Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen

Fan, Wei; Wu, Yong; Li, Xiankun; Yao, Nian Huan; Li, Xun; Yu, Yongguo; Li, Hai

doi:10.1016/j.ejmech.2011.05.029

Cited by 38 publications

(27 citation statements)

References 24 publications

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“…Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs (DeGorter et al 2012). The frequently exploited transporters include peptide, amino acid, and glucose transporters (Fan et al 2011, Giacomini et al 2010, Gynther et al 2008.…”

Section: Introductionmentioning

confidence: 99%

Vectorization of agrochemicals: amino acid carriers are more efficient than sugar carriers to translocate phenylpyrrole conjugates in the Ricinus system

Marhadour

Lei

et al. 2016

Environ Sci Pollut Res

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Producing quality food in sufficient quantity while using less agrochemical inputs will be one of the great challenges of the twenty-first century. One way of achieving this goal is to greatly reduce the doses of plant protection compounds by improving the targeting of pests to eradicate. Therefore, we developed a vectorization strategy to confer phloem mobility to fenpiclonil, a contact fungicide from the phenylpyrrole family used as a model molecule. It consists in coupling the antifungal compound to an amino acid or a sugar, so that the resulting conjugates are handled by active nutrient transport systems. The method of click chemistry was used to synthesize three conjugates combining fenpiclonil to glucose or glutamic acid with a spacer containing a triazole ring. Systemicity tests with the Ricinus model have shown that the amino acid promoiety was clearly more favorable to phloem mobility than that of glucose. In addition, the transport of the amino acid conjugate is carrier mediated since the derivative of the L series was about five times more concentrated in the phloem sap than its counterpart of the D series. The systemicity of the L-derivative is pH dependent and almost completely inhibited by the protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP). These data suggest that the phloem transport of the L-derivative is governed by a stereospecific amino acid carrier system energized by the proton motive force.

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Section: Introductionmentioning

confidence: 99%

Vectorization of agrochemicals: amino acid carriers are more efficient than sugar carriers to translocate phenylpyrrole conjugates in the Ricinus system

Marhadour

Lei

et al. 2016

Environ Sci Pollut Res

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“…However, only a small portion of NP can penetrate into the brain which greatly limits its use in treatment of brain diseases. Many moieties like glucosyl thiamine disulfide, L-ascorbic acid, and dimethylamino have been reported to increase the NP concentration in the brain, but very few neuroprotection evaluation studies were performed using animal model [9,43,44]. Thus, to fully evaluatethe targeting approach using cyclic tertiary amine moieties, we examined the neuroprotective effect in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery

Wang

et al. 2017

Journal of Controlled Release

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Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H/OC antiporter in a pH-dependent, Na-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC and C in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H/OC antiporter.

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“…For example, profungicides, which are likely to concentrate in plant phloem tissues, can be applied to control vascular diseases that most existing fungicides are unable to access. One attractive prodrug approach is to conjugate a drug with endogenous substrates, so that the resulting molecules can be recognised and transported by peptide, amino acid or glucose transporters …”

Section: Introductionmentioning

confidence: 99%

“…Phloem systemicity dependence of the acidic derivative(9) and the L--amino acid conjugate (L-14) of fenpiclonil at apoplastic pH values (from pH 5.0 to 6.5). The thickness of each arrow is related to the concentrations of both compounds found in the phloem sap.…”

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confidence: 99%

Vectorisation of agrochemicals via amino acid carriers: influence of the spacer arm structure on the phloem mobility of phenylpyrrole conjugates in the Ricinus system

Marhadour

Yang

et al. 2017

Pest Management Science

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Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen

Cited by 38 publications

References 24 publications

Vectorization of agrochemicals: amino acid carriers are more efficient than sugar carriers to translocate phenylpyrrole conjugates in the Ricinus system

Vectorization of agrochemicals: amino acid carriers are more efficient than sugar carriers to translocate phenylpyrrole conjugates in the Ricinus system

Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery

Vectorisation of agrochemicals via amino acid carriers: influence of the spacer arm structure on the phloem mobility of phenylpyrrole conjugates in the Ricinus system

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