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

C. Balachandran, K. Chennakesava Rao, Y. Arun, N. Emi, Naoki Yamamoto, Y. Inaguma, Akinao Okamoto, K. Easwaramoorthi, P. T. Perumal

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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.

Original languageEnglish
Pages (from-to)96946-96962
Number of pages17
JournalRSC Advances
Volume6
Issue number99
DOIs
Publication statusPublished - 01-01-2016

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Derivatives
Cell proliferation
Cell growth
Cell death
Binding energy
Heterografts
Caspase 3
Tumors
Condensation
Cells
Apoptosis
Proteins
cytochrome c(3)

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Balachandran, C. ; Chennakesava Rao, K. ; Arun, Y. ; Emi, N. ; Yamamoto, Naoki ; Inaguma, Y. ; Okamoto, Akinao ; Easwaramoorthi, K. ; Perumal, P. T. / Synthetic investigation on chirally pure Mannich derivatives of pseudophenylpropanolamine and their anticancer properties against HepG-2 cells with inhibition of JAK2/STAT3. In: RSC Advances. 2016 ; Vol. 6, No. 99. pp. 96946-96962.
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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.",
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Synthetic investigation on chirally pure Mannich derivatives of pseudophenylpropanolamine and their anticancer properties against HepG-2 cells with inhibition of JAK2/STAT3. / Balachandran, C.; Chennakesava Rao, K.; Arun, Y.; Emi, N.; Yamamoto, Naoki; Inaguma, Y.; Okamoto, Akinao; Easwaramoorthi, K.; Perumal, P. T.

In: RSC Advances, Vol. 6, No. 99, 01.01.2016, p. 96946-96962.

Research output: Contribution to journalArticle

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AU - Balachandran, C.

AU - Chennakesava Rao, K.

AU - Arun, Y.

AU - Emi, N.

AU - Yamamoto, Naoki

AU - Inaguma, Y.

AU - Okamoto, Akinao

AU - Easwaramoorthi, K.

AU - Perumal, P. T.

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