Synthesis of alkylated sugar amino acids: conformationally restricted l-Xaa-l-Ser/Thr mimics

Risseeuw, Martijn; Mazurek, Jarosław; Langenvelde, Arjan van; Marel, Gijsbert A. van der; Overkleeft, Herman S.; Overhand, Mark

doi:10.1039/b705750d

Cited by 22 publications

(13 citation statements)

References 31 publications

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“…Recently, creation and development of non-natural oligomeric peptide mimics, the so-called peptidomimetics, have become a field of large interest in biomedicine [3]. Examples include peptoids [4], β-peptides [5], γ- and δ-peptides [6], azapeptides [7], α-aminoxy-peptides [8], sugar-based peptides [9], α/β-peptides [10], phenylene ethynylenes [11], and AApeptides [12, 13], to name a few. By introducing unnatural backbones, these oligomers are more stable against proteolysis and are believed to have reduced immunogenicity [14].…”

Section: Introductionmentioning

confidence: 99%

Modulation of lipid membrane structural and mechanical properties by a peptidomimetic derived from reduced amide scaffold

Khadka¹,

Teng²,

Cai³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Understanding how antimicrobial peptidomimetics interact with lipid membranes is important in battling multidrug resistant bacterial pathogens. We study the effects of a recently reported peptidomimetic on lipid bilayer structural and mechanical properties. The compound referred to as E107-3 is synthesized based on the acylated reduced amide scaffold and has been shown to exhibit good antimicrobial potency. Our vesicle leakage essay indicates that the compound increases lipid bilayer permeability. We use micropipette aspiration to explore the kinetic response of giant unilamellar vesicles (GUVs). Exposure to the compound causes the GUV protrusion length LP to spontaneously increase and then decrease, followed by GUV rupture. Solution atomic force microscopy (AFM) is used to visualize lipid bilayer structural modulation within a nanoscopic regime. Unlike melittin, which produces pore-like structures, the peptidomimetic compound is found to induce nanoscopic heterogeneous structures. Finally, we use AFM-based force spectroscopy to study the impact of the compound on lipid bilayer mechanical properties. We find that incremental addition of the compound to planar lipid bilayers results in a moderate decrease of the bilayer puncture force FP and a 39% decrease of the bilayer area compressibility modulus KA. To explain our experimental data, we propose a membrane interaction model encompassing disruption of lipid chain packing and extraction of lipid molecules. The later action mode is supported by our observation of a double-bilayer structure in the presence of fusogenic calcium ions.

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Section: Introductionmentioning

confidence: 99%

Modulation of lipid membrane structural and mechanical properties by a peptidomimetic derived from reduced amide scaffold

Khadka¹,

Teng²,

Cai³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…The successful addition of ArMgBr on to 1-formyl-α-C-glucoside, and isolated report of addition onto 1-formyl--C-glucoside, [16] tempted us to use the building block 6a for the synthesis of our targeted compounds 4 and 5. Multigram quantities of building block 6a, 1-formyl--C-glucoside were prepared according to the method described by Frederic Labeguere.…”

Section: Resultsmentioning

confidence: 99%

“…Multigram quantities of building block 6a, 1-formyl--C-glucoside were prepared according to the method described by Frederic Labeguere. [17] The addition of simple alkynylmagnesium bromide and phenylmagnesium bromide at 0°C, led to the formation of corresponding addition products 7a [9] and 7b [16] along with recovery of starting material 6a (10-15 %)(entry 1 and 2 in Table 1). However, in an attempt to optimize and generalize the addition of few other Grignard reagents, extensive formation of elimination product 8 was also observed.…”

Section: Resultsmentioning

confidence: 99%

Acyl and Benzyl‐C‐β‐D‐Glucosides: Synthesis and Biostudies for Glucose‐Uptake‐Promoting Activity in C2C12 Mytotubes

et al. 2019

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A convenient and scalable synthetic approach has been developed for the synthesis of acyl‐C‐β‐d‐glucosides and benzyl‐C‐β‐d‐glucosides. The use of Weinreb‐amide (WA) functionality was crucial for this accomplishment as the other apparently capable alternatives, had severe limitations for the access to acyl‐C‐glucosides. The synthesized compounds, acyl and benzyl‐C‐glucosides promote glucose‐uptake activity in the C2C12 (mouse skeletal muscle) cell lines through PPAR‐γ mediated GLUT4 expression. The developed synthetic scheme for acyl‐and benzyl‐C‐β‐d‐glucosides and biostudies evaluating their activity as glucose‐uptake promoters are disclosed herein.

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“…With this background we envisaged exploring compounds 108/109, wherein the kojic acid unit present in 187 and 188 has been replaced by non- The synthesis of acyl and benzyl C-β-D-Glucosides 108 and 109, respectively was visualized through the simple addition of arylmagnesium bromides onto C-1 functionalized building blocks 115/189(Figure 22). Few reports of successful addition onto 1-formyl-α-C-glucoside [115] and 1-formyl-β-Cglucoside 115 [116] was inspiring. However, our attempts to generalize and optimize the addition of arylmagnesium bromides (beyond phenylmagnesium bromide) were plagued with extensive formation of the elimination product 191 and purification difficulties.…”

Section: C-glucosides As Glucose Uptake Promotersmentioning

confidence: 99%

Natural Products & Bioactivity Inspired Synthetic Pursuits Interfacing with Carbohydrates: Ongoing Journey with C‐Glycosides

Aidhen

Thoti

2021

The Chemical Record

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Natural products, remains the most important source for the discovery of new drugs for the treatment of human diseases. This has inspired the synthetic community to design and develop mimics of natural products either to answer important questions in biology or to explore their therapeutic potentials. Glycosides present themselves abundantly in nature, right from the cell surface receptors to natural products of any origin. The O-Glycosides are hydrolytically less stable compared to C-glycosides and this feature has presented a great opportunity for drug discovery. The discovery of Dapagliflozin, an SGLT inhibitor and C-glucoside, for the treatment of diabetes is one such example. Aryl acyl-anion chemistry has been explored for the synthesis of 2-deoxy-C-aryl furanoside/pyranoside/septanosides. Besides success, the studies have provided valuable insight into the natural propensities of the architectural framework for the cascade to furan derivatives. The aryl acyl-anion chemistry has also enabled the synthesis of biologically active diaryl heptanoids. Inspired from sucesss of Dapagliflozin, new analogues have been synthesized with pyridine and isocoumarin heterocycle as the proximal ring. C-glucosides of isoliquiritigenin have been synthesized for the first time and evaluated as an efficient aldose reductase inhibitor. The synthesis and evaluation of acyl-C-β-D-glucosides and benzyl-C-β-Dglucoside as glucose-uptake promoters has revealed promise in small molecules. The concept of building blocks has been used to obtain natural oxylipins, D-xylo and L-xylo-configured alkane tetrols and novel lipophilic ketones with erythro/threo configured trihydroxy polar head-group as possible anti-mycobacterial agents.

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Synthesis of alkylated sugar amino acids: conformationally restricted l-Xaa-l-Ser/Thr mimics

Cited by 22 publications

References 31 publications

Modulation of lipid membrane structural and mechanical properties by a peptidomimetic derived from reduced amide scaffold

Modulation of lipid membrane structural and mechanical properties by a peptidomimetic derived from reduced amide scaffold

Acyl and Benzyl‐C‐β‐D‐Glucosides: Synthesis and Biostudies for Glucose‐Uptake‐Promoting Activity in C2C12 Mytotubes

Natural Products & Bioactivity Inspired Synthetic Pursuits Interfacing with Carbohydrates: Ongoing Journey with C‐Glycosides

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