Synthesis of a new transition-state analog of the sialyl donor. Inhibition of sialyltransferases

Sun, Hongbin; Yang, Jia-Zhen; Amaral, Katie E.; Horenstein, Benjamin A.

doi:10.1016/s0040-4039(01)00204-0

Cited by 31 publications

(11 citation statements)

References 21 publications

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“…Compound 139 was found to be a more effective inhibitor (30% inhibition at 21 mM) of GM3 a(2-8)sialyltransferase (GD3 synthase), but the selectivity was not high. The bicyclic transition state analogue 134, already discussed (Section 23.3.1) as an inhibitor of a(2-6)sialyltransferase, was found to be a more potent inhibitor (K i = 10 lM) of a(2-3)sialyltransferase [192]. Inhibitory activity in the same range was determined [180] for the two epimers of the hydroxy phosphonate derivative 136 a (K i = 15/22 lM), already discussed (see Section 23.3.1) as very good inhibitors of a(2-6)sialyltransferase.…”

Section: Glycosyltransferases Utilizing Nmp-sugar Donorsmentioning

confidence: 82%

“…In this case, derivative 132 with the unnatural side chain at C-6 exhibited less inhibition activity (K i = 2.4/ 3.5 lM) [191]. An approach applying a completely different framework was also reported [192]; the bicyclic compound 134 (diastereoisomeric mixture), in which the CMP and the carboxylate group are not connected through a short bridge, exhibited good inhibition activity (K i = 20 lM). The transition state analogues containing carbocyclic or pyran rings with at least one double bond (Scheme 23.33), especially compounds 126 and 129-133, are the most active inhibitors of a(2-6)sialyltransferase yet found; their inhibition constants (K i = 0.03-0.06 lM) represent a 1000-fold higher affinity for the enzyme than the donor substrate (CMP-Neu5Ac, K M = 46 lM).…”

Section: Glycosyltransferases Utilizing Nmp-sugar Donorsmentioning

confidence: 90%

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Glycosyltransferase Inhibitors

Jung¹,

Schmidt²

2003

Carbohydrate‐Based Drug Discovery

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Section: Glycosyltransferases Utilizing Nmp-sugar Donorsmentioning

confidence: 82%

Section: Glycosyltransferases Utilizing Nmp-sugar Donorsmentioning

confidence: 90%

Glycosyltransferase Inhibitors

Jung¹,

Schmidt²

2003

Carbohydrate‐Based Drug Discovery

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“…Unfortunately, the K i values against ST3 were not reported. The elongation of the C1-O glycosidic bond by adding a single methylene group between the anomeric carbon and the phosphate oxygen gave TSAI against ST3 with K i = 10–20 μM [ 454 ]. The same approach was used to prepare TSAIs against FucT [ 455 ].…”

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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“…In analogy to some inhibitors mimicking the transition‐state bearing a bicyclo[3.1.0]hex‐2‐ene moiety first described by Sun, Niwayama et al. developed diacid derivatives .…”

Section: Sialyltransferase Inhibitorsmentioning

confidence: 99%

Advancement of Sialyltransferase Inhibitors: Therapeutic Challenges and Opportunities

Szabo

Skropeta

2016

Medicinal Research Reviews

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Hypersialylation of tumor cell surface proteins along with a marked upregulation of sialyltransferase (ST) activity is a well-established hallmark of cancer. Due to the critical role of STs in tumor growth and progression, ST inhibition has emerged as a potential new antimetastatic strategy for a range of cancers including pancreatic and ovarian. Human STs are divided into subtypes based on their linkage and acceptor molecule, with each subtype controlling the synthesis of specific sialylated structures with unique biological roles. This has important implications for inhibitor development, as STs also play significant roles in immune responses, inflammation, viral infection, and neurological disorders. Thus, the current goal in order to advance to the clinic is the development of subtype selective, cell-permeable and synthetically accessible, smallmolecule ST inhibitors. Herein is a comprehensive review of the latest developments in ST inhibitors from design, Nature, and high-throughput screening, addressing both the challenges and opportunities in targeting cell surface sialylation. The review features an overview of the biological evaluation methods, computational and imaging tools, inhibitor molecular diversity, and selectivity toward ST subtypes, along with the emerging role of ST inhibitors as diagnostic tools for disease imaging.

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Synthesis of a new transition-state analog of the sialyl donor. Inhibition of sialyltransferases

Cited by 31 publications

References 21 publications

Glycosyltransferase Inhibitors

Glycosyltransferase Inhibitors

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

Advancement of Sialyltransferase Inhibitors: Therapeutic Challenges and Opportunities

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