Bicyclo[6.1.0]nonyne carboxylic acid for the production of stable molecular probes

Abstract

We report a novel strained alkyne, coined BCN acid. This compound participates efficiently in diverse bioorthogonal reactions and allows the facile production of amide probes, which showed superior in vitro stability compared to carbamate analogues.

Synthesis and stability studies of bicyclo[6.1.0]nonyne scaffolds for automated solid-phase oligonucleotide synthesis

“…In addition, using 1 as amidite allows the possibility to introduce additional handles for multiple and/or orthogonal conjugation due to the presence of the removable DMT protecting group of the linear aminodiol derivative. As carbamates represent the most encountered type of BCN derivatives and are used in prodrug design, 29 we initially chose to attach the scaffold 1 to the BCN carbinol via a carbamate linkage ( Fig. 1 , A).…”

“…Rady et al demonstrated that the presence of a carboxylic acid on the BCN scaffold does not change alkyne reactivity and gives a straightforward approach to derivatize BCN with an amine of choice via amide formation. 29 It was also shown that BCN amide is a better alternative for molecular probe design which require hydrolytic stability in biological media. 29 The synthesis of both linkers A and B started with the preparation of a common intermediate dimethoxytrityl-5N-[(methyl)-benzoyl]-aminopentane-1,3-diol 1 (Fig.…”

“…29 It was also shown that BCN amide is a better alternative for molecular probe design which require hydrolytic stability in biological media. 29 The synthesis of both linkers A and B started with the preparation of a common intermediate dimethoxytrityl-5N-[(methyl)-benzoyl]-aminopentane-1,3-diol 1 (Fig. 1 and ESI Fig.…”

“…While carbamates remain the most common and commercially available BCN derivatives, a few approaches were developed to equip BCN carbinol with other relevant functionalities. [22][23][24][25][26][27][28] For example, an intriguing alternative to use BCN carboxylic acid as a reactive handle instead of BCN carbinol was quite recently presented by Rady et al 29 The stabilities of BCN amide and BCN carbamate were compared in various media. The results showed that BCN linked with a carbamate is less suitable for biological applications where prolonged incubation is required but BCN linked with an amide could be used instead.…”

“…The results showed that BCN linked with a carbamate is less suitable for biological applications where prolonged incubation is required but BCN linked with an amide could be used instead. 29 On the other hand, the less stable carbamate may be desirable in certain circumstances, e.g. prodrug design.…”