Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 24;8(22):20056-20065.
doi: 10.1021/acsomega.3c02331. eCollection 2023 Jun 6.

Design, Synthesis, and Evaluation of a New Series of Hydrazones as Small-Molecule Akt Inhibitors for NSCLC Therapy

Burak Erdönmez  1 , Mehlika Dilek Altıntop  2 , Gülşen Akalın Çiftçi  3 , Ahmet Özdemir  2 , Abdulilah Ece  4
Affiliations

Design, Synthesis, and Evaluation of a New Series of Hydrazones as Small-Molecule Akt Inhibitors for NSCLC Therapy

Burak Erdönmez et al. ACS Omega. .

Abstract

In an endeavor to identify small molecules for the management of non-small-cell lung carcinoma, 10 new hydrazone derivatives (3a-j) were synthesized. MTT test was conducted to examine their cytotoxic activities against human lung adenocarcinoma (A549) and mouse embryonic fibroblast (L929) cells. Compounds 3a, 3e, 3g, and 3i were determined as selective antitumor agents on A549 cell line. Further studies were conducted to figure out their mode of action. Compounds 3a and 3g markedly induced apoptosis in A549 cells. However, both compounds did not show any significant inhibitory effect on Akt. On the other hand, in vitro experiments suggest that compounds 3e and 3i are potential anti-NSCLC agents acting through Akt inhibition. Furthermore, molecular docking studies revealed a unique binding mode for compound 3i (the strongest Akt inhibitor in this series), which interacts with both hinge region and acidic pocket of Akt2. However, it is understood that compounds 3a and 3g exert their cytotoxic and apoptotic effects on A549 cells via different pathway(s).

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Pyrimidine-based hydrazones reported previously as anticancer agents by our research team.
Scheme 1
Scheme 1. Synthesis of Compounds 3a–j
(i) ClCH2COOEt, K2CO3, acetone, reflux, 10 h; (ii) NH2NH2.H2O, ethanol, stirring at room temperature, 5 h; (iii) ArCHO, ethanol, reflux, 8 h.
Figure 2
Figure 2
Flow cytometric analysis of A549 cells treated with IC50 values of compounds 3a, 3e, 3g, 3i, and cisplatin. At least 10,000 cells were analyzed per sample, and quadrant analysis was performed. Q1-UL, Q1-LL, Q1-UR, and Q1-LR quadrants represent necrosis, viability, and late and early apoptosis, respectively. (A) The main gate selected from the cell population, (B) control, (C) compound 3a, (D) compound 3e, (E) compound 3g, (F) compound 3i, and (G) cisplatin.
Figure 3
Figure 3
Binding mode of compound 3i within the binding region of Akt2.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Arya S. K.; Bhansali S. Lung cancer and its early detection using biomarker based biosensors. Chem. Rev. 2011, 111, 6783–6809. 10.1021/cr100420s. - DOI - PubMed
    1. Sung H.; Ferlay J.; Siegel R. L.; Laversanne M.; Soerjomataram I.; Jemal A.; Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. 10.3322/caac.21660. - DOI - PubMed
    1. Zhu T.; Bao X.; Chen M.; Lin R.; Zhuyan J.; Zhen T.; Xing K.; Zhou W.; Zhu S. Mechanisms and future of non-small cell lung cancer metastasis. Front. Oncol. 2020, 10, 58528410.3389/fonc.2020.585284. - DOI - PMC - PubMed
    1. Janku F.; Stewart D. J.; Kurzrock R. Targeted therapy in non-small-cell lung cancer-is it becoming a reality?. Nat. Rev. Clin. Oncol. 2010, 7, 401–414. 10.1038/nrclinonc.2010.64. - DOI - PubMed
    1. Jayan A. P.; Anandu K. R.; Madhu K.; Saiprabha V. N. A pharmacological exploration of targeted drug therapy in non-small cell lung cancer. Med. Oncol. 2022, 39, 147.10.1007/s12032-022-01744-6. - DOI - PubMed