Neuraminidase-triggered activation of prodrug-type substrate of 4-nitroaniline.

Takahiko Matsushita, Monique Nami Danyel, Tetsuo Koyama, Ken Hatano, Koji Matsuoka

Bioorganic & medicinal chemistry letters 2020 Jan 15

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Artificial substrates for probing neuraminidase activity are powerful tools for studying the physiological and pathological roles of neuraminidases. Most of the substrates are α-O-linked sialosides involving hydroxyl-containing reporters for visualization, and neuraminidase-catalyzed cleavage of the sialic acid residues directly activates the reporters. However, the use of amine-containing reporters has been avoided because α-N-linked sialosides are marginal substrates for neuraminidases. To expand the applicability of reporters to amine-containing compounds, we have focused on prodrug design. Herein we describe the synthesis and enzymatic study of a model substrate involving 4-nitroaniline as an amine-containing chromogenic reporter. The substrate can respond to neuraminidase from Clostridium perfringens. Neuraminidase-mediated hydrolysis of the sialic acid moiety of the substrate initiates self-immolative elimination of the linker moiety, leading the liberation of yellow-colored reporter 4-nitroaniline. The elimination process involves generation of quinone methide intermediate, which causes to neutralize neuraminidase. The substrate, thus, works as not only a chromogenic substrate but also a suicide inactivator. Copyright © 2019 Elsevier Ltd. All rights reserved.

Citation

Takahiko Matsushita, Monique Nami Danyel, Tetsuo Koyama, Ken Hatano, Koji Matsuoka. Neuraminidase-triggered activation of prodrug-type substrate of 4-nitroaniline. Bioorganic & medicinal chemistry letters. 2020 Jan 15;30(2):126883