Issue 25, 2020

Tuning activation and self-immolative properties of the bioorthogonal alkene–azide click-and-release strategy

Abstract

We report on a series of 4-azidobenzyloxy-substituted self-immolative linkers which undergo [3 + 2]-cycloaddition (click reaction) with functionalized trans-cyclooctenes (TCOs) at second-order rate constants in the range of 0.017 to 4.9 M−1 s−1. The choice of 4-azidobenzyloxy-substituted linker and the TCO play a critical role in the rate of all click-and-release steps, which includes the [3 + 2]-cycloaddition and subsequent degradation pathway of the triazoline to an aniline that undergoes 1,6- or 1,8-self-immolation of the phenol. We demonstrate that reacting a 4-azido-2,3,5,6-tetrafluorobenzyloxy-linker with a highly strained TCO (d-TCO) gives, to the best of our knowledge, the fastest TCO-strained alkene–azide click reaction to date (4.9 M−1 s−1), but with one caveat; release of phenol via 1,6-self-immolation is extremely slow. A methyl substituent attached to the benzyl carbon of this analogue maintains the rapid click-reaction rate, but has the added benefit of enabling the release of the phenol within hours. In an aqueous solvent at reagent concentrations in the micromolar range a maximium release was observed after 48 hours; ≈65 and ≈78% of phenol released depending on the TCO used. The new suite of linkers and their combination with TCOs of varying structure add to the toolbox of bioorthogonal click-and-release reactions.

Graphical abstract: Tuning activation and self-immolative properties of the bioorthogonal alkene–azide click-and-release strategy

Supplementary files

Article information

Article type
Paper
Submitted
06 မေ 2020
Accepted
04 ဇွန် 2020
First published
05 ဇွန် 2020

Org. Biomol. Chem., 2020,18, 4754-4762

Tuning activation and self-immolative properties of the bioorthogonal alkene–azide click-and-release strategy

J. M. Fairhall, M. Murayasu, S. Dadhwal, S. Hook and A. B. Gamble, Org. Biomol. Chem., 2020, 18, 4754 DOI: 10.1039/D0OB00936A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements