title: Design and synthesis of aminostilbene-arylpropenones as tubulin polymerization inhibitors.
abstract: A series of aminostilbene-arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI50) values in the range from < 0.01 to 19.9 μM. One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI50 value of < 0.01 μM. All of the synthesized compounds displayed cytotoxicity against A549 (non-small-cell lung cancer), HeLa (cervical carcinoma), MCF-7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC50) values ranging from 0.011 to 8.56 μM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79 μM. Moreover, dot-blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.
authors.affiliation: Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology Hyderabad, 500 007 (India); Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad-500 037 (India). ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: G Bharath
authors.initials: GB
authors.lastname: Kumar
authors.forename: Sowjanya
authors.initials: S
authors.lastname: Polepalli
authors.forename: Anver Basha
authors.initials: AB
authors.lastname: Shaik
authors.forename: Vangala Santhosh
authors.initials: VS
authors.lastname: Reddy
authors.forename: M Kashi
authors.initials: MK
authors.lastname: Reddy
authors.forename: Ch Ratna
authors.initials: ChR
authors.lastname: Reddy
authors.forename: Rasala
authors.initials: R
authors.lastname: Mahesh
authors.forename: Jeevak Sopanrao
authors.initials: JS
authors.lastname: Kapure
authors.forename: Nishant
authors.initials: N
authors.lastname: Jain
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D013267:Stilbenes / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D000475:Alkenes; D000970:Antineoplastic Agents; D056744:Cyclin B1; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C013658:propylene
keywords: antiproliferation; cell-cycle arrest; dot-blot analyses; molecular docking; polymerization