Sialyltransferase inhibitors: consideration of molecular shape and charge/hydrophobic interactions

Kumar, Ranjeet; Ravindranath, N.; Bhasin, Milan; Khieu, Nam Huan; Hsieh, Margaret; Gilbert, Michel; Jarrell, Harold C.; Zou, Wei; Jennings, Harold J.

doi:10.1016/j.carres.2012.12.017

Cited by 29 publications

(33 citation statements)

References 48 publications

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“…To address whether non-charged CMP-Neu5Ac can be effective competitive inhibitors to sialyltransferase, Zou and Jennings designed a library of CMP-Neu5Ac analogs with a non-charged linkers replaced with a nonionic triazole moiety (compounds 9, 10) ( Table 2) [28]. These mimics still contain both the sialic acid and cytidine residues responsible for binding to the sialyltransferase active site.…”

Section: Cmp-sialic Acid Analogsmentioning

confidence: 99%

“…These results indicated that increasing hydrophobicity of a molecule may improve its binding. As they pointed out, the better way to improve the bioavailability of a sialyltransferase inhibitor is not to eliminate the charge, but rather to temporary mask the charge and make a pro-inhibitor [28].…”

Section: Cmp-sialic Acid Analogsmentioning

confidence: 99%

“…However, these inhibitors all may have poor permeability across cell membranes and their bioavailability may be lower and thus their clinical applications are relatively limited. So far, few ST inhibitors with a cell-permeable property have been reported [21,28]. Chang's group designed and synthesized 16 lithocholic acid analogs (82-100) ( Table 7), which employed a steroidal moiety to improve their uptake, and demonstrated to be noncompetitive inhibitors of α2,3-sialyltransferase (α2, in the presence of CMP-Neu5Ac [45].…”

Section: Lithocholic Acid Analogsmentioning

confidence: 99%

“…Inhibition of enzyme: α2,6-STs (Ref: [28]) Inhibition of enzyme: α2,6-STs (Ref: [29]) Inhibition of enzyme: α2,6-STs (Ref: [29] 101 was cell-permeable and effectively attenuates total sialylation on cell surface. Interestingly, this inhibitor compound had no cytotoxicity but inhibited adhesion, migration, actin polymerization and invasion of α2,3-ST-overexpressing A549 and CL1.5 human lung cells.…”

Section: Lithocholic Acid Analogsmentioning

confidence: 99%

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Sialyltransferase inhibition and recent advances

Wang

Liu

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Sialic acids, existing as terminal sugars of glycoconjugates, play important roles in various physiological and pathological processes, such as cell-cell adhesion, immune defense, tumor cell metastasis, and inflammation. Sialyltransferases (STs) catalyze the transfer of sialic acid residues to non-reducing oligosaccharide chains of proteins and lipids, using cytidine monophosphate N-acetylneuraminic acid (CMP-Neu5Ac) as the donor. Elevated sialyltransferase activity leads to overexpression of cell surface sialic acids and contributes to many disease developments, such as cancer and inflammation. Therefore, sialyltransferases are considered as potential drug targets for disease treatment. Inhibitors of sialyltransferases thus are of medicinal interest, especially for the cancer therapy. In addition, sialyltransferase inhibitors are useful tool to study sialyltransferase function and related mechanisms. This review highlights recent development of inhibitors of sialyltransferases reported since 2004. The inhibitors are summarized as eight groups: 1) sialic acid analogs, 2) CMP-sialic acid analogs, 3) cytidine analogs, 4) oligosaccharide derivatives, 5) aromatic compounds, 6) flavonoids, 7) lithocholic acid analogs, and 8) others. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions.

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Section: Cmp-sialic Acid Analogsmentioning

confidence: 99%

Section: Cmp-sialic Acid Analogsmentioning

confidence: 99%

Section: Lithocholic Acid Analogsmentioning

confidence: 99%

Section: Lithocholic Acid Analogsmentioning

confidence: 99%

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Sialyltransferase inhibition and recent advances

Wang

Liu

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…In this study, to produce potent ST inhibitors that are readily accessible and with favourable pharmacokinetic properties, the replacement of the charged phosphodiester‐linker of the lead compound 2 with a neutral‐linker, such as a rigid 1,2,3‐triazole or a flexible carbamate, has been investigated. The 1,2,3‐triazole motif is a suitable choice as it has previously been shown to be an applicable phosphodiester isostere in transition‐state analogue ST inhibitors (Lee et al, ; Kumar et al, ), as well as being used as isosteres of pyrophosphate‐linkers (Chen et al, ) and phosphodiester‐linkers of oligonucleotides (El‐Sagheer and Brown, ). To date, there are a paucity of examples of carbamates being used as isosteres of phosphodiesters.…”

Section: Introductionmentioning

confidence: 99%

Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design

et al. 2015

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Human β-galactoside α-2,6-sialyltransferase I (hST6Gal I) catalyses the synthesis of sialylated glycoconjugates involved in cell-cell interactions. Overexpression of hST6Gal I is observed in many different types of cancers, where it promotes metastasis through altered cell surface sialylation. A wide range of sialyltransferase (ST) inhibitors have been developed based on the natural donor, cytidine 5′-monophosphate N-acetylneuraminic acid (CMP-Neu5Ac). Of these, analogues that are structurally similar to the transition state exhibit the highest inhibitory activity. In order to design inhibitors that are readily accessible synthetically and with favourable pharmacokinetic properties, an investigation of the replacement of the charged phosphodiesterlinker, present in many ST inhibitors, with a potential neutral isostere such as a carbamate or a 1,2,3-triazole has been undertaken. To investigate this, molecular docking and molecular dynamics simulations were performed. These simulations provided an insight into the binding mode of previously reported phosphodiester-linked ST inhibitors and demonstrated that targeting the proposed sialyl acceptor site is a viable option for producing selective inhibitors. The potential for a carbamate-or triazole-linker as an isosteric replacement for the phosphodiester in transition-state analogue ST inhibitors was established using molecular docking. Molecular dynamics simulations of carbamate-and phosphodiester-linked compounds revealed that both classes exhibit consistent interactions with hST6Gal I. Overall, the results obtained from this study provide a rationale for synthetic and biological evaluation of triazole-and carbamate-linked transition-state analogue ST inhibitors as potential new antimetastatic agents. Disciplines Medicine and Health Sciences | Social and Behavioral SciencesPublication Details Montgomery, A., Szabo, R., Skropeta, D. & Yu, H. (2016)

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Synthesis of Diverse Carbohydrate‐Based Molecules using Click Chemistry

Singh

Mishra

et al. 2016

Click Reactions in Organic Synthesis

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Sialyltransferase inhibitors: consideration of molecular shape and charge/hydrophobic interactions

Cited by 29 publications

References 48 publications

Sialyltransferase inhibition and recent advances

Sialyltransferase inhibition and recent advances

Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design

Synthesis of Diverse Carbohydrate‐Based Molecules using Click Chemistry

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