title: Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents.
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.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: G Bharath
authors.initials: GB
authors.lastname: Kumar
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: V Lakshma
authors.initials: VL
authors.lastname: Nayak
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Ibrahim Bin
authors.initials: IB
authors.lastname: Sayeed
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Vangala Santhosh
authors.initials: VS
authors.lastname: Reddy
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Anver Basha
authors.initials: AB
authors.lastname: Shaik
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Rasala
authors.initials: R
authors.lastname: Mahesh
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Mirza Feroz
authors.initials: MF
authors.lastname: Baig
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Mohd Adil
authors.initials: MA
authors.lastname: Shareef
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: A
authors.initials: A
authors.lastname: Ravikumar
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Catalytic Chemistry Chair, Chemistry Department College of Science, King Saud University, Riyadh, Saudi Arabia. Electronic address: ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010755:Organophosphates; D000078183:Oxindoles; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D001577:Benzophenones; D007211:Indoles; D010755:Organophosphates; D000078183:Oxindoles; D013267:Stilbenes; C000612886:isocombretastatin-oxindole; C000612885:phenstatin; C112107:phenstatin phosphate; C022960:2-oxindole
keywords: Annexin V-FITC and mitochondrial membrane depolarization; Phenstatin/isocombretastatin-oxindole; Tubulin depolymerization