduction of the aromatic disulfide triggers a gel-to-sol transition that, depending on the design of the particular LMWH, can be reverted by reoxidation of the resulting thiol. Finally, the hydrolysis of the cyclic imide moieties provides an additional trigger for the gel-to-sol transition with a timescale that is appropriate for use in drug-delivery applications. The efficient response to the multiple external stimuli, coupled to the modular design makes these LMWHs an excellent starting point for the development of smart nanomaterials with applications that include controlled drug release. These hydrogelators, which were discovered by serendipity rather than design, suggest nonetheless a general strategy for the introduction of multiple stimuli-sensitive chemical moieties, to offset the introduction of hydrophilic moieties with additional hydrophobic ones, in order to minimize the upsetting of the critical hydrophobic-hydrophilic balance of the LMWH.

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Catalysis of imido group hydrolysis in a maleimide conjugate

Cited by 75 publications

References 31 publications

Advances in Bioconjugation

Advances in Bioconjugation

Thiol-Selective Fluorogenic Probes for Labeling and Release

Versatile Low‐Molecular‐Weight Hydrogelators: Achieving Multiresponsiveness through a Modular Design

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