Characterization of inhibitory activities and binding mode of synthetic 6′-modified methyl N-acetyl-β-lactosaminide toward rat liver CMP-d-Neu5Ac: d-galactoside-(2 → 6)-α-d-sialyltransferase

Kajihara, Yasuhiro; Kodama, Hisashi; Wakabayashi, Tomio; Sato, Kenichi; Hashimoto, H.

doi:10.1016/0008-6215(93)84251-z

Cited by 39 publications

(10 citation statements)

References 11 publications

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“…Some have sufficiently low Km values that they compete with glycoprotein substrates and act as competitive inhibitors with Ki values in the micromolar to millimolar range. Specific modifications to the sugar residues can preclude their function as an acceptor, but some continue to bind at the active site of the target enzyme and block its activity (Palcic et al, 1990;Hindsgaul et al, 1991;Kajihara et al, 1992Kajihara et al, , 1993Khan et al, 1993;Lowary & Hindsgaul, 1993, 1994Reck et al, 1994;Helland et al, 1995;Paulsen et al, 1995;Reck et al, 1995;Lu et al, 1997). In theory, these compounds could act in intact cells, by flooding the Golgi with alternate substrates.…”

Section: Nucleotide Sugar and Acceptor Analogsmentioning

confidence: 96%

“…Hindsgaul and others have synthesized a number of compounds that target specific glycosyltransferases in vitro (Hindsgaul, 1991;Hindsgaul et al, 1991;Kajihara et al, 1992;Kajihara et al, 1993;Khan et al, 1993;Lowary & Hindsgaul, 1993;Helland et al, 1995;Paulsen et al, 1995;Lu et al, 1997;Chung et al, 1998;Laferte et al, 2000;Mukherjee et al, 2000;Brockhausen et al, 2005;Westerlind et al, 2005;Brockhausen et al, 2006). Bisubstrate analogs have also been prepared consisting of the nucleotide donor covalently attached to the acceptor substrate by way of a neutral bridging group (Palcic et al, 1989;Hashimoto et al, 1997;Takayama et al, 1999;Mitchell et al, 2002;Schwörer & Schmidt, 2002;Hinou et al, 2003;Skropeta et al, 2003;Izumi et al, 2005;Izumi et al, 2006).…”

Section: Acceptor Analogsmentioning

confidence: 97%

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Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Brown¹,

Crawford²

2007

Critical Reviews in Biochemistry and Molecular Biology

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Glycans, the carbohydrate chains of glycoproteins, proteoglycans, and glycolipids, represent a relatively unexploited area for drug development compared with other macromolecules. This review describes the major classes of glycans synthesized by animal cells, their mode of assembly, and available inhibitors for blocking their biosynthesis and function. Many of these agents have proven useful for studying the biological activities of glycans in isolated cells, during embryological development, and in physiology. Some are being used to develop drugs for treating metabolic disorders, cancer, and infection, suggesting that glycans are excellent targets for future drug development.

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Section: Nucleotide Sugar and Acceptor Analogsmentioning

confidence: 96%

Section: Acceptor Analogsmentioning

confidence: 97%

Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Brown¹,

Crawford²

2007

Critical Reviews in Biochemistry and Molecular Biology

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“…N ‐acetyl‐β‐lactosamide has been modified at the 6‐position of the galactose residue, including deoxy ( 28 ), mercapto ( 29 ), O ‐THP ( 30 ), and dissulfide ( 31 ) groups. These compounds afforded modest inhibitory activity against rST6Gal I ( K i = 0.76–4.14 mM) and revealed that the 6’‐OH group is not essential for substrate binding . Okazaki et al.…”

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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“…The Hashimoto group synthesized several analogues of methyl N-acetyl-β-lactosaminide from lactose, and identified the 6′-deoxy analogue as the first acceptor-analogue inhibitor with remarkable inhibitory activity toward α-2,6-sialyltransferases [ 139 ]. Okazaki et al also described a series of carba-oligosaccharides possessing a similar structure to the three-dimensional conformation of natural activated oligosaccharides, but unable to be metabolized by glycosidases [ 140 ].…”

Section: Sialyltransferase Inhibitorsmentioning

confidence: 99%

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Pietrobono¹,

Stecca²

2021

Cancers

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Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments.

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Characterization of inhibitory activities and binding mode of synthetic 6′-modified methyl N-acetyl-β-lactosaminide toward rat liver CMP-d-Neu5Ac: d-galactoside-(2 → 6)-α-d-sialyltransferase

Cited by 39 publications

References 11 publications

Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Advancement of Sialyltransferase Inhibitors: Therapeutic Challenges and Opportunities

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

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