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Bleicher, Lana; Bleicher, Taís

doi:10.7476/9788523220051

Cited by 2 publications

(3 citation statements)

References 7 publications

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“…However, cerebrosides are also reported to have neuroprotective activity such that increasing cerebroside levels by altering the de novo synthesis pathway of sphingolipids leads to deactivation of downstream apoptosis signaling pathways. 7,8 These results of different cerebroside levels reflect an incomplete understanding of the physiological roles of cerebrosides. A more complete understanding of this sphingolipid subclass will likely require both differentiation and quantification of the diastereomers in biological milieu.…”

Section: Introductionmentioning

confidence: 99%

Differentiation and Quantification of Diastereomeric Pairs of Glycosphingolipids Using Gas-Phase Ion Chemistry

Chao

McLuckey

2020

Anal. Chem.

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Glycosphingolipids (GSLs), including lyso-glycosphingolipids (lyso-GSLs) and cerebrosides (HexCer), constitute a sphingolipid subclass. The diastereomerism between their monosaccharide head groups, glucose and galactose in mammalian cells, gives rise to an analytical challenge in the differentiation of their biological roles in healthy and disease states. Shotgun tandem mass spectrometry has been demonstrated to be a powerful tool in lipidomics analysis, in which the differentiation of diastereomeric pairs of GSLs could be achieved with offline chemical modifications. However, the limited number of standards, as well as the lack in comprehensive coverage of the GSLs, complicates the qualitative and quantitative analysis of GSLs. In this work, we describe a novel strategy that couples shotgun tandem mass spectrometry with gas-phase ion chemistry to achieve both differentiation and quantification of the diastereomeric pairs of GSLs. In brief, deprotonated GSL anions, [GSL − H] − , and terpyridine-magnesium complex dications, [Mg(Terpy) 2 ] 2+ , are sequentially injected and mutually stored in a linear ion trap to form chargeinverted complex cations, [GSL -H + MgTerpy] + . Collision-induced dissociation of the chargeinverted complex cations leads to significant spectral differences between the diastereomeric pairs of GSLs, which permits their distinction. Moreover, we describe a relative quantification strategy with the normalized %Area extracted from selected diagnostic ions in binary mixtures. Analytical performance with the selected pure-component pairs, lyso-GSLs and HexCer(d18:1/18:0), were also evaluated in terms of accuracy, repeatability, and inter-day precision. The pure-components could be extended to different fatty acyl chains on cerebrosides with limited error, which allows for the relative quantitation of the diastereomeric pairs without all standards. We successfully applied the presented method to identify and quantify, on a relative basis, the GSLs in commercially available total cerebroside extracts from the porcine brain.

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Section: Introductionmentioning

confidence: 99%

Differentiation and Quantification of Diastereomeric Pairs of Glycosphingolipids Using Gas-Phase Ion Chemistry

Chao

McLuckey

2020

Anal. Chem.

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“…Hence a productive discussion of molecular diversity is contingent upon choice of meaningful molecular descriptors. 10 In this Perspective, we emphasize molecular descriptors that differentiate NP space from synthetic collections.…”

Section: Introductionmentioning

confidence: 99%

“…11a If a lead possesses poor physicochemical properties, its optimization begins from a disadvantaged starting point. Falling into this 'local minimum' can prove costly: on average, only small changes occur during optimization between lead and drug candidate, 10 and failure in clinical trials is expensive. On the other hand, if a lead is structurally advantaged but synthetically intractable, its quick advance through medicinal chemistry optimization is unlikely.…”

Section: Introductionmentioning

confidence: 99%

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Huffman

Shenvi

2019

J. Am. Chem. Soc.

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Drugs are discovered through the biological screening of collections of compounds, followed by optimization toward functional endpoints. The properties of screening collections are often balanced between diversity, physicochemical favorability, intrinsic complexity and synthetic tractability. 1 Whereas natural product (NP) collections excel in the first three attributes, NPs suffer a disadvantage on the last point. Academic total synthesis research has worked to solve this problem by devising syntheses of NP leads, diversifying late-stage intermediates or derivatizing the NP target. This work has led to the discovery of reaction mechanisms, the invention of new methods and the development of FDA-approved drugs. Few drugs, however, are themselves NPs; instead NP-analogs predominate. Here we highlight past examples of NP analog development and successful NP-derived drugs. More recently, chemists have explored how NP analogs alter the retrosynthetic analysis of complex scaffolds, merging structural design and synthetic design. This strategy maintains the intrinsic complexity of the NP but can alter the physicochemical properties of the scaffold, like core instability that renders the NP a poor chemotype. Focused libraries based on these syntheses may exclude the NP but maintain the molecular properties that distinguish NPspace from synthetic space, 2 properties that have statistical advantages in clinical progression. 3,4 Research that expedites synthetic access to NP-motifs can prevent homogeneity of chemical matter available for lead discovery. Easily accessed, focused libraries of NP scaffolds can fill empty but active gaps in screening sets and expand the molecular diversity of synthetic collections.

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Saúde para todos, já!

Cited by 2 publications

References 7 publications

Differentiation and Quantification of Diastereomeric Pairs of Glycosphingolipids Using Gas-Phase Ion Chemistry

Differentiation and Quantification of Diastereomeric Pairs of Glycosphingolipids Using Gas-Phase Ion Chemistry

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

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