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Novel Indole-fused benzo-oxazepines (IFBOs) inhibit invasion of hepatocellular
carcinoma by targeting IL-6 mediated JAK2/STAT3 oncogenic signals
#MMPMID29651140
Singh AK
; Bhadauria AS
; Kumar U
; Raj V
; Rai A
; Kumar P
; Keshari AK
; Kumar D
; Maity B
; Nath S
; Prakash A
; Saha S
Sci Rep
2018[Apr]; 8
(1
): 5932
PMID29651140
show ga
Inspired by the well-documented tumor protecting ability of paullones, recently,
we synthesized novel paullone-like scaffolds, indole-fused benzo-oxazepines
(IFBOs), and screened them against hepatocellular carcinoma (HCC) specific Hep-G2
cells. Three of the synthesized compounds significantly attenuated the
progression of HCC in vitro. By computational studies, we further discovered that
IFBOs exhibited a stable binding complex with the IL-6 receptor. In this context,
we investigated in vivo study using the nitrosodiethyl amine (NDEA)-induced HCC
model, which strengthened our previous findings by showing the blockade of the
IL-6 mediated JAK2/STAT3 oncogenic signaling pathway. Treatment with IFBOs showed
remarkable attenuation of cellular proliferation, as evidenced through a decrease
in the number of nodules, restoration of body weight, oxidative stress
parameters, liver marker enzymes and histological architecture. Interestingly,
using a metabolomic approach we further discovered that IFBOs can restore the
perturbed metabolic profile associated with the HCC condition to normalcy.
Particularly, the efficacy of compound 6a for an anti-HCC response was
significantly better than the marketed chemotherapeutic drug, 5-fluorouracil.
Altogether, these remarkable findings open up possibilities of developing IFBOs
as novel future candidate molecules for plausible alternatives for HCC treatment.
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