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. 2020 Mar 3;11(14):3713-3718.
doi: 10.1039/d0sc00532k.

Dynamic pH responsivity of triazole-based self-immolative linkers

Derrick A Roberts  1   2 , Ben S Pilgrim  3 , Tristan N Dell  4 , Molly M Stevens  2   4
Affiliations

Dynamic pH responsivity of triazole-based self-immolative linkers

Derrick A Roberts et al. Chem Sci. .

Abstract

Gating the release of chemical payloads in response to transient signals is an important feature of 'smart' delivery systems. Herein, we report a triazole-based self-immolative linker that can be reversibly paused or slowed and restarted throughout its elimination cascade in response to pH changes in both organic and organic-aqueous solvents. The linker is conveniently prepared using the alkyne-azide cycloaddition reaction, which introduces a 1,4-triazole ring that expresses a pH-sensitive intermediate during its elimination sequence. Using a series of model compounds, we demonstrate that this intermediate can be switched between active and dormant states depending on the presence of acid or base, cleanly gating the release of payload in response to a fluctuating external stimulus.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Overview of the self-immolation sequence for hybrid diamine–triazole linkers reported herein. Trigger removal from 1 leads to the formation of 1H-triazole 4, which can be reversibly switched between active and paused states to gate the release of the payload molecule. ‘Nu’ denotes a generic nucleophile. R-groups are specified in Scheme 2.
Scheme 2
Scheme 2. Synthesis and self-immolation of model compounds 1a–f. Conditions: (i) allyl phenyl carbonate, EtOH, rt; (ii) chloromethyl chloroformate, pyridine, CHCl3, 0 °C to rt; (iii) NaN3, DMF, 50 °C; (iv) CuSO4, sodium ascorbate, DMF, 50 °C; (v) Pd(PPh3)4, morpholine (50 equiv.), DMSO-d6, 60 °C.
Scheme 3
Scheme 3. Base-mediated self-immolation kinetics of model 1b (DMSO-d6, 60 °C), shown as a representative example. (a) Reaction scheme illustrating the three distinguishable steps in the self-immolation reaction. Markers denote proton environments tracked in (b). (b) Kinetics profiles showing different stages of the cascade. Pseudo-first-order rate constants (kobs) were calculated by fitting experimental data to monoexponential decays.
Fig. 1
Fig. 1. Normalised payload release profiles for (a) 1a–c and (b) 1d–f (1b and 1c shown in background) in DMSO-d6 at 60 °C with 50 equiv. morpholine. Release half-lives are shown in parentheses and were calculated from fitting analyses (ESI, Section S6†). Dotted lines are included as visual guides.
Scheme 4
Scheme 4. Representative acid-mediated pausing and reactivation of model 1b (DMSO-d6, 60 °C). (a) Scheme illustrating the switching equilibrium. Markers denote proton environments tracked in (b). The base is morpholine or Cs2CO3. (b) Kinetics profiles of key species during self-immolation. Arrows denote attempts to restart the cascade using sub-stoichiometric Cs2CO3.
See this image and copyright information in PMC

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