TY - JOUR
T1 - Synthesis and biological evaluation of imidazo[1,5-a]pyridine-benzimidazole hybrids as inhibitors of both tubulin polymerization and PI3K/Akt pathway
AU - Kamal, Ahmed
AU - Subba Rao, A. V.S.
AU - Lakshma Nayak, V. L.
AU - Subba Reddy, N. V.S.
AU - Swapna, Konderu
AU - Ramakrishna, G.
AU - Alvala, Mallika
N1 - Publisher Copyright:
© 2014 The Royal Society of Chemistry.
PY - 2014/12/28
Y1 - 2014/12/28
N2 - A series of imidazo[1,5-a]pyridine-benzimidazole hybrids (5a-aa) were prepared and evaluated for their cytotoxic activity against a panel of sixty human tumor cell lines. Among them compounds 5d and 5l showed significant cytotoxic activity with GI50 values ranging from 1.06 to 14.9 μM and 0.43 to 7.73 μM, respectively. Flow cytometric analysis revealed that these compounds arrest the cell cycle at G2/M phase and induced cell death by apoptosis. The tubulin polymerization assay (IC50 of 5d is 3.25 μM and 5l is 1.71 μM) and immunofluorescence analysis showed that these compounds effectively inhibited the microtubule assembly in human breast cancer cells (MCF-7). Further, the apoptotic effects of compounds were confirmed by Hoechst staining, mitochondrial membrane potential, cytochrome c release, ROS generation, caspase 9 activation and DNA fragmentation analysis. After treatment with these compounds for 48 h, p-PTEN and p-AKT levels were markedly decreased. Moreover, these compounds did not significantly inhibit the normal human embryonic kidney cells, HEK-293. The molecular docking simulations predicted the binding interactions of 5d and 5l with colchicine binding site of the tubulin, which is in compliance with the antiproliferative activity data.
AB - A series of imidazo[1,5-a]pyridine-benzimidazole hybrids (5a-aa) were prepared and evaluated for their cytotoxic activity against a panel of sixty human tumor cell lines. Among them compounds 5d and 5l showed significant cytotoxic activity with GI50 values ranging from 1.06 to 14.9 μM and 0.43 to 7.73 μM, respectively. Flow cytometric analysis revealed that these compounds arrest the cell cycle at G2/M phase and induced cell death by apoptosis. The tubulin polymerization assay (IC50 of 5d is 3.25 μM and 5l is 1.71 μM) and immunofluorescence analysis showed that these compounds effectively inhibited the microtubule assembly in human breast cancer cells (MCF-7). Further, the apoptotic effects of compounds were confirmed by Hoechst staining, mitochondrial membrane potential, cytochrome c release, ROS generation, caspase 9 activation and DNA fragmentation analysis. After treatment with these compounds for 48 h, p-PTEN and p-AKT levels were markedly decreased. Moreover, these compounds did not significantly inhibit the normal human embryonic kidney cells, HEK-293. The molecular docking simulations predicted the binding interactions of 5d and 5l with colchicine binding site of the tubulin, which is in compliance with the antiproliferative activity data.
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U2 - 10.1039/c4ob01930j
DO - 10.1039/c4ob01930j
M3 - Article
C2 - 25354805
AN - SCOPUS:84911869699
SN - 1477-0520
VL - 12
SP - 9864
EP - 9880
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 48
ER -