Synthesis and kinase inhibitory activity of new sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazines

Mariusz Mojzych; Veronika Šubertová; Anna Bielawska; Krzysztof Bielawski; Václav Bazgier; Karel Berka; Tomáš Gucký; Emilia Fornal; Vladimír Kryštof

doi:10.1016/j.ejmech.2014.03.054

Synthesis and kinase inhibitory activity of new sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazines

Eur J Med Chem. 2014 May 6:78:217-24. doi: 10.1016/j.ejmech.2014.03.054. Epub 2014 Mar 18.

Authors

Mariusz Mojzych¹, Veronika Šubertová², Anna Bielawska³, Krzysztof Bielawski³, Václav Bazgier², Karel Berka⁴, Tomáš Gucký², Emilia Fornal⁵, Vladimír Kryštof⁶

Affiliations

¹ Department of Chemistry, Siedlce University of Natural Sciences and Humanities, ul. 3 Maja 54, Siedlce 08-110, Poland.
² Centre of the Region Haná for Biotechnological and Agricultural Research, Laboratory of Growth Regulators, Faculty of Science, Palacký University, Šlechtitelů 11, 783 71 Olomouc, Czech Republic.
³ Department of Medicinal Chemistry and Drug Technology, Medical University of Bialystok, Bialystok, Poland.
⁴ Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University Olomouc, 17. listopadu 12, 77146 Olomouc, Czech Republic.
⁵ Department of Chemistry, Laboratory of Separation and Spectroscopic Method Applications, Center for Interdisciplinary Research, The John Paul II Catholic University of Lublin, al. Krasnicka 102, 20-718 Lublin, Poland.
⁶ Centre of the Region Haná for Biotechnological and Agricultural Research, Laboratory of Growth Regulators, Faculty of Science, Palacký University, Šlechtitelů 11, 783 71 Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz.

PMID: 24681986
DOI: 10.1016/j.ejmech.2014.03.054

Abstract

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine has been synthesized and characterized. Their anticancer activity was tested in vitro against multiple human cancer cell lines and were found to have dose-dependent antiproliferative effects. Furthermore, some of the new compounds inhibited the Abl protein kinase with low micromolar IC50 values and exhibited selective activity against the Bcr-Abl positive K562 and BV173 cell lines, providing starting points for the further development of this new kinase inhibitor scaffold.

Keywords: Bcr-Abl; Cancer; Inhibitor; Kinase; Leukaemia; Pyrazolo[4,3-e][1,2,4]triazine; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / metabolism
HL-60 Cells
Humans
K562 Cells
MCF-7 Cells
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemistry*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Triazines / chemistry*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Sulfonamides
Triazines
Fusion Proteins, bcr-abl