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Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I

Journal Article


Abstract


  • Sialic acid at the terminus of cell surface glycoconjugates is a critical element in cell-cell recognition, receptor binding and immune responses. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans are highly upregulated in cancer and the resulting hypersialylation of the tumour cell surface correlates strongly with tumour growth, metastasis and drug resistance. Inhibitors of human STs, in particular human ST6Gal I, are thus expected to be valuable chemical tools for the discovery of novel anticancer drugs. Herein, we report on the computationally-guided design and development of uridine-based inhibitors that replace the charged phosphodiester linker of known ST inhibitors with a neutral carbamate to improve pharmacokinetic properties and synthetic accessibility. A series of 24 carbamate-linked uridyl-based compounds were synthesised by coupling aryl and hetaryl α-hydroxyphosphonates with a 5′-amino-5′-deoxyuridine fragment. The inhibitory activities of the newly synthesised compounds against recombinant human ST6Gal I were determined using a luminescent microplate assay, and five promising inhibitors with Ki’s ranging from 1 to 20 µM were identified. These results show that carbamate-linked uridyl-based compounds are a potential new class of readily accessible, non-cytotoxic ST inhibitors to be further explored.

Publication Date


  • 2020

Citation


  • Montgomery, A. P., Dobie, C., Szabo, R., Hallam, L., Ranson, M., Yu, H., & Skropeta, D. (2020). Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I. Bioorganic and Medicinal Chemistry, 28(14). doi:10.1016/j.bmc.2020.115561

Scopus Eid


  • 2-s2.0-85085759032

Volume


  • 28

Issue


  • 14

Abstract


  • Sialic acid at the terminus of cell surface glycoconjugates is a critical element in cell-cell recognition, receptor binding and immune responses. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans are highly upregulated in cancer and the resulting hypersialylation of the tumour cell surface correlates strongly with tumour growth, metastasis and drug resistance. Inhibitors of human STs, in particular human ST6Gal I, are thus expected to be valuable chemical tools for the discovery of novel anticancer drugs. Herein, we report on the computationally-guided design and development of uridine-based inhibitors that replace the charged phosphodiester linker of known ST inhibitors with a neutral carbamate to improve pharmacokinetic properties and synthetic accessibility. A series of 24 carbamate-linked uridyl-based compounds were synthesised by coupling aryl and hetaryl α-hydroxyphosphonates with a 5′-amino-5′-deoxyuridine fragment. The inhibitory activities of the newly synthesised compounds against recombinant human ST6Gal I were determined using a luminescent microplate assay, and five promising inhibitors with Ki’s ranging from 1 to 20 µM were identified. These results show that carbamate-linked uridyl-based compounds are a potential new class of readily accessible, non-cytotoxic ST inhibitors to be further explored.

Publication Date


  • 2020

Citation


  • Montgomery, A. P., Dobie, C., Szabo, R., Hallam, L., Ranson, M., Yu, H., & Skropeta, D. (2020). Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I. Bioorganic and Medicinal Chemistry, 28(14). doi:10.1016/j.bmc.2020.115561

Scopus Eid


  • 2-s2.0-85085759032

Volume


  • 28

Issue


  • 14