Dioxazocinium Ortho Esters: A Class of Highly pH‐Vulnerable Amphiphiles

Abstract

Making and breaking lipids: A general synthesis of a new class of ortho ester lipids from a dioxazocinium ketene acetal is disclosed. Both single‐ and dual‐chain analogues were prepared, and the most sensitive of these (see structure) was shown to disassemble at 38 °C within 6 h at pH 5.0.

Supramolecularly engineered phospholipids constructed by nucleobase molecular recognition: upgraded generation of phospholipids for drug delivery

“…25,26 A variety of pH-sensitive phospholipids have been developed as smart carriers containing different pH-sensitive linkers, such as acetal, ketal, vinyl ether and ortho ester. [27][28][29][30][31] However, the chemical bonds in the aforementioned covalent phospholipids usually cannot promptly respond to the mildly acidic pH condition, which limits the fast release of the loaded cargos from liposomes for therapeutic purposes. Moreover, these pH-sensitive and covalently bonded phospholipids are not easy to be prepared and generally require tedious synthesis work, which prevents them from practical pharmaceutical development.…”

Aqueous Solution Properties of the Acid-Labile Thermoresponsive Poly(meth)acrylamides with Pendent Cyclic Orthoester Groups

“…In the case of acid-triggered hydrolysis of the monomers, we can observe the same trend by comparing the vinyl proton signals (a′ and a′′ in Scheme S1 and Figures S20−S24). As shown in Scheme , hydrolysis of the cyclic orthoester proceeds mainly through two competing paths: the endocyclic ring cleavage (path A) and the breaking of the exocyclic alkyloxy group (path B). , Path A results in the formation of both unit I and unit II while in path B only unit II can be obtained. The present 1 H NMR results demonstrated that path A became more important as R 3 changed from methyl to ethyl and to isopropyl whose electron-donating capability gradually increased.…”

pH‐Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

“…[10,11] We envisioned that equipping the non-glycone segment in this type of conjugates with an appropriate acid-sensitive functionality could be exploited to program as harp switch in the hydrophobic-hydrophilic balance of the molecule on going from the neutral ER to the acidic lysosome,t hereby leading to irreversible dissociation of the PC:enzyme complex after correct processing and trafficking of the mutant enzyme.A mong the battery of functional groups reported in the literature to impart pH sensititvity, [12][13][14] the orthoester group was selected for our purpose since it represents one of the most acid-labile motifs, remaining stable under neutral conditions and undergoing fast cleavage in ap hysiologically useful pH window ( Figure 1). [15,16] Coupling of isothiocyanates 5a-c (Scheme 1) [17] with 1deoxynojirimycin (DNJ), ac lassical iminosugar glucopyranose mimic, [18] afforded the corresponding sp 2 -iminosugar adducts 6a-c with total chemoselectivity and high yields.The incorporation of athiourea linker in the conjugation step was an integral part of our approach. First, it favors hydrogen bonding over electrostatic interactions with amino acid residues at the catalytic site, [19] thus preventing enhanced enzyme binding in the lysosome as ac onsequence of protonation.…”