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
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
Affiliations
Ihab Shawish
Department of Math and Sciences, College of Humanities and Sciences, Prince Sultan University, P.O. Box 66833, Riyadh 11586, Saudi Arabia
Assem Barakat
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Ali Aldalbahi
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Walhan Alshaer
Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
Fadwa Daoud
Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
Dana A. Alqudah
Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
Mazhar Al Zoubi
Department of Basic Medical Sciences, Faculty of Sciences, Yarmouk University, Irbid 21163, Jordan
Ma’mon M. Hatmal
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan
Mohamed S. Nafie
Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
Matti Haukka
Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland
Anamika Sharma
KwaZulu-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 Africa
Beatriz G. de la Torre
KwaZulu-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 Africa
Fernando Albericio
Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa
Here, we described the synthesis of novel pyrazole-s-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 N,N-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-s-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-s-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 s-triazine compounds induced cytotoxicity in all the cell lines tested. However, compounds 7d, 7f and 7c, which all have a piperidine or morpholine moiety with one aniline ring or two aniline rings in their structures, were the most effective. Compounds 7f and 7d showed potent EGFR inhibitory activity with IC50 values of 59.24 and 70.3 nM, respectively, compared to Tamoxifen (IC50 value of 69.1 nM). Compound 7c exhibited moderate activity, with IC50 values of 81.6 nM. Interestingly, hybrids 7d and 7f 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 7d-treatment, and to 2.39, 25.34 and 57.6 ng/mL in the 7f-treatment compared to the untreated control.
