A1 Journal article (refereed)
Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl s-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) via EGFR/PI3K/AKT/mTOR Signaling Cascades (2022)

Shawish, I., Barakat, A., Aldalbahi, A., Alshaer, W., Daoud, F., Alqudah, D. A., Al Zoubi, M., Hatmal, M. M., Nafie, M. S., Haukka, M., Sharma, A., de la Torre, B. G., Albericio, F., & El-Faham, A. (2022). Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl s-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) via EGFR/PI3K/AKT/mTOR Signaling Cascades. Pharmaceutics, 14(8), Article 1558. https://doi.org/10.3390/pharmaceutics14081558

JYU authors or editors

Publication details

All authors or editors: Shawish, Ihab; Barakat, Assem; Aldalbahi, Ali; Alshaer, Walhan; Daoud, Fadwa; Alqudah, Dana A.; Al Zoubi, Mazhar; Hatmal, Ma’mon M.; Nafie, Mohamed S.; Haukka, Matti; et al.

Journal or series: Pharmaceutics

eISSN: 1999-4923

Publication year: 2022

Publication date: 27/07/2022

Volume: 14

Issue number: 8

Article number: 1558

Publisher: MDPI AG

Publication country: Switzerland

Publication language: English

DOI: https://doi.org/10.3390/pharmaceutics14081558

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/82961

Abstract

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.

Keywords: heterocyclic compounds; chemical synthesis; bioactive compounds; inhibitors; pharmaceutical chemistry

Free keywords: one-pot synthesis; DMF-DMA; pyrazolyl-s-triazine; anticancer profile; EGFR/PI3K/AKT/mTOR; apoptosis

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2022

Preliminary JUFO rating: 1