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  3. Exploration of isoxazole analogs: Synthesis, COX inhibition, anticancer screening, 3D multicellular tumor spheroids, and molecular modeling

Exploration of isoxazole analogs: Synthesis, COX inhibition, anticancer screening, 3D multicellular tumor spheroids, and molecular modeling

  • Eur J Med Chem. 2024 May 5:271:116397. doi: 10.1016/j.ejmech.2024.116397.
Mohammed Hawash 1,  Samer Abdallah 2,  Mahmoud Abudayyak 3,  Yarob Melhem 4,  Mohammed Abu Shamat 4,  Meera Aghbar 4,  Irfan Çapan 5,  Murad Abualhasan 4,  Anil Kumar 6,  Michał Kamiński 6,  Tomasz Góral 7,  Paulina Maria Dominiak 6,  Shorooq Sobuh 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine. Electronic address: mohawash@najah.edu.
  • 2 Department of Biology & Biotechnology, Faculty of Science, An-Najah National University, Nablus, 00970, Palestine.
  • 3 Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul University, 34116, Istanbul, Turkey.
  • 4 Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine.
  • 5 Department of Material and Material Processing Technologies, Technical Sciences Vocational College, Gazi University, 06560, Ankara, Turkey; Basic and Engineering Sciences Central Laboratory Application and Research Center (GUTMAM), Gazi University, 06500, Ankara, Turkey.
  • 6 Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Ul. Zwirki I Wigury 101, 02-089, Warsaw, Poland.
  • 7 Centre of New Technologies, University of Warsaw, Ul. S. Banacha 2c, 02-097, Warsaw, Poland.
  • 8 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine.
PMID: 38626522 DOI: 10.1016/j.ejmech.2024.116397
Abstract

In this study, a new series of Isoxazole-carboxamide derivatives were synthesized and characterized via HRMS, 1H-, 13CAPT-NMR, and MicroED. The findings revealed that nearly all of the synthesized derivatives exhibited potent inhibitory activities against both COX Enzymes, with IC50 values ranging from 4.1 nM to 3.87 μM. Specifically, MYM1 demonstrated the highest efficacy among the compounds tested against the COX-1, displaying an IC50 value of 4.1 nM. The results showed that 5 compounds possess high COX-2 isozyme inhibitory effects with IC50 value in range 0.24-1.30 μM with COX-2 selectivity indexes (2.51-6.13), among these compounds MYM4 has the lowest IC50 value against COX-2, with selectivity index around 4. Intriguingly, this compound displayed significant antiproliferative effects against CaCo-2, Hep3B, and HeLa Cancer cell lines, with IC50 values of 10.22, 4.84, and 1.57 μM, respectively, which was nearly comparable to that of doxorubicin. Compound MYM4 showed low cytotoxic activities on normal cell lines LX-2 and Hek293t with IC50 values 20.01 and 216.97 μM respectively, with safer values than doxorubicin. Furthermore, compound MYM4 was able to induce the Apoptosis, suppress the colonization of both HeLa and HepG2 cells. Additionally, the induction of Reactive Oxygen Species (ROS) production could be the mechanism underlying the apoptotic effect and the cytotoxic activity of the compound. In the 3D multicellular tumor spheroid model, results revealed that MYM4 compound hampered the spheroid formation capacity of Hep3B and HeLa Cancer cells. Moreover, the molecular docking of MYM4 compound revealed a high affinity for the COX2 Enzyme, with energy scores (S) -7.45 kcal/mol, which were comparable to celecoxib (S) -8.40 kcal/mol. Collectively, these findings position MYM4 as a promising pharmacological candidate as COX Inhibitor and Anticancer agent.

Keywords

3D multicellular spheroids; Apoptosis; COX; Cancer; HeLa; Isoxazole; MircoED.

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