title: Design, synthesis and SAR analysis of antitumour styryl lactones related to (+)-crassalactones B and C.
abstract: A series of styryl lactones containing the cinnamic acid ester groups such as (+)-crassalactones B (3a) and C (4a), 5,7-di-O-cinamoyl derivative 6, the corresponding 7-epimers and 7-deoxy derivatives have been synthesized, characterized and evaluated for their in vitro antitumour activity against a panel of several human tumour cell lines. Twelve new analogues such as 5-O- or 7-O-(4-methoxycinnamoyl), 5-O- or 7-O-(4-nitrocinnamoyl) and 5-O- or 7-O-(4-fluorocinnamoyl) esters of (+)-goniofufurone (3b-d), 7-epi-(+)-goniofufurone (epi-3b-d), as well as 7-deoxy derivatives 5b-d have been prepared to correlate all compounds in a SAR study. Some of the analogues displayed powerful antiproliferative effects on selected human tumour cell lines, but none of them demonstrated cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). Thus, for the 7-epi-crassalactone B (epi-3a) was found to be a potent inhibitor of HL-60 cells growth, with an IC50 value that is approximately 46-fold lower than that observed for the commercial antitumour drug doxorubicin in the culture of the same cells. A SAR analysis performed on these lactones reveals the main structural features that affect their antiproliferative activity, such as nature of the substituents at the C-4 in the aromatic rings of cinnamoyl moieties, the absolute stereochemistry, as well as the presence of a deoxy function at the C-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: 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: 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: 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: 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*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; C000599655:crassalactone B; C524151:crassalactone C
keywords: Antitumour activity; Cinnamoates; Crassalactone B; Crassalactone C; Structure–activity relationships; Styryl lactone