Synthesis and Biological Evaluation of Antifungal Activities of Novel 1,2‐<i>trans</i> Glycosphingolipids

Ding, Ning; Zhang, Wei; Lv, Guokai; Li, Yingxia

doi:10.1002/ardp.201000335

Cited by 6 publications

(2 citation statements)

References 18 publications

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“…A series of analogues of the natural CST substrate galactocerebroside with variations in the galactose moiety (α- and β-glycosides, substitution of the sugar moiety), in the hydroxylated alkyl chain, and in the fatty acid residue was designed and synthesised. β-KRN7000 21 and α-glycosides 11 , 13 – 16 and 18 – 21 were prepared as previously described. 22–27 The synthetic route to obtain α-galactosylceramides 12 , 17 and 22 is depicted in Scheme 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the a-galactoside anomer of compound 10, KRN7000 (18) showed about the same conversion rate and K m value indicating that for this series of more polar, hydrated sphingosine-derived synthetic lipids, the enzyme did not discriminate between aand b-glycosidic configuration. Thus, we investigated further a-galactosyl-lipids (11)(12)(13)(14)(15)(16)(17)(19)(20)(21)(22) derived from KRN7000 (18) mainly with modification of the fatty acid residue. KRN7000 (18) had previously been found to display immunostimulatory and antitumor activity in several in vivo models, and was advanced to clinical trials [29][30][31] .…”

Section: Substratesmentioning

confidence: 99%

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Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor

Guillaume²,

Wachsmann

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A leading to the lysosomal accumulation of cerebroside sulphate (sulphatide) causing subsequent demyelination in patients. The enzyme galactosylceramide (cerebroside) sulphotransferase (CST) catalyses the transfer of a sulphate group from 3 0-phosphoadenosine-5'-phosphosulphate (PAPS) to cerebrosides producing sulphatides. Substrate reduction therapy for arylsulphatase A by inhibition of CST was proposed as a promising therapeutic approach. To identify competitive CST inhibitors, we synthesised and investigated analogues of the substrate galactosylceramide with variations at the anomeric position, the acyl substituent and the carbohydrate moiety, and investigated their structure-activity relationships. While most of the compounds behaved as substrates, a-galactosylceramide 16 was identified as the first competitive CST inhibitor. Compound 16 can serve as a new lead structure for the development of drugs for the treatment of this devastating disease, MLD, for which small molecule therapeutics are currently not available.

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Section: Resultsmentioning

confidence: 99%

Section: Substratesmentioning

confidence: 99%

Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor

Guillaume²,

Wachsmann

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Arginolipid: A membrane‐active antifungal agent and its synergistic potential to combat drug resistance in clinical Candida isolates

Patil

Wanjare²,

Borse

et al. 2019

Archiv der Pharmazie

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Antifungal drug resistance exhibits a major clinical challenge for treating nosocomial fungal infections. To find a possible solution, we synthesized and studied the antifungal activities of three different arginolipids (Nα‐acyl‐arginine ethyl ester) against clinical drug‐resistant isolates of Candida. The most active arginolipid, oleoyl arginine ethyl ester (OAEE) consisting of a long unsaturated hydrophobic chain, was tested for its mode of action, which revealed that it altered ergosterol biosynthesis and compromised the fungal cell membrane. Also, OAEE was found to exhibit synergistic interactions with fluconazole (FLU) or amphotericin B (AmB) against planktonic Candida cells, wherein it reduced the inhibitory concentrations of these drugs to their in vitro susceptible range. Studies conducted against the C. tropicalis biofilm revealed that the OAEE+AmB combination synergistically reduced the metabolic activity and hyphal density in biofilms, whereas OAEE+FLU was found to be additive against most cases. Finally, the evaluated selective toxicity of OAEE toward fungal cells over mammalian cells could establish it as an alternative treatment for combating drug‐resistant Candida infections.

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ChemInform Abstract: Synthesis and Biological Evaluation of Antifungal Activities of Novel 1,2‐trans Glycosphingolipids.

Ding

Zhang

et al. 2012

ChemInform

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Synthesis and Biological Evaluation of Antifungal Activities of Novel 1,2‐trans Glycosphingolipids

Cited by 6 publications

References 18 publications

Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor

Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor

Arginolipid: A membrane‐active antifungal agent and its synergistic potential to combat drug resistance in clinical Candida isolates

ChemInform Abstract: Synthesis and Biological Evaluation of Antifungal Activities of Novel 1,2‐trans Glycosphingolipids.

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