Synthetic investigation on chirally pure Mannich derivatives of pseudophenylpropanolamine and their anticancer properties against HepG-2 cells with inhibition of JAK2/STAT3Electronic supplementary information (ESI) available. CCDC 1443803. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra22480f

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. In vitro and in vivo anticancer activity of compound 3a was proved as a novel blocker of JAK2/STAT3 signaling pathway and exerts both anti-proliferative and apoptotic activities in HepG-2 cells with xenograft mice model.