title: Design and synthesis of 4'-O-alkylamino-tethered-benzylideneindolin-2-ones as potent cytotoxic and apoptosis inducing agents.
abstract: A series of new 4'-O-alkylamino-tethered-benzylideneindolin-2-one derivatives has been synthesized and evaluated for their anti-proliferative activity against selected human cancer cell lines of lung (A549), prostate (DU-145), breast (BT549 and MDA-MB-231) and normal breast epithelial cells (MCF-10A). Gratifyingly, the compounds 5j, 5o and 5r exhibited potent cytotoxicity against breast cancer cell lines (BT549 and MDA-MB-231) with IC50 values in the range of 1.26-2.77μM, and are found to be safer with lesser cytotoxicity on normal breast epithelial cells (MCF-10A). Further, experiments were conducted with these compounds 5j, 5o and 5r on MDA-MB-231 cancer cells to study the mechanism of growth inhibition and apoptosis inducing effect. Treatment of MDA-MB-231 cells with test compounds resulted in inhibition of cell migration through disorganization and disruption of F-actin capping protein. The flow-cytometry analysis results showed that the compound 5o arrested MDA-MB-231 cells in G0/G1 phase of cell cycle in a dose dependent manner. Hoechst staining study revealed that the test compounds inhibited tumor cell proliferation through induction of apoptosis. In addition, the mitochondrial membrane potential (DΨm) was affected and the increased level of reactive oxygen species (ROS) was noted in MDA-MB-231 cells.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Kishna Ram
authors.initials: KR
authors.lastname: Senwar
authors.affiliation: Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne 3001, Australia.
authors.forename: T Srinivasa
authors.initials: TS
authors.lastname: Reddy
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thummuri
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne 3001, Australia.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Bharghava
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: V G M
authors.initials: VG
authors.lastname: Naidu
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar@niperhyd.ac.in.
authors.forename: Nagula
authors.initials: N
authors.lastname: Shankaraiah
mesh_terms: D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008856:Microscopy, Fluorescence; D000078183:Oxindoles; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; C022960:2-oxindole
keywords: 3-Alkenyl-oxindole; Anticancer; Apoptosis; Benzylideneindolinone; Knoevenagel reaction