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. 2007 Nov 15;17(22):6286-9.
doi: 10.1016/j.bmcl.2007.09.002. Epub 2007 Sep 7.

Catalysis of Imido Group Hydrolysis in a Maleimide Conjugate

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Free PMC article

Catalysis of Imido Group Hydrolysis in a Maleimide Conjugate

Jeet Kalia et al. Bioorg Med Chem Lett. .
Free PMC article

Abstract

Maleimides are often used for biomolecular conjugation with thiols. An underappreciated aspect of the imido group in a maleimide conjugate is its susceptibility to spontaneous hydrolysis, resulting in undesirable heterogeneity. Here, a chromophoric maleimide is used to demonstrate that both molybdate and chromate catalyze the hydrolysis of an imido group near neutral pH. Tungstate and 4-(dimethylamino)pyridine are less effective as catalysts. This work reveals a new mode of chemical reactivity for molybdate and chromate, and provides a strategy for decreasing the heterogeneity of bioconjugates derived from maleimides.

Figures

Figure 1
Figure 1
Molybdate-catalyzed hydrolysis of imido groups. (A) Raw data for catalysis of the hydrolysis of succinimide 2. (B) Transformed data for the hydrolysis of maleimide 1 (k2 = 2.5 M−1 min−1) and succinimide 2 (k2 = 0.28 M−1 min−1).
Figure 2
Figure 2
HPLC analysis of succinimide 2 after incubation for 2 h at room temperature with a putative catalyst (0.10 M) of hydrolysis. The twin peaks at ~40 min correspond to the hydrolysis products; the peak at ~45 min corresponds to intact succinimide 2.
Figure 3
Figure 3
Comparison of molybdate and chromate as catalysts for the hydrolysis of succinimide 2. Assays were performed by HPLC, as shown in Figure 2. Data were fitted to the equation: [hydrolyzed 2]t = [hydrolyzed 2]t=∞(1 − e−kt), where k is the apparent first-order rate constant.
Scheme 1
Scheme 1
Route for the synthesis of succinimide 2.
Scheme 2
Scheme 2
Putative mechanism for the molybdate- and chromate-catalyzed hydrolysis of succinimide 2.

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