A Self-Immolative Linker for the pH-Responsive Release of Amides

Abstract

The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.5, a classical 1,6-benzyl elimination mechanism takes place, releasing more than 80% of the drug in 24 h.

A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides

“…33 Despite their importance, there are very few bioreversible prodrugs or self-immolative linkers for bioconjugation and traceless release of amides. 34 They are poor nucleophiles, and the low acidity of the amide hydrogen (p K a > 14) prevents nucleofugacity from carriers and donor systems. To introduce the NPYM linker, we adopt an indirect approach by first binding the NPYM to primary amines 23–25 and then acylating the secondary amine formed.…”

A Computational Perspective on the Reactivity of π‐spacers in Self‐Immolative Elimination Reactions

“…The fundamental approach involves using a chemical reaction as the trigger, [13,15] and various adaptations of this concept have been proposed to enhance the selectivity of the trigger reaction, even within physiological environments. These adaptations include leveraging pH conditions, [1,[16][17][18] enzymatic reactions, [19] or light activation. [20][21][22][23] An intriguing alternative avenue explores the use of mechanical triggers, [24][25][26][27] although, up to this point, this approach has been primarily applied to self-immolative polymers.…”

Unlocking Amides: A General Method for the Self‐Immolative Release of Amide‐Containing Molecules

“…Amides are heavily underrepresented as payload-release handles, despite their ubiquity in FDA-approved drugs, polymers, and immense biological importance in proteins and peptides. A few approaches have been developed to release amides, [38][39][40][41] with a desire to enhance physicochemical properties, safety, and efficacy, however, with limited success.…”

“…[42][43][44][45][46][47] Whilst libraries of analogues have been synthesised to try improve the properties of linezolid, [48][49][50] the number of strategies that release the native molecule remain scarce due to the lack of a conventional free amine, alcohol or thiol function group. [39,41] Herein, a general and modular synthesis of an aminomethyl carbamate linker system that allows for complete choice over the amide and trigger components is described. It enables the creation of stable constructs that undergo selective and controlled self-immolative release using a range of trigger systems.…”

“…One of the best examples of this is linezolid, a synthetic oxazolidinone antibiotic used mainly for the treatment of Gram‐positive and mycobacteria infections, where it prevents protein synthesis initiation by binding to ribosomal subunits [42–47] . Whilst libraries of analogues have been synthesised to try improve the properties of linezolid, [48–50] the number of strategies that release the native molecule remain scarce due to the lack of a conventional free amine, alcohol or thiol function group [39,41] …”