Design, Synthesis of Phenstatin/isocombretastatin-Oxindole Conjugates as Antimitotic agents

Publication date: Available online 3 March 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): G. Bharath Kumar, V. Lakshma Nayak, Ibrahim Bin Sayeed, Vangala Santhosh Reddy, Anver Basha Shaik, Mirza Feroz Baig, Mohd Adil Shareef, A. Ravikumar, Rasala Mahesh, Ahmed Kamal
A series of phenstatin/isocombretasatin-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 0.049-38.90 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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