Synthesis, chemo-informatics, and anticancer evaluation of fluorophenyl-isoxazole derivatives

Tahrir Shtayeh,Shahd Issa,Ahmed Mousa,Mohammed Hawash,Serkan Levent,Johnny Amer,Murad Abualhasan,Nidal Jaradat,Sameeha Ibrahim,Aseel Ayaseh

doi:10.1515/chem-2021-0078

Tahrir Shtayeh, Shahd Issa + Show 8 more

Open Access

https://doi.org/10.1515/chem-2021-0078

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Journal: Open Chemistry	Publication Date: Aug 20, 2021
Citations: 16	License type: CC BY 4.0

Affiliation: An-Najah National University, Anadolu University

Abstract

Abstract The current study aimed to design and synthesize a novel series of fluorophenyl-isoxazole-carboxamide derivatives and evaluate their antiproliferative activities. Anticancer activities of the novel compounds were evaluated by MTS assay against four cancer cell lines, including liver (Hep3B, HepG2), cervical (HeLa), and breast (MCF-7), and α-fetoprotein tumor marker, cell cycle analysis, and annexin V tests. Chemo-informatics analysis showed that all synthesized derivatives 2a–2f obeyed Lipinski’s rule. Compound 2f was the most potent compound against Hep3B and Hep-G2 cancer cell lines with IC50 values of 5.76 and 34.64 µg/mL, respectively. Moreover, compounds 2a–2c and 2e showed potent inhibitory activity against Hep3B with an IC50 value range of 7.66–11.60 µg/mL. Hep3B secretions of α-fetoprotein (α-FP) results showed that compound 2f reduced the secretion of Hep3B to 168.33 ng/mL and compound 2d reduced the secretion to value approximately 598.33 ng/mL, in comparison with untreated cells’ value of 1116.67 ng/mL. Furthermore, cell cycle analysis showed that the 2f compound induced arrest in the G2-M phase in 6.73% of the total cells and that was lower than the activity of the positive control doxorubicin (7.4%). Moreover, 2b and 2f compounds reduced the necrosis rate of Hep3B to 4-folds and shifted the cells to apoptosis.

Highlights

Cancer is a disease that has spread in recent decades, and it is one of the main reasons for mortality and death worldwide [1,2,3]
The current study aims to synthesize novel fluorophenyl-isoxazole-carboxamide analogs with different substituents and evaluate their anticancer activity on various cancer cell lines including, HeLa, MCF-7, HepG2, and HepB3, utilizing different anticancer tests (α-fetoprotein, cell cycle analysis, and apoptosis/necrosis)
The coupling reaction to form the fluorophenyl-isoxazole-carboxamide compounds 2a–2f was afforded by using EDCI

Summary

Introduction

Cancer is a disease that has spread in recent decades, and it is one of the main reasons for mortality and death worldwide [1,2,3]. In 2016, about 17.2 million new cases of cancer and 8.9 million deaths were registered around the world. From 2006 to 2016, there was an increase in cancer cases of about 28% [4]. In 2018, the number of deaths was estimated at 9.6 million, and according to the World Health Organization (WHO), the distribution of the most common cancers was as follows: breast (2.09 million), lung (2.09 million), colorectal (1.80 million), prostate (1.28 million), and skin cancer (1.04 million) [3]. Hepatocellular carcinoma (HCC), the fourth most common type of cancer, was one of the leading causes of cancer-related deaths in 2020. Surgical therapy was associated with postoperative complications and a high risk of recurrence. Radio-frequency ablation, microwave ablation, radioembolization, molecular targeted therapies, and chemotherapy remain the alternative ways of treatment [5,6]

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