Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades
Here, we described the synthesis of novel pyrazole-<i>s</i>-triazine derivatives via an easy one-pot procedure for the reaction of β-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with <i>N</i>,<i>N</i>-dimethylfo...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/8/1558 |
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| author | Ihab Shawish Assem Barakat Ali Aldalbahi Walhan Alshaer Fadwa Daoud Dana A. Alqudah Mazhar Al Zoubi Ma’mon M. Hatmal Mohamed S. Nafie Matti Haukka Anamika Sharma Beatriz G. de la Torre Fernando Albericio Ayman El-Faham |
| author_facet | Ihab Shawish Assem Barakat Ali Aldalbahi Walhan Alshaer Fadwa Daoud Dana A. Alqudah Mazhar Al Zoubi Ma’mon M. Hatmal Mohamed S. Nafie Matti Haukka Anamika Sharma Beatriz G. de la Torre Fernando Albericio Ayman El-Faham |
| author_sort | Ihab Shawish |
| collection | DOAJ |
| description | Here, we described the synthesis of novel pyrazole-<i>s</i>-triazine derivatives via an easy one-pot procedure for the reaction of β-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with <i>N</i>,<i>N</i>-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-<i>s</i>-triazine either in ethanol-acetic acid or neat acetic acid to afford a novel pyrazole and pyrazole-fused cycloalkanone systems. The synthetic protocol proved to be efficient, with a shorter reaction time and high chemical yield with broad substrates. The new pyrazolyl-<i>s</i>-triazine derivatives were tested against the following cell lines: MCF-7 (breast cancer); MDA-MB-231 (triple-negative breast cancer); U-87 MG (glioblastoma); A549 (non-small cell lung cancer); PANC-1 (pancreatic cancer); and human dermal fibroblasts (HDFs). The cell viability assay revealed that most of the <i>s</i>-triazine compounds induced cytotoxicity in all the cell lines tested. However, compounds <b>7d</b>, <b>7f</b> and <b>7c</b>, which all have a piperidine or morpholine moiety with one aniline ring or two aniline rings in their structures, were the most effective. Compounds <b>7f</b> and <b>7d</b> showed potent EGFR inhibitory activity with IC<sub>50</sub> values of 59.24 and 70.3 nM, respectively, compared to Tamoxifen (IC<sub>50</sub> value of 69.1 nM). Compound <b>7c</b> exhibited moderate activity, with IC<sub>50</sub> values of 81.6 nM. Interestingly, hybrids <b>7d</b> and <b>7f</b> exerted remarkable PI3K/AKT/mTOR inhibitory activity with 0.66/0.82/0.80 and 0.35/0.56/0.66-fold, respectively, by inhibiting their concentrations to 4.39, 37.3, and 69.3 ng/mL in the <b>7d</b>-treatment, and to 2.39, 25.34 and 57.6 ng/mL in the <b>7f</b>-treatment compared to the untreated control. |
| first_indexed | 2024-03-09T09:50:34Z |
| format | Article |
| id | doaj.art-0b588e5dc50d4139b29e6a558dcf209d |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T09:50:34Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-0b588e5dc50d4139b29e6a558dcf209d2023-12-02T00:09:22ZengMDPI AGPharmaceutics1999-49232022-07-01148155810.3390/pharmaceutics14081558Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling CascadesIhab Shawish0Assem Barakat1Ali Aldalbahi2Walhan Alshaer3Fadwa Daoud4Dana A. Alqudah5Mazhar Al Zoubi6Ma’mon M. Hatmal7Mohamed S. Nafie8Matti Haukka9Anamika Sharma10Beatriz G. de la Torre11Fernando Albericio12Ayman El-Faham13Department of Math and Sciences, College of Humanities and Sciences, Prince Sultan University, P.O. Box 66833, Riyadh 11586, Saudi ArabiaDepartment of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi ArabiaDepartment of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi ArabiaCell Therapy Center, The University of Jordan, Amman 11942, JordanCell Therapy Center, The University of Jordan, Amman 11942, JordanCell Therapy Center, The University of Jordan, Amman 11942, JordanDepartment