title: Synthesis and antiproliferative activity of goniobutenolides A and B, 5-halogenated crassalactone D derivatives and the corresponding 7-epimers.
abstract: A new synthesis of goniobutenolides A (1) and B (2) and the corresponding 7-epimers has been achieved starting from diacetone d-glucose. The key step of the synthesis is a new one-pot sequence that commenced with Z-selective Wittig (or Horner-Wadsworth-Emmons) olefination, followed by successive γ-lactonisation and β-elimination. The above-mentioned unsaturated lactones were then converted to the corresponding 5-halogenated crassalactone D derivatives by using the appropriate haloetherification protocol. The most of synthesized compounds exhibited potent cytotoxic activities against a panel of tumour cell lines. The main structural features responsible for their antitumour potency have been revealed by means of SAR analysis. Flow cytometry data suggested that cytotoxic effects of these compounds in the culture of K562 cells might be mediated by apoptosis, additionally revealing that these molecules induced changes in cell cycle distribution of these cells. Results of semi-quantitative Western blot analysis indicate that the most of synthesized compounds induce apoptosis in a caspase-dependent manner.
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: Goran
authors.initials: G
authors.lastname: Benedeković
authors.affiliation: Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204, Sremska Kamenica, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Kojić
authors.affiliation: Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204, Sremska Kamenica, Serbia.
authors.forename: Dimitar
authors.initials: D
authors.lastname: Jakimov
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: Marko V
authors.initials: MV
authors.lastname: Rodić
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Srdić-Rajić
authors.affiliation: Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204, Sremska Kamenica, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Bogdanović
authors.affiliation: Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 4, 21000 Novi Sad, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divjaković
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*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D013141:Spiro Compounds; C545739:crassalactone D; C578361:goniobutenolide A; C578362:goniobutenolide B
keywords: Antitumour activity; Apoptosis; Crassalactone D; Goniobutenolide A; Goniobutenolide B; Haloetherification; Structure-activity relationships