N,O‐Iminoboronates: Reversible Iminoboronates with Improved Stability for Cancer Cells Targeted Delivery

Abstract

Herein a new class of iminoboronates obtained from 2-acetylbenzene boronic acids and aminophenols is presented. The N,O-ligand topology enabled the formation of an additional B-O bond that locks the boron center in a tetrahedral geometry. This molecular arrangement decisively contributes to improve the construct's stability in biocompatible conditions and retaining the iminoboronate reversibility in more acidic environments. 2-Acetylbenzene boronic acid was reacted with a fluorescent amino-coumarin to yield a stable and non-fluorescent N,O-iminoboronate. This mechanism was further used to assemble a folate receptor targeting conjugate that selectively delivered the fluorescent amino-coumarin to MDA-MB-231 human breast cancer cells.

Boronic acids as building blocks for the construction of therapeutically useful bioconjugates

“…Continuing the development of iminoboronates and aiming to improve their stability, Gois and co-workers reported the synthesis of N,O-iminoboronates, a class of iminoboronates that showed improved resistance to hydrolysis (o12% hydrolysis in 7 days). 147 This new class of iminoboronates was prepared by the reaction of 2-FBBA or 2-ABBA with aminomethyl phenols, which provide an additional point of coordination to the boron centre, leading to a remarkably stable bicyclic structure. The constructs built with this core proved to be stable in human plasma (o20% degradation in 48 h) while still being hydrolysed at acidic pH, making them suitable linkers for payload delivery in cancer tissues.…”

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

“…The resulting N,O-iminoboronates showedi mproved stability at neutral pH and in human plasma, while efficientlyr eleasing their amine cargoesa tl ow pH values. [56] Similarly,t he reaction of ortho-acetyl phenylboronica cid( 10)w ith carbohydrazide derivatives gives rise to as ix-membered benzodiazaborine ring (DAB, such as 13 and 14). [57] The latter shows remarkable serum stability andh ydrophilicity (due to its zwitterionic nature)a nd for theser easonsi th as been mostly exploiteds o far for the fast assembly of highlys table bioconjugates.…”

“…The resulting N,O ‐iminoboronates showed improved stability at neutral pH and in human plasma, while efficiently releasing their amine cargoes at low pH values . Similarly, the reaction of ortho ‐acetyl phenylboronic acid ( 10 ) with carbohydrazide derivatives gives rise to a six‐membered benzodiazaborine ring (DAB, such as 13 and 14 ) .…”

Dual stimuli-responsive dynamic covalent peptide tags: Towards sequence-controlled release in tumor-like microenvironments

“…13,14 Gois and coworkers incorporated additional interactions through a N,O-bidentate ligand to lock the thiazolidino boronate boron atom by an additional boron−oxygen bond, which appeared to be remarkably stable with less than 20% hydrolysis for two days. 15 However, long reaction times are required for bond formation (~48 h). Conversely, bioconjugates with dynamic covalent hydrazones/hydrazides, oximes (pH-responsive) and disulfides (redox responsive) bonds [16][17][18] also showed slow association rates leading to prolonged reaction times and low conjugation yields.…”

“…Therefore, achieving fast association in combination with slow dissociation still represents an inherent limitation that has not been solved yet. 15,23 Therefore, new design strategies are required that are based on two complementary DCvRs compensating each other's weaknesses. 24 Scott and coworkers have investigated a DNAmimetic dynamic covalent system exploiting pH responsive BA-CA (fast) and hydrazinealdehyde (slow) interactions.…”