Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids

Heise, Torben; Pijnenborg, Johan F. A.; Büll, Christian; Hilten, Niek van; Kers‐Rebel, Esther D.; Balneger, Natasja; Elferink, Hidde; Adema, Gosse J.; Boltje, Thomas J.

doi:10.1021/acs.jmedchem.8b01757

Cited by 60 publications

(77 citation statements)

References 32 publications

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“…To the best of our knowledge, immobilized NAL has never been used in a continuous flow setup for the preparation of synthetic Neu5Ac derivatives. Based on the broad experience with chemoenzymatic reactions in our group, both in batch and in flow systems, and on our expertise in the chemistry and biology of sialic acids, we herewith report a straightforward continuous flow system containing immobilized NAL providing a new and efficient chemoenzymatic entry into biologically relevant N ‐functionalized Neu5Ac derivatives.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to monitoring conversions, the sialic acid products 11 – 17 were also obtained in fairly reasonable isolated yields confirming the synthetic feasibility of this system (Scheme ). This includes the propargyloxycarbonyl (Poc)‐functionalized Neu5Ac derivative 16 which has been extensively used in our group and was shown to be an effective substrate in bioorthogonal glycobiology research …”

Section: Methodsmentioning

confidence: 99%

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Chemoenzymatic Synthesis of Sialic Acid Derivatives Using Immobilized N‐Acetylneuraminate Lyase in a Continuous Flow Reactor

Bloemendal¹,

Moons²,

Heming³

et al. 2019

Adv Synth Catal

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The synthesis of N‐acetylneuraminic acid (Neu5Ac) derivatives is drawing more and more attention in glycobiology research because of the important role of sialic acids in e. g. cancer, bacterial, and healthy cells. Chemical preparation of these carbohydrates typically relies on multistep synthetic procedures leading to low overall yields. Herein we report a continuous flow process involving N‐acetylneuraminate lyase (NAL) immobilized on Immobead 150P (Immobead‐NAL) to prepare Neu5Ac derivatives. Batch experiments with Immobead‐NAL showed equal activity as the native enzyme. Moreover, by using a fivefold excess of either N‐acetyl‐D‐mannosamine (ManNAc) or pyruvate the conversion and isolated yield of Neu5Ac were significantly improved. To further increase the efficiency of the process, a flow setup was designed providing a chemoenzymatic entry into a series of N‐functionalized Neu5Ac derivatives in conversions of 48–82%, and showing excellent stability over 1 week of continuous use.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Chemoenzymatic Synthesis of Sialic Acid Derivatives Using Immobilized N‐Acetylneuraminate Lyase in a Continuous Flow Reactor

Bloemendal¹,

Moons²,

Heming³

et al. 2019

Adv Synth Catal

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“…As a result, cells lost their selectin binding affinity, and leukocyte rolling was damaged. It has been recently shown that 5-carbamate derivatives of peracetylated-[3F ax ]-Neu5Ac exhibited a prolonged and increased inhibition of STs in several cell lines [ 406 ].…”

Section: Carbohydrate Processing Inhibitorsmentioning

confidence: 99%

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

2020

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Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological processes. The sialylated and fucosylated tetrasaccharide sLex is an essential glycan recognized by selectins. Several glycosyltransferases are responsible for the biosynthesis of the sLex tetrasaccharide. Selectins are involved in a sequence of interactions of circulated leukocytes with endothelial cells in the blood called the adhesion cascade. Recently, it has become evident that cancer cells utilize a similar adhesion cascade to promote metastases. However, like Dr. Jekyll and Mr. Hyde’s two faces, selectins also contribute to tissue destruction during some infections and inflammatory diseases. The most prominent function of selectins is associated with the initial stage of the leukocyte adhesion cascade, in which selectin binding enables tethering and rolling. The first adhesive event occurs through specific non-covalent interactions between selectins and their ligands, with glycans functioning as an interface between leukocytes or cancer cells and the endothelium. Targeting these interactions remains a principal strategy aimed at developing new therapies for the treatment of immune and inflammatory disorders and cancer. In this review, we will survey the significant contributions to and the current status of the understanding of the structure of selectins and the role of selectins in various biological processes. The potential of selectins and their ligands as therapeutic targets in chronic and acute inflammatory diseases and cancer will also be discussed. We will emphasize the structural characteristic of selectins and the catalytic mechanisms of glycosyltransferases involved in the biosynthesis of glycan recognition determinants. Furthermore, recent achievements in the synthesis of selectin inhibitors will be reviewed with a focus on the various strategies used for the development of glycosyltransferase inhibitors, including substrate analog inhibitors and transition state analog inhibitors, which are based on knowledge of the catalytic mechanism.

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“…Recently, Siglec-9 and Siglec-15 have been reported as crucial inhibitors of anti-tumor immunity, which can be blocked by mAbs in the novel anticancer management [103,104]. Recent advances in the field of immunotherapy suggest that targeting Siglec receptors with specific antibodies or fluorinated sialic acid analogs, called "false sialic acids," help to control autoimmunity, pathogen invasion, and malignancies [105,106].…”

Section: Cancer Progressionmentioning

confidence: 99%

Sialic Acid-Siglec Axis as Molecular Checkpoints Targeting of Immune System: Smart Players in Pathology and Conventional Therapy

Wielgat

Rogowski

Niemirowicz-Laskowska

et al. 2020

IJMS

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The sialic acid-based molecular mimicry in pathogens and malignant cells is a regulatory mechanism that leads to cross-reactivity with host antigens resulting in suppression and tolerance in the immune system. The interplay between sialoglycans and immunoregulatory Siglec receptors promotes foreign antigens hiding and immunosurveillance impairment. Therefore, molecular targeting of immune checkpoints, including sialic acid-Siglec axis, is a promising new field of inflammatory disorders and cancer therapy. However, the conventional drugs used in regular management can interfere with glycome machinery and exert a divergent effect on immune controlling systems. Here, we focus on the known effects of standard therapies on the sialoglycan-Siglec checkpoint and their importance in diagnosis, prediction, and clinical outcomes.

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Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids

Cited by 60 publications

References 32 publications

Chemoenzymatic Synthesis of Sialic Acid Derivatives Using Immobilized N‐Acetylneuraminate Lyase in a Continuous Flow Reactor

Chemoenzymatic Synthesis of Sialic Acid Derivatives Using Immobilized N‐Acetylneuraminate Lyase in a Continuous Flow Reactor

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

Sialic Acid-Siglec Axis as Molecular Checkpoints Targeting of Immune System: Smart Players in Pathology and Conventional Therapy

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