title: New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and antiproliferative activity of (-)-cleistenolide and analogues.
abstract: A stereoselective total synthesis of (-)-cleistenolide (1) from d-glucose has been achieved. This new approach for the synthesis of (-)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC50 0.02μM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized δ-lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position.
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Benedeković
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kovačević
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Popsavin
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Jovana
authors.initials: J
authors.lastname: Francuz
authors.affiliation: Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Kojić
authors.affiliation: Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Bogdanović
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: velimir.popsavin@dh.uns.ac.rs.
authors.forename: Velimir
authors.initials: V
authors.lastname: Popsavin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D011753:Pyrones; C550131:cleistenolide
keywords: Analogue synthesis; Antitumour δ-lactones; Cleistenolide; Cleistenolide mimics; SAR