title: Synthesis and biological evaluation of benzo[b]furans as inhibitors of tubulin polymerization and inducers of apoptosis.
abstract: A series of benzo[b]furans was synthesized with modification at the 5-position of the benzene ring by introducing C-linked substituents (aryl, alkenyl, alkynyl, etc.). These compounds were evaluated for their antiproliferative activities, inhibition of tubulin polymerization, and cell-cycle effects. Some compounds in this series displayed excellent activity in the nanomolar range against lung cancer (A549) and renal cell carcinoma (ACHN) cancer cell lines. (6-Methoxy-5-((4-methoxyphenyl)ethynyl)-3-methylbenzofuran-2-yl)(3,4,5-trimethoxyphenyl)methanone (26) and (E)-3-(6-methoxy-3-methyl-2-(1-(3,4,5-trimethoxyphenyl)vinyl)benzofuran-5-yl)prop-2-en-1-ol (36) showed significant activity in the A549 cell line, with IC₅₀ values of 0.08 and 0.06 μM, respectively. G₂/M cell-cycle arrest and subsequent apoptosis was observed in the A549 cell line after treatment with these compounds. The most active compound in this series, 36, also inhibited tubulin polymerization with a value similar to that of combretastatin A-4 (1.95 and 1.86 μM, respectively). Furthermore, detailed biological studies such as Hoechst 33258 staining, DNA fragmentation and caspase-3 assays, and western blot analyses with the pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 also suggested that these compounds induce cell death by apoptosis. Molecular docking studies indicated that compound 36 interacts and binds efficiently with the tubulin protein.
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: N V Subba
authors.initials: NV
authors.lastname: Reddy
authors.forename: V Lakshma
authors.initials: VL
authors.lastname: Nayak
authors.forename: V Saidi
authors.initials: VS
authors.lastname: Reddy
authors.forename: B
authors.initials: B
authors.lastname: Prasad
authors.forename: Vijaykumar D
authors.initials: VD
authors.lastname: Nimbarte
authors.forename: Vunnam
authors.initials: V
authors.lastname: Srinivasulu
authors.forename: M V P S
authors.initials: MV
authors.lastname: Vishnuvardhan
authors.forename: C Suresh
authors.initials: CS
authors.lastname: Reddy
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D058105:Polymerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001572:Benzofurans; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D050257:Tubulin Modulators; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; C105430:benzofuran
keywords: antiproliferation; antitumor agents; apoptosis; benzofurans; tubulin polymerization