Synthesis of symmetrical 4,4′- and 6,6′- bis(D-glucose)-based probes as tools for the study of D-glucose transport proteins

Abbadi, Mehdi; Holman, Geoffrey D.; Morin, Christophe; Rees, William D.; Yang, Jing

doi:10.1016/s0040-4039(99)01241-1

Cited by 14 publications

(7 citation statements)

References 24 publications

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“…The 4‐OH position has been found to most useful for derivatisation with photoreactive groups as there is good tolerance of bulky groups at this position 21. We have therefore synthesised a series of compounds starting from the glucose acetal compound 13 (Scheme ) 22.…”

Section: Resultsmentioning

confidence: 99%

Cell-Surface Recognition of Biotinylated Membrane Proteins Requires Very Long Spacer Arms: An Example from Glucose-Transporter Probes

2001

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Glucose transporters (GLUTs) can be photoaffinity labelled by (diazirinetrifluoroethyl)benzoyl-substituted glucose derivatives and the adduct can be recognised, after detergent solubilisation of membranes, by using streptavidin-based detection systems. However, in intact cells recognition of photolabelled GLUTs by avidin and anti-biotin antibodies only occurs if the bridge between the photoreactive and the biotin moieties has a minimum of 60--70 spacer atoms. We show that a suitably long bridge can be synthesised with a combination of polyethylene glycol and tartarate groups and that introduction of these spacers generates hydrophilic products that can be cleaved with periodate. Introduction of the very long spacers does not appreciably reduce the affinity of interaction of the probes with the transport system.

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Section: Resultsmentioning

confidence: 99%

Cell-Surface Recognition of Biotinylated Membrane Proteins Requires Very Long Spacer Arms: An Example from Glucose-Transporter Probes

2001

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“…5,6) This information, combined with the possibility that introducing such ring substituents may also increase the rate of activation of the derivatives in response to UV irradiation, prompted us to synthesize and examine new bis-glucose compounds in which nitro and iodo groups were substituted into the aromatic ring of 3-phenyl-3-trifluoromethyldiazirine photophore. * To whom correspondence should be addressed.…”

Section: )mentioning

confidence: 99%

“…10) Compounds 4 and 5 therefore have higher affinities for GLUT4 confirming that introduction of nitro-and iodo groups into GLUT4 ligands lead to tighter binding. 5,6) The iodide group is one of the most common radioisotopes and very useful to detect the labeled components. We have previously established that introduction of radioisotopic iodine on 3-(trifluoromethyl) aryldiazirine is possible.…”

Section: )mentioning

confidence: 99%

“…The requirements for a GLUT4 tag are opposite to these and high affinity interaction is required in a photolabel as the ligand/protein complex has to be occupied at a high enough level to be efficiently converted to a covalent complex following UV irradiation. 5) We have developed a series of photoaffinity probes based on bis-hexose structures. 6) These compounds contain hexoses linked via their 4-OH positions to a propyl-2-amine spacer.…”

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Improvement in the Properties of 3-Phenyl-3-trifluoromethyldiazirine Based Photoreactive Bis-Glucose Probes for GLUT4 Following Substitution on the Phenyl Ring.

Hashimoto

Yang

Hatanaka

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recent human genome sequencing has led to the realisation that the family of facilitative sugar transporters (GLUTs: glucose transporters) in mammals is more extensive than the group of five members (GLUTs 1-5) described a decade ago. Now the GLUTs are known to be a more complex family of thirteen isomeric proteins that is divisible into three subgroups based on sequence similarities. 1) Class 1 consists of the glucose transporters (GLUTs 1-4) which preferentially transport D-glucose. 2) Of these transporters GLUT4 is particularly important both in physiological and pathophysiological processes as it is present only in insulin-responsive tissues such as adipose, heart and skeletal muscle. Following insulin signaling, there is an increase in GLUT4 exocytosis from intracellular storage vesicles and incorporation of the protein into the surface membrane of the insulin target cells. 3) Loss of responsiveness of this protein to insulin is one of the contributing factors to the pathogenesis of Type 2 diabetes. 4) To effectively examine the mechanisms involved in exposure of GLUT4 at the cell surface of adipocytes, high affinity analogues that can tag the transporter are required. Synthesizing suitable analogues is a difficult task since sugars have relatively low affinity for the transporter molecules. D-Glucose for example, when interacting with GLUT4, does so with an affinity constant (K m ) of around 8 mM. Physiologically the high K m is important as if the affinity for D-glucose were very high then this substrate would bind very strongly to the transporter rather than being transported through it. In addition, blood glucose levels are generally 5 mM (or slightly higher following a carbohydrate rich meal) and therefore a high affinity (low K m ) system would become too easily saturated and unable to respond to the fluctuations in circulating blood glucose levels. The requirements for a GLUT4 tag are opposite to these and high affinity interaction is required in a photolabel as the ligand/protein complex has to be occupied at a high enough level to be efficiently converted to a covalent complex following UV irradiation. 5) We have developed a series of photoaffinity probes based on bis-hexose structures. 6) These compounds contain hexoses linked via their 4-OH positions to a propyl-2-amine spacer. Because the bis-hexose structure renders the compounds large and hydrophilic the derivatives are impermeant and just probe those glucose transporters (GLUT4) that appear at the cell-surface in response to insulin. We have already synthesized photoreactive bis-mannose derivatives containing arylazide, 7) benzophenone 8) and 3-phenyl-3-trifluoromethyldiazirine 9) substitutions for use in glucose transporter cell surface labeling. Recently, we have synthesized photoreactive bis-glucose derivatives containing the 3-phenyl-3-trifluoromethyldiazirine group. 10) These can easily be synthesised preparative scale and have slightly higher affinity for GLUT4 than the equivalent bis-mannose compounds.Arylazide ligands were found to b...

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“…The 4-OH position has been found to most useful for derivatisation with photoreactive groups as there is good tolerance of bulky groups at this position. [21] We have therefore synthesised a series of compounds starting from the glucose acetal compound 13 (Scheme 3). [22] Allylation of 13 with allyl bromide and sodium hydride gave 14 in quantitative yield.…”

Section: Synthesis Of Hexose Photolabelsmentioning

confidence: 99%

Cell-Surface Recognition of Biotinylated Membrane Proteins Requires Very Long Spacer Arms: An Example from Glucose-Transporter Probes

2001

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Synthesis of symmetrical 4,4′- and 6,6′- bis(D-glucose)-based probes as tools for the study of D-glucose transport proteins

Cited by 14 publications

References 24 publications

Cell-Surface Recognition of Biotinylated Membrane Proteins Requires Very Long Spacer Arms: An Example from Glucose-Transporter Probes

Cell-Surface Recognition of Biotinylated Membrane Proteins Requires Very Long Spacer Arms: An Example from Glucose-Transporter Probes

Improvement in the Properties of 3-Phenyl-3-trifluoromethyldiazirine Based Photoreactive Bis-Glucose Probes for GLUT4 Following Substitution on the Phenyl Ring.

Cell-Surface Recognition of Biotinylated Membrane Proteins Requires Very Long Spacer Arms: An Example from Glucose-Transporter Probes

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