Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors.

Autor: Tangadanchu VKR; Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA., Jiang H; Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA., Yu Y; Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA., Graham TJA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Liu H; Department of Surgery, University of Cincinnati, Cincinnati, OH, 45267, USA., Rogers BE; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA., Gropler R; Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA., Perlmutter J; Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA; Departments of Neurology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St Louis, MO, 63110, USA., Tu Z; Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA. Electronic address: tuz@mir.wustl.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2020 Nov 15; Vol. 206, pp. 112713. Date of Electronic Publication: 2020 Aug 08.
DOI: 10.1016/j.ejmech.2020.112713
Abstrakt: Sphingosine kinase (SphK) is primarily responsible for the production of Sphingosine-1-phosphate (S1P) that plays an important role in many biological and pathobiological processes including cancer, inflammation, neurological and cardiovascular disorders. Most research has focused on developing inhibitors of SphK1 rather than inhibitors of the other isoform SphK2 which has great importance in several pathophysiologic pathways. Exploration of new analogues for improving the potency and selectivity of SphK2 inhibitors is critical. We now have designed, synthesized, and evaluated eighteen new 1,2,3-triazole analogues for their SphK2 inhibitory activity using a ADP-Glo kinase assay, and explored their in vivo anti-tumor bioactivity. Several compounds including 21c, 21e, 21g, 25e-h, 29a-c have high selectivity for SphK2 over SphK1; compound 21g displayed the highest potency with an IC 50 value of 0.23 μM. In addition, three compounds 21a, 21b, and 25b have high anti-tumor activity against U-251 MG human glioblastoma cells. Molecular modeling study was performed to elucidate the polar head group and 1,2,3-triazole pharmacophore impact on the SphK2 selectivity.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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