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

Journal Article


Abstract


  • The critical role of sialyltransferase (ST) enzymes in tumour cell growth and metastasis, as well as links to multi-drug and radiation resistance, has seen STs emerge as a target for potential antimetastatic cancer treatments. One promising class of ST inhibitors that improve upon the pharmacokinetic issues of previous inhibitors is the 1,2,3-triazole-linked transition-state analogues. Herein, we present the design and synthesis of a new generation of 1,2,3-triazole-linked sialyltransferase inhibitors, along with their biological evaluation demonstrating increased potency for phosphonate bearing compounds. The six most promising inhibitors presented in this work exhibited a greater number of binding modes for hST6Gal I over hST3Gal I, withKiranging from 3-55 μM. This work highlights phosphonate bearing triazole-linked compounds as a promising class of synthetically accessible ST inhibitors that warrant further investigation.

Publication Date


  • 2021

Citation


  • Dobie, C., Montgomery, A. P., Szabo, R., Yu, H., & Skropeta, D. (2021). Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors. RSC Medicinal Chemistry, 12(10), 1680-1689. doi:10.1039/d1md00079a

Scopus Eid


  • 2-s2.0-85117689680

Start Page


  • 1680

End Page


  • 1689

Volume


  • 12

Issue


  • 10

Abstract


  • The critical role of sialyltransferase (ST) enzymes in tumour cell growth and metastasis, as well as links to multi-drug and radiation resistance, has seen STs emerge as a target for potential antimetastatic cancer treatments. One promising class of ST inhibitors that improve upon the pharmacokinetic issues of previous inhibitors is the 1,2,3-triazole-linked transition-state analogues. Herein, we present the design and synthesis of a new generation of 1,2,3-triazole-linked sialyltransferase inhibitors, along with their biological evaluation demonstrating increased potency for phosphonate bearing compounds. The six most promising inhibitors presented in this work exhibited a greater number of binding modes for hST6Gal I over hST3Gal I, withKiranging from 3-55 μM. This work highlights phosphonate bearing triazole-linked compounds as a promising class of synthetically accessible ST inhibitors that warrant further investigation.

Publication Date


  • 2021

Citation


  • Dobie, C., Montgomery, A. P., Szabo, R., Yu, H., & Skropeta, D. (2021). Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors. RSC Medicinal Chemistry, 12(10), 1680-1689. doi:10.1039/d1md00079a

Scopus Eid


  • 2-s2.0-85117689680

Start Page


  • 1680

End Page


  • 1689

Volume


  • 12

Issue


  • 10