title: Synthesis of C5-tethered indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors.
abstract: A series of C5-tethered Indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 7f displayed cytotoxicity of IC50= 140 nM towards DU145 cancer cell line. The treatment of DU145 cells with 7f led to inhibition of cell migration ability. Futher, the detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 7f induced apoptosis in DU145 cells. The influence of the cytotoxic compound 7f on the cell cycle distribution was assessed on the DU145 cell line, exhibiting a cell cycle arrest at the G2/M phase (hallmark of tubulin polymerization) and next inhibited tubulin polymerization with IC500.40 μM. Furthermore, the treatment with compound 7f caused collapse of mitochondrial membrane potential and elevated intracellular superoxide ROS levels in DU145 cells. Western blotting was performed to examine the levels of apoptotic proteins (Bcl-2 and Bax); the study confirmed that compound 7f induced apoptosis through apoptosis-related protein expression. Thus, these studies provided a new molecular scaffold for the further development of anticancer agents that target tubulin.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Sravanthi Devi
authors.initials: SD
authors.lastname: Guggilapu
authors.affiliation: Pharmacology and Toxicology Division, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Guntuku
authors.initials: G
authors.lastname: Lalita
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 Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Prajapti
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Atulya
authors.initials: A
authors.lastname: Nagarsenkar
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Shymala
authors.initials: S
authors.lastname: Ramu
authors.affiliation: Pharmacology and Toxicology Division, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Uma Rani
authors.initials: UR
authors.lastname: Brahma
authors.affiliation: Pharmacology and Toxicology Division, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Uppa Jaya
authors.initials: UJ
authors.lastname: Lakshmi
authors.affiliation: Pharmacology and Toxicology Division, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Ganga Modi Naidu
authors.initials: GMN
authors.lastname: Vegi
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: Bhargava
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: bathini@niperhyd.ac.in.
authors.forename: Bathini Nagendra
authors.initials: BN
authors.lastname: Babu
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006038:Glyoxylates / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D058105:Polymerization; D013481:Superoxides / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D006038:Glyoxylates; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators; D013481:Superoxides
keywords: Anticancer; Apoptosis; Indolyl-3-glyoxylamide; Tubulin polymerization inhibitor