Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors

Dobie, Christopher; Montgomery, Andrew P.; Szabo, Rémi; Yu, Haibo; Skropeta, Danielle

doi:10.1039/d1md00079a

Cited by 4 publications

(1 citation statement)

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“…1,2,3-Triazole as one of the most important classes of nitrogen-containing heterocycle exhibits potent anticancer activity 6 . 1,2,3-triazole-benzoxazole hybrid 1 ( Figure 1 ) displayed antiproliferative activity against SKBr3, HepG2, and HeLa cells with IC 50 values of 7.1, 11.2, and 6.8 μg/mL 7 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer

Qin

Bai

Yan

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 1,2,3-triazole analogues as novel fat mass and obesity-associated protein (FTO) inhibitors were synthesised in this study. Among all 1,2,3-triazoles, compound C6 exhibited the most robust inhibition of FTO with an IC 50 value of 780 nM. It displayed the potent antiproliferative activity against KYSE-150, KYSE-270, TE-1, KYSE-510, and EC109 cell lines with IC 50 value of 2.17, 1.35, 0.95, 4.15, and 0.83 μM, respectively. In addition, C6 arrested the cell cycle at G2 phase against TE-1 and EC109 cells in a concentration-dependent manner. Analysis of cellular mechanisms demonstrated that C6 concentration-dependently regulated epithelial mesenchymal transition (EMT) pathway and PI3K/AKT pathway against TE-1 and EC109 cells. Molecular docking studies that C6 formed important hydrogen-bond interaction with Lys107, Asn110, Tyr108, and Leu109 of FTO. These findings suggested that C6 as a novel FTO inhibitor and orally antitumor agent deserves further investigation to treat esophageal cancer.

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Section: Introductionmentioning

confidence: 99%

Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer

Qin

Bai

Yan

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Synthesis of α‐Hydroxy‐1,2,3‐Triazole‐linked Sialyltransferase Inhibitors and Evaluation of Selectivity Towards ST3GAL1, ST6GAL1 and ST8SIA2

Szabo,

Dobie,

Montgomery

et al. 2024

ChemMedChem

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Tumour‐derived sialoglycans, bearing the charged nonulosonic sugar sialic acid at their termini, play a critical role in tumour cell adhesion and invasion, as well as evading cell death and immune surveillance. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans, are highly upregulated in cancer, with tumour hypersialylation strongly correlated with tumour growth, metastasis and drug resistance. As a result, desialylation of the tumour cell surface using either targeted delivery of a pan‐ST inhibitor (or sialidase) or systemic delivery of a non‐toxic selective ST inhibitors are being pursued as potential new anti‐metastatic strategies against multiple cancers including pancreatic, ovarian, breast, melanoma and lung cancer. Herein, we have employed molecular modelling to give insights into the selectivity observed in a series of selective ST inhibitors that incorporate a uridyl ring in place of the cytidine of the natural donor (CMP‐Neu5Ac) and replace the charged phosphodiester linker of classical ST inhibitors with a neutral a‐hydroxy‐1,2,3‐triazole linker. The inhibitory activities of the nascent compounds were determined against recombinant human ST enzymes (ST3GAL1, ST6GAL1, ST8SIA2) showing promising activity and selectivity towards specific ST sub‐types. Our ST inhibitors are non‐toxic and show improved synthetic accessibility and drug‐likeness compared to earlier nucleoside‐based ST inhibitors.

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Recent advances in the development of sialyltransferase inhibitors to control cancer metastasis: A comprehensive review

Saoud

Hamrouni

Idris

et al. 2023

Biomedicine & Pharmacotherapy

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Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors

Abstract: Key modifications of previous sialyltransferase inhibitors increased their activity against hST6Gal I and has further implications for synthetically accessible ST inhibitor design.

Cited by 4 publications

References 50 publications

Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer

Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer

Synthesis of α‐Hydroxy‐1,2,3‐Triazole‐linked Sialyltransferase Inhibitors and Evaluation of Selectivity Towards ST3GAL1, ST6GAL1 and ST8SIA2

Recent advances in the development of sialyltransferase inhibitors to control cancer metastasis: A comprehensive review

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