Synthesis and biocompatibility evaluation of fluorinated, single-tailed glucopyranoside surfactants

Li, Xueshu; Tuřánek, Jaroslav; Knotigová, Pavlína Turánek; Kudláčková, Hana; Mašek, Josef; Pennington, D. Brant; Rankin, Stephen E.; Knutson, Barbara L.; Lehmler, Hans‐Joachim

doi:10.1039/b805015e

Cited by 31 publications

(49 citation statements)

References 53 publications

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“…Such interactions are characteristic for fluorous substituents and cannot be readily achieved with unsubstituted alkyl and aryl groups which mainly act by lipophilic van der Waals contacts and/or π-stacking. In addition, due to the strong aliphatic carbon-fluorine single bonds, fluorous compounds are usually biologically inert, non-toxic and thus potentially well tolerated (Li et al 2008, Li et al 2009) . Both, the tertiary amine as well as the ether bond are also biochemically very stable moieties.…”

Section: Discussionmentioning

confidence: 99%

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1‐gangliosidosis and Morquio B disease

Fantur

Wrodnigg

Stütz

et al. 2011

J of Inher Metab Disea

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Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N(2)-(dansyl)-N(6)-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a dansyl group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)(2)OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino-D: -galactitol) and (TFM)(3)OHex-DGJ (N-(Nonafluoro-tert-butyloxy)hexyl-1,5-dideoxy-1,5-imino-D: -galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5-10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.

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Section: Discussionmentioning

confidence: 99%

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1‐gangliosidosis and Morquio B disease

Fantur

Wrodnigg

Stütz

et al. 2011

J of Inher Metab Disea

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“…The potent activity of 4 (MIC o0.25) against methicillin-resistant Staphylococcus epidermidis is especially noteworthy. Replacement of the C 16 -lipid in 4 by a partially fluorinated lipid tail with comparable hydrophobicity 12 as in compound 5 does not improve the antibacterial activity and generally leads to an expected two-fold reduction in MIC when the increase in MW is considered. It is noteworthy that compound 5 displays good antibacterial activity (MIC ¼ 16) against two Pseudomonas aeruginosa strains.…”

Section: Resultsmentioning

confidence: 99%

Antibacterial activity of amphiphilic tobramycin

et al. 2012

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Amphiphilic aminoglycoside antimicrobials are an emerging class of new antibacterial agents with novel modes of action. Previous studies have shown that amphiphilic neomycin-B and kanamycin-A analogs restore potent antibacterial activity against Gram-positive neomycin-B-and kanamycin-A-resistant organisms. In this paper, we investigated the antibacterial properties of a series of amphiphilic tobramycin analogs. We prepared tobramycin-lipid conjugates, as well as tobramycin-peptide triazole conjugates, and studied their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains, including isolates obtained from Canadian hospitals. Our results demonstrate that the antibacterial activity of amphiphilic tobramycin is greatly affected by the length and nature of the hydrophobic lipid tail, whereas the nature of the polycationic headgroup or the number of cationic charges appear to be less important. Replacement of the hydrophobic tail by a fluorinated lipid confers good activity against two Pseudomonas strains and reduces hemolytic activity. However, susceptibility studies in the presence of bovine serum albumin indicate that all amphiphilic tobramycin analogs are strongly protein-bound, leading to a typical four-to eight-fold increase in MIC.

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“…A new series of single chain (F-alkyl)alkylated β-D-glucopyranosides has been synthesized that has potential for the development of reverse water-in-FC emulsions for pulmonary drug delivery systems [27]. Initial biocompatibility assessment indicated low toxicity on cell cultures and lower hemolytic activity than for the hydrocarbon analogs.…”

Section: Introductionmentioning

confidence: 99%

Highly fluorinated amphiphilic molecules and self-assemblies with biomedical potential

Riess¹

2009

Current Opinion in Colloid & Interface Science

123

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Synthesis and biocompatibility evaluation of fluorinated, single-tailed glucopyranoside surfactants

Cited by 31 publications

References 53 publications

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1‐gangliosidosis and Morquio B disease

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1‐gangliosidosis and Morquio B disease

Antibacterial activity of amphiphilic tobramycin

Highly fluorinated amphiphilic molecules and self-assemblies with biomedical potential

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Synthesis and biocompatibility evaluation of fluorinated, single-tailed glucopyranoside surfactants

Cited by 31 publications

References 53 publications

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1‐gangliosidosis and Morquio B disease

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1‐gangliosidosis and Morquio B disease

Antibacterial activity of amphiphilic tobramycin

Highly fluorinated amphiphilic molecules and self-assemblies with biomedical potential

Contact Info

Product

Resources

About

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1‐gangliosidosis and Morquio B disease

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing G_M1‐gangliosidosis and Morquio B disease