Synthetic investigation on chirally pure Mannich derivatives of pseudophenylpropanolamine and their anticancer properties against HepG-2 cells with inhibition of JAK2/STAT3?

RSC Advances Pub Date: 2016-10-07 DOI: 10.1039/C6RA22480F

Abstract

A novel series of Mannich derivatives of 3a–g and 3a′–g′ were designed and synthesized from pseudophenylpropanolamine (Ψ-PPA). The stereo chemical aspects of the synthesized compounds were studied and all compounds were well characterized with respect to spectral techniques. All Mannich derivatives, 3a–g and 3a′–g′ were evaluated for their anti-proliferative activity against A549 and HepG-2 cells. Among the tested compounds, 3a showed significant anti-proliferative activity against HepG-2 cells at 25 μM when compared to other compounds. The treatment of 3a exhibited morphological changes, nuclear condensation, colony formatting ability, apoptosis and cell cycle arrest at G2/M phase in HepG-2 cells. Besides, 3a triggered mitochondrial mediated apoptotic pathway as indicated by down regulation of Bcl-2, up-regulation of Bax, and release of cytochrome c and caspases-3. Furthermore, 3a effectively suppressed the cell proliferation and cell growth via JAK2/STAT3 signaling pathway in a time and dose dependent manner. In vivo administration of 3a inhibited tumor growth without significant change in body weight in HepG-2 xenograft mice model. Molecular docking studies revealed that good binding energies of compound 3a against JAK2 (?6.10 kcal mol?1) and Bcl-2 (?6.04 kcal mol?1) receptors. Taken together, 3a possessed potent antitumor activity; it could be a promising lead candidate for the potential treatment of human hepatocellular carcinoma.

Graphical abstract: Synthetic investigation on chirally pure Mannich derivatives of pseudophenylpropanolamine and their anticancer properties against HepG-2 cells with inhibition of JAK2/STAT3
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