Synthesis,antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies |
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Authors: | Adel S. El-Azab Alaa A.-M. Abdel-Aziz Laila A. Abou-Zeid Walaa M. El-Husseiny Ahmad M. El_Morsy Manal A. El-Gendy |
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Affiliation: | 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;2. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;3. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;4. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;5. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt |
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Abstract: | A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8?b selectively inhibited the COX-2 enzyme (IC50?=?~0.20–0.69?μM), with SI values of (>72.5–250) compared with celecoxib (IC50?=?0.16?μM, COX-2 SI:?>?312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC50?>?50?μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10?μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition?=?~0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds. |
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Keywords: | NSAID thioesters in vitro antitumour COX-1/COX-2 kinase inhibition assay molecular docking |
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