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 language | English |
|---|---|
| Pages (from-to) | 96946-96962 |
| Number of pages | 17 |
| Journal | RSC Advances |
| Volume | 6 |
| Issue number | 99 |
| DOIs | |
| Publication status | Published - 01-01-2016 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Chemical Engineering(all)
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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, N.; Inaguma, Y.; Okamoto, A.; Easwaramoorthi, K.; Perumal, P. T.
In: RSC Advances, Vol. 6, No. 99, 01.01.2016, p. 96946-96962.Research output: Contribution to journal › Article
TY - JOUR
T1 - Synthetic investigation on chirally pure Mannich derivatives of pseudophenylpropanolamine and their anticancer properties against HepG-2 cells with inhibition of JAK2/STAT3
AU - Balachandran, C.
AU - Chennakesava Rao, K.
AU - Arun, Y.
AU - Emi, N.
AU - Yamamoto, N.
AU - Inaguma, Y.
AU - Okamoto, A.
AU - Easwaramoorthi, K.
AU - Perumal, P. T.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84991730377&partnerID=8YFLogxK
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U2 - 10.1039/c6ra22480f
DO - 10.1039/c6ra22480f
M3 - Article
AN - SCOPUS:84991730377
VL - 6
SP - 96946
EP - 96962
JO - RSC Advances
JF - RSC Advances
SN - 2046-2069
IS - 99
ER -