The activity of pyrazolo[4,3-e][1,2,4]triazine and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures

Abstract

In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.

Keywords:

• Pyrazolo[43-e]tetrazolo[15-b][1,2,4]triazine
• pyrazolo[43-e][1,2,4]triazine
• anticancer
• sulphonamide
• spheroid

Author contributions

Conceptualisation, R.C., M.M., K.K.-M., A.B.; methodology, R.C., A.S., D.R. M.M.; investigation, A.S., D.R., R.C., M.M.; writing – original draft preparation, A.S., R.C., M.M.; writing – review and editing, R.C., A.B., K.B., M.M, K.K.-M.; visualisation, D.R., A.S., R.C., M.M.; supervision, R.C., K.B., M.M., A.B.; funding acquisition, K.B., A.B., R.C., M.M. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors report no conflicts of interest.

Data availability statement

Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.

Additional information

Funding

The research was partly financed by research projects: Medical University of Bialystok (B.SUB.23.408), Siedlce University of Natural Sciences and Humanities (UPH/WNSP/ICH/zadaniebadawcze/143/23/B), and Medical University of Lublin (DS 730). A.S. is supported by Polish National Agency for Academic Exchange (NAWA) within the Bekker Programme (BPN/BEK/2021/1/00115).