Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action
Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2648 |
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| author | Mehlika Dilek Altıntop Gülşen Akalın Çiftçi Nalan Yılmaz Savaş İpek Ertorun Betül Can Belgin Sever Halide Edip Temel Özkan Alataş Ahmet Özdemir |
| author_facet | Mehlika Dilek Altıntop Gülşen Akalın Çiftçi Nalan Yılmaz Savaş İpek Ertorun Betül Can Belgin Sever Halide Edip Temel Özkan Alataş Ahmet Özdemir |
| author_sort | Mehlika Dilek Altıntop |
| collection | DOAJ |
| description | Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds <b>3b</b> and <b>4a</b> were found to be the most selective COX-1 inhibitors in this series with IC<sub>50</sub> values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1<i>H</i>-Indol-3-yl)-<i>N</i>′-(4-morpholinobenzylidene)acetohydrazide (<b>3b</b>) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound <b>3b</b> decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound <b>3b</b> diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound <b>3b</b> stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor. |
| first_indexed | 2024-03-11T09:40:37Z |
| format | Article |
| id | doaj.art-23db509aa79b425cbd9ab752088d7afb |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:40:37Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-23db509aa79b425cbd9ab752088d7afb2023-11-16T17:00:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243264810.3390/ijms24032648Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory ActionMehlika Dilek Altıntop0Gülşen Akalın Çiftçi1Nalan Yılmaz Savaş2İpek Ertorun3Betül Can4Belgin Sever5Halide Edip Temel6Özkan Alataş7Ahmet Özdemir8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, TurkeyDepartment of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, TurkeyGraduate School of Health Sciences, Anadolu University, 26470 Eskişehir, TurkeyDepartment of Medical Biochemistry, Faculty of Medicine, Eskisehir Osmangazi University, 26480 Eskişehir, TurkeyDepartment of Medical Biochemistry, Faculty of Medicine, Eskisehir Osmangazi University, 26480 Eskişehir, TurkeyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, TurkeyDepartment of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, TurkeyDepartment of Medical Biochemistry, Faculty of Medicine, Eskisehir Osmangazi University, 26480 Eskişehir, TurkeyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, TurkeyTargeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds <b>3b</b> and <b>4a</b> were found to be the most selective COX-1 inhibitors in this series with IC<sub>50</sub> values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1<i>H</i>-Indol-3-yl)-<i>N</i>′-(4-morpholinobenzylidene)acetohydrazide (<b>3b</b>) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound <b>3b</b> decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound <b>3b</b> diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound <b>3b</b> stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor.https://www.mdpi.com/1422-0067/24/3/2648Aktanti-inflammatory actionCOX-1hydrazonesnon-small cell lung cancerthiosemicarbazides |
| spellingShingle | Mehlika Dilek Altıntop Gülşen Akalın Çiftçi Nalan Yılmaz Savaş İpek Ertorun Betül Can Belgin Sever Halide Edip Temel Özkan Alataş Ahmet Özdemir Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action International Journal of Molecular Sciences Akt anti-inflammatory action COX-1 hydrazones non-small cell lung cancer thiosemicarbazides |
| title | Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action |
| title_full | Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action |
| title_fullStr | Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action |
| title_full_unstemmed | Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action |
| title_short | Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action |
| title_sort | discovery of small molecule cox 1 and akt inhibitors as anti nsclc agents endowed with anti inflammatory action |
| topic | Akt anti-inflammatory action COX-1 hydrazones non-small cell lung cancer thiosemicarbazides |
| url | https://www.mdpi.com/1422-0067/24/3/2648 |
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