of Basic Medical Sciences, Faculty of Sciences, Yarmouk University, Irbid 21163, JordanDepartment of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, JordanDepartment of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, EgyptDepartment of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, FinlandKwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South AfricaKwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South AfricaPeptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South AfricaChemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 12321, EgyptHere, we described the synthesis of novel pyrazole-<i>s</i>-triazine derivatives via an easy one-pot procedure for the reaction of β-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with <i>N</i>,<i>N</i>-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-<i>s</i>-triazine either in ethanol-acetic acid or neat acetic acid to afford a novel pyrazole and pyrazole-fused cycloalkanone systems. The synthetic protocol proved to be efficient, with a shorter reaction time and high chemical yield with broad substrates. The new pyrazolyl-<i>s</i>-triazine derivatives were tested against the following cell lines: MCF-7 (breast cancer); MDA-MB-231 (triple-negative breast cancer); U-87 MG (glioblastoma); A549 (non-small cell lung cancer); PANC-1 (pancreatic cancer); and human dermal fibroblasts (HDFs). The cell viability assay revealed that most of the <i>s</i>-triazine compounds induced cytotoxicity in all the cell lines tested. However, compounds <b>7d</b>, <b>7f</b> and <b>7c</b>, which all have a piperidine or morpholine moiety with one aniline ring or two aniline rings in their structures, were the most effective. Compounds <b>7f</b> and <b>7d</b> showed potent EGFR inhibitory activity with IC<sub>50</sub> values of 59.24 and 70.3 nM, respectively, compared to Tamoxifen (IC<sub>50</sub> value of 69.1 nM). Compound <b>7c</b> exhibited moderate activity, with IC<sub>50</sub> values of 81.6 nM. Interestingly, hybrids <b>7d</b> and <b>7f</b> exerted remarkable PI3K/AKT/mTOR inhibitory activity with 0.66/0.82/0.80 and 0.35/0.56/0.66-fold, respectively, by inhibiting their concentrations to 4.39, 37.3, and 69.3 ng/mL in the <b>7d</b>-treatment, and to 2.39, 25.34 and 57.6 ng/mL in the <b>7f</b>-treatment compared to the untreated control.https://www.mdpi.com/1999-4923/14/8/1558one-pot synthesisDMF-DMApyrazolyl-<i>s</i>-triazineanticancer profileEGFR/PI3K/AKT/mTORapoptosis |
| spellingShingle | Ihab Shawish Assem Barakat Ali Aldalbahi Walhan Alshaer Fadwa Daoud Dana A. Alqudah Mazhar Al Zoubi Ma’mon M. Hatmal Mohamed S. Nafie Matti Haukka Anamika Sharma Beatriz G. de la Torre Fernando Albericio Ayman El-Faham Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades Pharmaceutics one-pot synthesis DMF-DMA pyrazolyl-<i>s</i>-triazine anticancer profile EGFR/PI3K/AKT/mTOR apoptosis |
| title | Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades |
| title_full | Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades |
| title_fullStr | Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades |
| title_full_unstemmed | Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades |
| title_short | Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl <i>s</i>-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) <i>via</i> EGFR/PI3K/AKT/mTOR Signaling Cascades |
| title_sort | acetic acid mediated for one pot synthesis of novel pyrazolyl i s i triazine derivatives for the targeted therapy of triple negative breast tumor cells mda mb 231 i via i egfr pi3k akt mtor signaling cascades |
| topic | one-pot synthesis DMF-DMA pyrazolyl-<i>s</i>-triazine anticancer profile EGFR/PI3K/AKT/mTOR apoptosis |
| url | https://www.mdpi.com/1999-4923/14/8/1558 |
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