title: Synthesis and antiproliferative activity of ligerin and new fumagillin analogs against osteosarcoma.
abstract: Ligerin (1) is a natural chlorinated merosesquiterpenoid related to fumagillin (2) exhibiting a selective antiproliferative activity against osteosarcoma cell lines and an in vivo antitumor activity in a murine model. Semisynthesis of ligerin analogs was performed in order to study the effects of the C3-spiroepoxide substitution by a halogenated moiety together with the modulation of the C6 chain. Results showed that all derivatives exhibited an in vitro antiproliferative activity against osteosarcoma cell lines and that chlorohydrin compounds were equally or more active than their spiroepoxy analogs. Among semisynthetic analogs, the parent compound 1 was the best candidate for further studies since it exhibited higher or equivalent activity compared to TNP470 (3) against SaOS2 and MG63 human osteosarcoma cells with a four times weaker toxicity against HFF2 human fibroblasts. Quantitative videomicroscopy analysis was conducted and allowed a better understanding of the mechanism of its antiproliferative activity.
authors.affiliation: University of Nantes, Faculty of Pharmacy, MMS-EA260, Nantes F-44000, France; Atlanthera, Atlantic Bone Screen, Nantes, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Blanchet
authors.affiliation: University of Nantes, Faculty of Pharmacy, MMS-EA260, Nantes F-44000, France.
authors.forename: Marieke
authors.initials: M
authors.lastname: Vansteelandt
authors.affiliation: Atlanthera, Atlantic Bone Screen, Nantes, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Le Bot
authors.affiliation: Atlanthera, Atlantic Bone Screen, Nantes, France.
authors.forename: Maxim
authors.initials: M
authors.lastname: Egorov
authors.affiliation: University of Nantes, Faculty of Pharmacy, MMS-EA260, Nantes F-44000, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Guitton
authors.affiliation: University of Nantes, Faculty of Pharmacy, MMS-EA260, Nantes F-44000, France.
authors.forename: Yves François
authors.initials: YF
authors.lastname: Pouchus
authors.affiliation: University of Nantes, Faculty of Pharmacy, MMS-EA260, Nantes F-44000, France. Electronic address: olivier.grovel@univ-nantes.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Grovel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C580644:ligerin; C026211:fumagillin
keywords: Antiproliferative; Cytostatic; Fumagillin; Ligerin; Marine-derived Penicillium; Osteosarcoma