title: Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity.
abstract: We here report the synthesis and biological evaluation of several combretastatin A-4 derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined. In addition, the ability of these compounds to inhibit the production of the vascular endothelial growth factor (VEGF) was measured. Finally, the expression of genes controlling the production of telomerase was measured. Some of the compounds were found to have an activity comparable or higher than that of combretastatin A-4 in at least one of the aforementioned biological properties. The compounds with the (E)-arylalkene fragment were in general terms more active than the simple O-alkyl derivatives. However, no clear structure/activity correlations were perceived when comparing the observed compound activities across the three biological properties. This points out the existence of marked differences between the mechanisms responsible for their cytotoxicity.
authors.affiliation: Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Torijano-Gutiérrez
authors.forename: Santiago
authors.initials: S
authors.lastname: Díaz-Oltra
authors.forename: Eva
authors.initials: E
authors.lastname: Falomir
authors.forename: Juan
authors.initials: J
authors.lastname: Murga
authors.forename: Miguel
authors.initials: M
authors.lastname: Carda
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Marco
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001632:Bibenzyls; D042461:Vascular Endothelial Growth Factor A; C040105:combretastatin; D019098:Telomerase
keywords: Antiangiogenic compounds; Anticancer drugs; Combretastatin A-4 derivatives; Cytotoxic compounds; Telomerase; VEGF