Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action


ALTINTOP M. D., AKALIN ÇİFTÇİ G., Yılmaz Savaş N., Ertorun İ., CAN B., SEVER B., ...More

International Journal of Molecular Sciences, vol.24, no.3, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 24 Issue: 3
  • Publication Date: 2023
  • Doi Number: 10.3390/ijms24032648
  • Journal Name: International Journal of Molecular Sciences
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: Akt, anti-inflammatory action, COX-1, hydrazones, non-small cell lung cancer, thiosemicarbazides, CELL LUNG-CANCER, BIOLOGICAL EVALUATION, HYDRAZONE DERIVATIVES, THIOSEMICARBAZONE DERIVATIVES, ANTICANCER AGENTS, NITRIC-OXIDE, INFLAMMATION, DRUG, INDOMETHACIN, DESIGN
  • Eskisehir Osmangazi University Affiliated: Yes

Abstract

© 2023 by the authors.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 3b and 4a were found to be the most selective COX-1 inhibitors in this series with IC50 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-(1H-Indol-3-yl)-N′-(4-morpholinobenzylidene)acetohydrazide (3b) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound 3b decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound 3b diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound 3b stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor.