Background: Flavonoids are naturally occurring compounds with versatile healthpromoting
effects against various diseases.
Objective: This aim of this paper is to synthesize and evaluate the biological activity of novel
flavone derivatives against cancer.
Methods: A new series of 2-hydroxy-α,β-unsaturated ketones 2a-h, was synthesized via the reaction
of N-substituted-indole-3-carboxaldehyde 1a-h with 2-hydroxy acetophenone in the presence
of piperidine. The oxidative cyclization of 2a-h using hydrogen peroxide/KOH and/or dimethyl
sulfoxide/I2 produced the corresponding 2-(N-substituted-1H-indol-3-yl)-3-hydroxy-4H-chromen-
4-ones 3a-h and 2-(N-substituted-1H-indol-3-yl)-4H-chromen-4-ones 4a-h, respectively. Antiproliferative
activities for synthesized series were investigated against HCT-116 colon and MCF-
7 breast cancer cell lines. Molecular downstream effects were evaluated using RT-PCR. Moreover,
molecular docking was carried out to pinpoint the binding mode of the most active compounds
into the active site of Akt enzyme (PDB ID: 3QKK).
Results: All compounds exhibited an anti-proliferative activity range of 52-97% and 67.2-99%
against HCT-116 and MCF-7, respectively. Compounds 3b, 3h, 3g and 4h had a minimal inhibitory
effect on normal BJ1 cells indicating their safety profile. Compounds 3b and 4h, in particular,
exhibited the most potent antiproliferative activity against HCT116 and MCF7, meanwhile
compounds 3g, 3h and 4g showed potent to moderate activity. Compound 3b had IC50 of 78.3 μM
and 53.9 μM against HCT-116 and MCF-7 respectively with comparable IC50 for doxorubicin of
65.1 μM and 45.02 μM. Compound 3b exhibited significant down-regulation for Akt and significant
up-regulation of CAS9 and CDKN1genes in all tested cell lines.
Conclusion: The synthesized flavone derivatives and particularly compound 3b exhibited promising
anticancer activity through Akt inhibition.