Abstract
In an attempt to develop potent anticancer agents targeting Akt, new thiazole derivatives (1–10) were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma, and NIH/3T3 (healthy) mouse embryonic fibroblast cell lines. The most potent compounds were also investigated for their effects on apoptosis and Akt pathway. The most promising anticancer agent was found to be 2-[2-((4-(4-cyanophenoxy)phenyl)methylene)hydrazinyl]-4-(4-cyanophenyl)thiazole (6), due to its selective inhibitory effects on A549 and C6 cells with IC50 values of 12.0 ± 1.73 µg/mL and 3.83 ± 0.76 µg/mL, respectively. Furthermore, compound 6 increased early and late apoptotic cell population (32.8%) in C6 cell line more than cisplatin (28.8%) and significantly inhibited the Akt enzyme. The molecular docking study was performed to predict the possible binding modes of compounds A, 6, and 8 inside the active site of Akt (PDB code: 4EJN). Molecular docking simulations were found to be in accordance with in vitro studies and, hence, supported the biological activity. A computational study for the prediction of absorption, distribution, metabolism and excretion (ADME) properties of all compounds was also performed. On the basis of Lipinski’s rule of five, the compounds were expected to be potential orally bioavailable agents.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women [1].As the most common lung cancer type, non-small cell lung cancer (NSCLC) poses a continuous and serious threat to public health
Prompted by the aforementioned findings [29,30,31] and in the continuation of our ongoing research on thiazolyl hydrazones [32,33,34] related to their anticancer activity, we described the design and synthesis of a new series of thiazolyl hydrazone derivatives as potential anticancer agents targeting Akt
The structures of the compounds were confirmed by IR, 1 H-NMR, 13 C-NMR, and mass spectral data
Summary
As the most common lung cancer type, non-small cell lung cancer (NSCLC) poses a continuous and serious threat to public health. Despite significant advances in both diagnostic and therapeutic approaches, the overall survival for NSCLC patients still remains poor [2]. One main impediment for the treatment of NSCLC is that most patients are diagnosed at a late stage when the prognosis is poor and therapeutic options are limited [2,3,4]. Gliomas are the most common primary malignant brain tumors and ranked among the most aggressive human cancers [5,6]. Despite advances in standard therapy, the prognosis for patients with gliomas remains poor [6]. Current standard therapy for glioma patients is surgery followed by radiotherapy and adjuvant chemotherapy [5,6]. Efficacy of chemotherapy is limited due to poor drug delivery and inherent chemo- and radio-resistance [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
