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

Autor: Hawash M; Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine. Electronic address: mohawash@najah.edu., Abdallah S; Department of Biology & Biotechnology, Faculty of Science, An-Najah National University, Nablus, 00970, Palestine., Abudayyak M; Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul University, 34116, Istanbul, Turkey., Melhem Y; Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine., Abu Shamat M; Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine., Aghbar M; Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine., Çapan I; 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., Abualhasan M; Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine., Kumar A; Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Ul. Zwirki I Wigury 101, 02-089, Warsaw, Poland., Kamiński M; Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Ul. Zwirki I Wigury 101, 02-089, Warsaw, Poland., Góral T; Centre of New Technologies, University of Warsaw, Ul. S. Banacha 2c, 02-097, Warsaw, Poland., Dominiak PM; Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Ul. Zwirki I Wigury 101, 02-089, Warsaw, Poland., Sobuh S; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, 00970, Palestine.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 May 05; Vol. 271, pp. 116397. Date of Electronic Publication: 2024 Apr 15.
DOI: 10.1016/j.ejmech.2024.116397
Abstrakt: In this study, a new series of Isoxazole-carboxamide derivatives were synthesized and characterized via HRMS, 1 H-, 13 C APT -NMR, and MicroED. The findings revealed that nearly all of the synthesized derivatives exhibited potent inhibitory activities against both COX enzymes, with IC 50 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 IC 50 value of 4.1 nM. The results showed that 5 compounds possess high COX-2 isozyme inhibitory effects with IC 50 value in range 0.24-1.30 μM with COX-2 selectivity indexes (2.51-6.13), among these compounds MYM4 has the lowest IC 50 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 IC 50 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 IC 50 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohammed Hawash reports financial support and equipment, drugs, or supplies were provided by An-Najah National University. Paulina Maria Dominiak reports financial support was provided by University of Warsaw Centre of New Technologies. Mohammed Hawash reports a relationship with An-najah National University Faculty of Medicine and Health Sciences that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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