Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis
The current study continues the evaluation of the anticancer potential of three de novo synthesized pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine sulfonamides—<b>MM129</b>, <b>MM130</b>, and <b>MM131</b>—against human cancer...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2023-05-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/24/10/8504 |
_version_ | 1797599910320668672 |
---|---|
author | Karol Bukowski Beata Marciniak Mateusz Kciuk Somdutt Mujwar Mariusz Mojzych Renata Kontek |
author_facet | Karol Bukowski Beata Marciniak Mateusz Kciuk Somdutt Mujwar Mariusz Mojzych Renata Kontek |
author_sort | Karol Bukowski |
collection | DOAJ |
description | The current study continues the evaluation of the anticancer potential of three de novo synthesized pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine sulfonamides—<b>MM129</b>, <b>MM130</b>, and <b>MM131</b>—against human cancer cells of HeLa, HCT 116, PC-3, and BxPC-3 lines. The pro-apoptotic activity of the investigated sulfonamides was shown by observations of changes in the mitochondrial transmembrane potential of the tested cells, externalization of phosphatidylserine on the cellular membrane surface, and cell morphology in microscopic imaging. The computational studies have shown that <b>MM129</b> exhibited the lowest binding energy values when docked against CDK enzymes. In addition, the highest stability was shown for complexes formed between MM129 and CDK5/8 enzymes. All examined compounds induced cell cycle arrest in the G0/G1 phase in the BxPC-3 and PC-3 cells and simultaneously caused the accumulation of cells in the S phase in the HCT 116 cells. In addition, the increase in the subG1 fraction was observed in PC-3 and HeLa cells. The application of a fluorescent H<sub>2</sub>DCFDA probe revealed the high pro-oxidative properties of the tested triazine derivatives, especially <b>MM131</b>. In conclusion, the obtained results suggest that <b>MM129</b>, <b>MM130</b>, and <b>MM131</b> exhibited strong pro-apoptotic properties towards investigated cells, mainly against the HeLa and HCT 116 cell lines, and high pro-oxidative potential as well. Moreover, it is suggested that the anticancer activity of the tested compounds may be associated with their ability to inhibit CDK enzymes activities. |
first_indexed | 2024-03-11T03:40:59Z |
format | Article |
id | doaj.art-dfc7859b66684f5a9788ae5158800d6b |
institution | Directory Open Access Journal |
issn | 1661-6596 1422-0067 |
language | English |
last_indexed | 2024-03-11T03:40:59Z |
publishDate | 2023-05-01 |
publisher | MDPI AG |
record_format | Article |
series | International Journal of Molecular Sciences |
spelling | doaj.art-dfc7859b66684f5a9788ae5158800d6b2023-11-18T01:36:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410850410.3390/ijms24108504Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle AnalysisKarol Bukowski0Beata Marciniak1Mateusz Kciuk2Somdutt Mujwar3Mariusz Mojzych4Renata Kontek5Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, PolandDepartment of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, PolandDepartment of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, PolandChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaDepartment of Chemistry, Siedlce University of Natural Sciences and Humanities, 08-110 Siedlce, PolandDepartment of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, PolandThe current study continues the evaluation of the anticancer potential of three de novo synthesized pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine sulfonamides—<b>MM129</b>, <b>MM130</b>, and <b>MM131</b>—against human cancer cells of HeLa, HCT 116, PC-3, and BxPC-3 lines. The pro-apoptotic activity of the investigated sulfonamides was shown by observations of changes in the mitochondrial transmembrane potential of the tested cells, externalization of phosphatidylserine on the cellular membrane surface, and cell morphology in microscopic imaging. The computational studies have shown that <b>MM129</b> exhibited the lowest binding energy values when docked against CDK enzymes. In addition, the highest stability was shown for complexes formed between MM129 and CDK5/8 enzymes. All examined compounds induced cell cycle arrest in the G0/G1 phase in the BxPC-3 and PC-3 cells and simultaneously caused the accumulation of cells in the S phase in the HCT 116 cells. In addition, the increase in the subG1 fraction was observed in PC-3 and HeLa cells. The application of a fluorescent H<sub>2</sub>DCFDA probe revealed the high pro-oxidative properties of the tested triazine derivatives, especially <b>MM131</b>. In conclusion, the obtained results suggest that <b>MM129</b>, <b>MM130</b>, and <b>MM131</b> exhibited strong pro-apoptotic properties towards investigated cells, mainly against the HeLa and HCT 116 cell lines, and high pro-oxidative potential as well. Moreover, it is suggested that the anticancer activity of the tested compounds may be associated with their ability to inhibit CDK enzymes activities.https://www.mdpi.com/1422-0067/24/10/8504pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazinesulfonamidesMM compoundsanticancer agentscancer cellscell cycle |
spellingShingle | Karol Bukowski Beata Marciniak Mateusz Kciuk Somdutt Mujwar Mariusz Mojzych Renata Kontek Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis International Journal of Molecular Sciences pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine sulfonamides MM compounds anticancer agents cancer cells cell cycle |
title | Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis |
title_full | Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis |
title_fullStr | Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis |
title_full_unstemmed | Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis |
title_short | Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis |
title_sort | pyrazolo 4 3 i e i tetrazolo 1 5 i b i 1 2 4 triazine sulfonamides as novel potential anticancer agents apoptosis oxidative stress and cell cycle analysis |
topic | pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][1,2,4]triazine sulfonamides MM compounds anticancer agents cancer cells cell cycle |
url | https://www.mdpi.com/1422-0067/24/10/8504 |
work_keys_str_mv | AT karolbukowski pyrazolo43ieitetrazolo15ibi124triazinesulfonamidesasnovelpotentialanticanceragentsapoptosisoxidativestressandcellcycleanalysis AT beatamarciniak pyrazolo43ieitetrazolo15ibi124triazinesulfonamidesasnovelpotentialanticanceragentsapoptosisoxidativestressandcellcycleanalysis AT mateuszkciuk pyrazolo43ieitetrazolo15ibi124triazinesulfonamidesasnovelpotentialanticanceragentsapoptosisoxidativestressandcellcycleanalysis AT somduttmujwar pyrazolo43ieitetrazolo15ibi124triazinesulfonamidesasnovelpotentialanticanceragentsapoptosisoxidativestressandcellcycleanalysis AT mariuszmojzych pyrazolo43ieitetrazolo15ibi124triazinesulfonamidesasnovelpotentialanticanceragentsapoptosisoxidativestressandcellcycleanalysis AT renatakontek pyrazolo43ieitetrazolo15ibi124triazinesulfonamidesasnovelpotentialanticanceragentsapoptosisoxidativestressandcellcycleanalysis |