A new series of thiazole‐hydrazone hybrids for Akt‐targeted therapy of non‐small cell lung cancer

• Published in: Drug development research Vol. 84; no. 2; pp. 185 - 199
• Main Authors: Orujova, Turana, Ece, Abdulilah, Akalın Çiftçi, Gülşen, Özdemir, Ahmet, Altıntop, Mehlika D.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-04-2023
• Subjects: Adenocarcinoma; Akt inhibition; AKT protein; Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; Apoptosis; Binding; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cisplatin - pharmacology; Cytotoxicity; Drug Screening Assays, Antitumor; Embryo fibroblasts; Fibroblasts; Humans; Hybrids; hydrazone; Hydrazones; Hydrazones - pharmacology; induced‐fit docking; Lung cancer; Lung Neoplasms - drug therapy; Methylene; Mice; Molecular Docking Simulation; Molecular Structure; Non-small cell lung carcinoma; Proto-Oncogene Proteins c-akt; Structure-Activity Relationship; thiazole; Thiazoles - chemistry; Thiazoles - pharmacology; lung cancer; induced-fit docking; apoptosis; hydrazone; Akt inhibition; thiazole
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.22022

In an attempt to identify potent antitumor agents for the fight against non‐small cell lung cancer, new thiazolyl hydrazones (2a–n) were synthesized and examined for their in vitro cytotoxic effects on A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells by means of the MTT assay. Furthermore, the effects of the most potent anticancer agents on apoptosis and Akt inhibition were investigated. 2‐[2‐((Isoquinolin‐5‐yl)methylene)hydrazinyl]−4‐(4‐methylsulfonylphenyl)thiazole (2k) (IC50 = 1.43 ± 0.12 µM) and 2‐[2‐((isoquinolin‐5‐yl)methylene)hydrazinyl]−4‐(1,3‐benzodioxol‐5‐yl)thiazole (2l) (IC50 = 1.75 ± 0.07 µM) displayed more pronounced anticancer activity than cisplatin (IC50 = 3.90 ± 0.10 µM) on A549 cell lines; 2‐[2‐((isoquinolin‐5‐yl)methylene)hydrazinyl]−4‐(4‐methoxyphenyl)thiazole (2j) (IC50 = 3.93 ± 0.06 µM) showed anticancer activity close to cisplatin. These compounds were found to induce apoptosis in A549 cells. Compound 2j (IC50 = 3.55 ± 0.64 µM) showed stronger Akt inhibitory activity than GSK690693 (IC50 = 4.93 ± 0.06 µM), while compounds 2k and 2l did not cause Akt inhibition at IC50 concentrations (1.43 and 1.75 µM, respectively). To comprehensively elucidate the binding pose of compound 2j and to provide a detailed understanding on the ligand' binding mechanism, induced‐fit docking calculations were also conducted. Both in vitro and in silico studies suggest that compound 2j shows its cytotoxic and apoptotic effects on A549 cell lines via Akt inhibition. However, it is understood that compounds 2k and 2l exert their strong anticancer effects on A549 cells through different pathways.