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

Abstract

We synthesized eight G8 molecular transporters (MTs) based on 4 different monosaccharide scaffolds, and studied their biological properties with a special focus on possible mitochondrial targeting and tissue selectivity. The mitochondrial affinity of these MTs was found to be clearly related to the scaffold stereochemistry and also tenuously with the lipophilicity. It may be suggested that in the practical delivery strategy of drugs for the brain and mitochondrial diseases the BBB permeability and mitochondrial affinity should be considered as key parameters, and that an enhanced mitochondrial affinity appears possible by further research on the structure-property relationship of guanidine-rich molecular transporters.

Preparation of a Camptothecin‐conjugated Molecular Carrier and its Cytotoxic Effect Toward Human Colorectal Carcinoma In Vitro

“…According to the observations with a fluorescent microscope (Axioplan 2, Carl Zeiss, Oberkochen, Germany), the conjugate was found mainly in kidney, lung, spleen, and also to small extent in brain (Figure ). These results are different from those of past tissue distribution experiments with other sorbitol‐G8 conjugates where fluorescence was also seen in the brain . However, the CPT‐conjugate show much less distribution in the brain, suggesting the conjugate is difficult to reach the brain through the Blood Brain Barrier (BBB).…”

“…Recently, our group has designed and developed a series of advanced molecular carriers that contain carbohydrates as a scaffold. For example, monosaccharides ( e.g ., glucose, mannose, allose, and galactose), disaccharides ( e.g ., lactose and trehalose), stereoisomers of inositols, and sorbitol were utilized as scaffolds . Similar to CPP, multiple guanidine units were attached to the carbohydrate scaffold via linkers to facilitate cell membrane penetration.…”

On Guanidinium and Cellular Uptake

“…Other scaffolds investigated by Chung and co-workers include the disaccharides lactose, sucrose, and trehalose (Figure ), the monosaccharides glucose, mannose, allose, and galactose (Figure ), and monomeric myo - and scyllo -inositols (Figure ) . Both the lactose- and sucrose-based transporters feature seven guanidinium groups tethered to the sugar through linkers of different lengths (Figure a,b).…”

Synthesis of Bisdesmosidic Oleanolic Acid Saponins via a Glycosylation-Deprotection Sequence under Continuous Microfluidic/Batch Conditions

“…The structure of orthoester 8a was determined by a chemical shift in the 1 H NMR at the anomeric proton compared to the β glycosidic bond. The batch glycosylation using benzoylated glucosyl imidate donor 6a minimizes orthoester formation (see Supporting Information for details).…”

“…For the versatility of this approach to be examined, microfluidic C-3 glycosylation was applied to different carbohydrates. Benzoylated galactosyl- and xylosyl-type ( 6b and 6c , respectively) imidate donors were prepared from the corresponding commercially available monosaccharides by procedures described in the literature . Under the optimized conditions, the microfluidic glycosylation at C-3 afforded protected diglycosides 7b and 7c in 71 and 81% yields, respectively (entries 8 and 9), which are ∼10% higher than the yields of the corresponding batch reactions.…”