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

Ghosh, Subhash; Kim, Boram; Im, Jungkyun; Lee, Woo-Sirl; Im, Chang‐Nim; Chang, Young‐Tae; Kim, Wanil; Kim, Kyong‐Tai; Chung, Sung‐Kee

doi:10.5012/bkcs.2010.31.12.3623

Cited by 9 publications

(6 citation statements)

References 30 publications

(34 reference statements)

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“…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).…”

Section: Guanidinoglycosides Inositol and Carbohydrate Scaffoldsmentioning

confidence: 99%

“…Derivatives of myo -inositol were found to target the mitochondria, whereas the more symmetric scyllo -inositol derivatives did not show significant mitochondrial colocalization. In addition, while all the transporters showed good affinity for brain tissues, scyllo -inositol-based transporters, unlike their myo -inositol stereoisomers, were widely distributed in all organs . It seems that although the structures of the saccharide scaffolds are closely related, several parameters need to be tuned for optimal organellar selectivity and tissue distribution.…”

Section: Guanidinoglycosides Inositol and Carbohydrate Scaffoldsmentioning

confidence: 99%

“…Representative structures of monomeric inositol-based transporters: (a) myo -inositol and (b) scyllo -inositol …”

Section: Guanidinoglycosides Inositol and Carbohydrate Scaffoldsmentioning

confidence: 99%

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On Guanidinium and Cellular Uptake

2014

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Guanidinium-rich scaffolds facilitate cellular translocation and delivery of bioactive cargos through biological barriers. Although impressive uptake has been demonstrated for nonoligomeric and nonpept(o)idic guanidinylated scaffolds in cell cultures and animal models, the fundamental understanding of these processes is lacking. Charge pairing and hydrogen bonding with cell surface counterparts have been proposed, but their exact role remains putative. The impact of the number and spatial relationships of the guanidinium groups on delivery and organelle/organ localization is yet to be established.

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Section: Guanidinoglycosides Inositol and Carbohydrate Scaffoldsmentioning

confidence: 99%

Section: Guanidinoglycosides Inositol and Carbohydrate Scaffoldsmentioning

confidence: 99%

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On Guanidinium and Cellular Uptake

2014

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“…The relative intensity of each signal was recorded according to a line through cells ( Figures 3(d–f) ), supporting that G4-Nal-F has high selectivity toward mitochondria. In other studies, it was reported that compounds containing multiple guanidines showed poor localization in mitochondria or localized in several organelles in addition to mitochondria, such as lysosomes and endoplasmic reticulum (Sibrian-Vazquez et al., 2008 ; Ghosh et al., 2010 ; Hamill et al., 2016 ). Therefore, it is clear that guanidines are necessary for efficient cellular uptake, but this does not assure selective localization in mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex

et al. 2022

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As mitochondria are potential therapeutic targeting sites for the treatment of human diseases, delivering cytotoxic drugs, antioxidants, and imaging molecules to mitochondria can provide new therapeutic opportunities. In an attempt to develop a new mitochondria-targeting vector, we synthesized sorbitol-based molecular transporters with multiple guanidines, measured their partition coefficients, compared their targeting efficiency using fluorescent images and Pearson's correlation coefficients, and studied cellular uptake mechanisms. To increase the targeting ability of these molecular transporters to mitochondria, alanine-naphthalene as a lipophilic group was attached to the molecular transporter, which improved translocation across cellular membranes and led to higher accumulation in mitochondria. The molecular transporter was able to form an ionic complex with antibiotics, resulting in low cell viability. These data demonstrate that the molecular transporter with a lipophilic group could be utilized as a potential drug delivery vector for treating mitochondrial dysfunction.

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“…We have recently developed several types of guanidinerich molecular carriers with high molecular weights and good water solubility that readily cross the BBB and display efficient distributions in the mouse brain [20,21]. In particular, the G8 (having eight guanidine groups) molecular carrier based on carbohydrate, such as sorbitol, was found to be very effective in delivering conjugated drugs to mouse brain [22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Ibuprofen Conjugated Molecular Transporter Capable of Enhanced Brain Penetration

Biswas

Kim

et al. 2017

Journal of Chemistry

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Based on the strong evidences between inflammation and neurodegeneration, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are considered as effective agents to reduce the risk of Alzheimer’s and Parkinson’s disease. However, the clinical use of NSAIDs in these diseases is limited by low brain distribution. In this study, we had synthesized ibuprofen conjugate which has good brain penetration.S-(+)-Ibuprofen was covalently attached to a molecular transporter having FITC and eight terminal guanidine groups. This conjugate showed good cellular uptake property in live cells. It was also injected into a mouse and the distribution of the compound was examined in each organ. The conjugate was well delivered to mouse brain indicating the conjugate is able to cross the blood-brain barrier. Our novel synthetic ibuprofen conjugate will hopefully deliver other NSAIDs into brain and is therefore applicable to the neurodegenerative diseases treatment or prevention.

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

Cited by 9 publications

References 30 publications

On Guanidinium and Cellular Uptake

On Guanidinium and Cellular Uptake

Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex

Synthesis of Ibuprofen Conjugated Molecular Transporter Capable of Enhanced Brain Penetration

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