Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation

Kciuk, Mateusz; Marciniak, Beata; Celik, Ismail; Zerroug, Enfale; Dubey, Amit; Sundaraj, Rajamanikandan; Mujwar, Somdutt; Bukowski, Karol; Mojzych, Mariusz; Kontek, Renata

doi:10.3390/ijms241310959

Open AccessArticle

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation

by

Mateusz Kciuk

^1,2

,

Beata Marciniak

¹

,

Ismail Celik

³

,

Enfale Zerroug

⁴,

Amit Dubey

^5,6,

Rajamanikandan Sundaraj

⁷,

Somdutt Mujwar

⁸

,

Karol Bukowski

¹

,

Mariusz Mojzych

⁹

and

Renata Kontek

^1,*

¹

Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland

²

Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland

³

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38280, Turkey

⁴

Group of Computational and Pharmaceutical Chemistry, LMCE Laboratory, University of Biskra, BP 145, Biskra 07000, Algeria

⁵

Computational Chemistry and Drug Discovery Division, Quanta Calculus, Greater Noida 274203, Uttar Prades, India

⁶

Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai 602105, Tamil Nadu, India

⁷

Centre for Drug Discovery, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India

⁸

Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India

⁹

Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(13), 10959; https://doi.org/10.3390/ijms241310959

Submission received: 17 June 2023 / Revised: 26 June 2023 / Accepted: 28 June 2023 / Published: 30 June 2023

(This article belongs to the Special Issue Pharmaceutically-Active Pyrazole Compounds)

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Abstract

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM-compounds (MM134, -6, -7, and -9). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds’ cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06–0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC₅₀ concentrations of MM134, -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM-compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches.

Keywords: apoptosis; cytotoxicity; heterocycles; pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine; sulfonamides

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MDPI and ACS Style

Kciuk, M.; Marciniak, B.; Celik, I.; Zerroug, E.; Dubey, A.; Sundaraj, R.; Mujwar, S.; Bukowski, K.; Mojzych, M.; Kontek, R. Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation. Int. J. Mol. Sci. 2023, 24, 10959. https://doi.org/10.3390/ijms241310959

AMA Style

Kciuk M, Marciniak B, Celik I, Zerroug E, Dubey A, Sundaraj R, Mujwar S, Bukowski K, Mojzych M, Kontek R. Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation. International Journal of Molecular Sciences. 2023; 24(13):10959. https://doi.org/10.3390/ijms241310959

Chicago/Turabian Style

Kciuk, Mateusz, Beata Marciniak, Ismail Celik, Enfale Zerroug, Amit Dubey, Rajamanikandan Sundaraj, Somdutt Mujwar, Karol Bukowski, Mariusz Mojzych, and Renata Kontek. 2023. "Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation" International Journal of Molecular Sciences 24, no. 13: 10959. https://doi.org/10.3390/ijms241310959

APA Style

Kciuk, M., Marciniak, B., Celik, I., Zerroug, E., Dubey, A., Sundaraj, R., Mujwar, S., Bukowski, K., Mojzych, M., & Kontek, R. (2023). Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation. International Journal of Molecular Sciences, 24(13), 10959. https://doi.org/10.3390/ijms241310959

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Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery—In Vitro and In Silico Evaluation

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