Design, Synthesis, and Membrane‐Translocation Studies of Inositol‐Based Transporters

Abstract

Cell membrane systems represent formidable physical barriers for the trafficking of unintended molecules. Only those molecules with an appropriate range of molecular size, polarity, and charge are allowed to pass through cell membranes. Many potential drug molecules have to overcome these barriers, and a variety of chemical and physical methods have been proposed as means of accomplishing this challenging task. A number of peptides have been reported to

The design of guanidinium-rich transporters and their internalization mechanisms

“…5) based on an inositol dimer scaffold [34,35]. The dimers are prepared by linking two units of myo-or scyllo-inositol, and multiple guanidine functionalities are introduced through a peracylation of the inositol scaffold with ω-aminocarboxylate derivatives of varying length.…”

Mitochondrial Affinity of Guanidine-rich Molecular Transporters Built on Monosaccharide Scaffolds: Stereochemistry and Lipophilicity

“…[7][8][9][10][11][12] These guanidine-rich MTs generally exhibited good uptake properties and displayed rather diverse intracellular organellar and tissue selectivity. A series of G8 molecular transporters based on the sorbitol scaffold showed colocalization with MitoTracker Red in HeLa as well as CD34…”

Mitochondrial Affinity of Guanidine-rich Molecular Transporters Built on myo- and scyllo-Inositol Scaffolds: Stereochemistry Dependency

“…[14][15][16][17] For the synthesis of transporter 1, the C1-OH of compound 6 was condensed with N-Cbz protected 6-aminohexanoic acid using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 4-dimethylaminopyridine (DM-AP), and then the acetonide protecting groups were removed by treatment with EtOAc saturated with HCl (g) to provide compound 8. Exhaustive coupling of 8 with bisguanidinylated carboxylic acid 12a and 12b 15 in the presence of EDC and DMAP gave the acylated products in good yields.…”

“…Recently we have explored novel classes of synthetic molecular transporters, in which multiple units of the guanidine functionality are attached through linear or branched chain carboxylate linkers to various scaffolds such as inositol dimers, sorbitol, lactose, and sucrose. [14][15][16][17] Many of these MTs exhibited good cellular uptake properties, and moreover diverse intracellular organellar and tissue selectivity was observed somewhat unexpectedly. For example, several G8 (containing eight guanidine residues) molecular transporters based on the sorbitol scaffold and branched chain linkers showed intracellular selectivity, namely a good affinity toward mitochondria in HeLa as well as CD34…”