Phosphate‐Based Self‐Immolative Linkers for Tuneable Double Cargo Release

Abstract

Phosphorus-based self-immolative (SI) linkers offer a wide range of applications, such as smart materials and drugdelivery systems. Phosphorus SI linkers are ideal candidates for double-cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1 day to 2 hours or 5 minutes, as shown for linkers containing p-fluoro phenol. In turn, double cargo linkers bearing p-methyl phenol released their cargo more slowly (4 days, 4 hours, and 15 minutes) than their p-fluoro analogues. The α-hydroxyisobutyrate linker released both cargos in 25 minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms.

Recent advances in self-immolative linkers and their applications in polymeric reporting systems

“…248 Recently, Baszczyňski and Procházková have described a set of UV light triggered, phosphate-based self-immolative entities that facilitate the release of two reporter groups, exploiting that particular advantage of using a phosphate over, say, a carbamate (Scheme 57). 249 The release of more than one reporter group has mainly been achieved by the use of dendritic and polymeric systems (vide infra) though, for example, Phillips has described an acetal-based system for achieving this (Scheme 9, and Fig. 4).…”

“…250 Scheme 57 Baszczyňski and Procházková's phosphate-based self-immolative entity 256 for release of two reporter groups. 249…”

Chemical RNA Cross-Linking: Mechanisms, Computational Analysis, and Biological Applications

“…Another important shortcoming that potentially can be addressed with improved chemistry is the existence of monoadducts that complicate analysis. Recent advances in the field of self-immolative linkers , may provide inspiration for chemical cross-linkers that display significantly fewer monoadducts.…”

Chemical RNA Crosslinking: Mechanisms, Computational Analysis and Biological Applications

“…Another important shortcoming that potentially can be addressed with improved chemistry is the existence of monoadducts that complicate analysis. Recent advances in the field of self-immolative linkers 130,131 may provide inspiration for chemical crosslinkers that display significantly fewer monoadducts. 6.2.…”