Design,synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents |
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| Institution: | 1. Medicinal Chemistry and Pharmacology, CSIR—Indian Institute of Chemical Technology, Hyderabad 500 007, India;2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;3. Catalytic Chemistry Chair, Chemistry Department College of Science, King Saud University, Riyadh, Saudi Arabia;1. Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, 1370 Sankyuk-dong, Taegu 702-701, Republic of Korea;2. Department of Chemistry, Shaheed Benazir Bhutto University, Sheringal, Dir (Upper), Khyber Pakhtunkhwa, Pakistan |
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| Abstract: | A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin. |
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| Keywords: | Phenstatin/isocombretastatin-oxindole Tubulin depolymerization Annexin V-FITC and mitochondrial membrane depolarization |
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