Background:
Akt is overexpressed or activated in a variety of human cancers, including
gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction
of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted
to the discovery of potent antitumor drugs targeting Akt.
Objectives:
The objective of this work was to identify potent anticancer agents targeting Akt.
Methods:
New hydrazone derivatives were synthesized and investigated for their cytotoxic effects
on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast
cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were
evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric
assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME)
studies were also performed using Schrödinger’s Maestro molecular modeling package.
Results and Discussion:
Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells
(with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with
cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced
apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin-
2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared
with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed
good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the
compound also complies with Lipinski's rule of five and Jorgensen's rule of three.
Conclusion:
Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis
inducer targeting Akt.
