title: Synthesis and biological activity of fluorinated combretastatin analogues.
abstract: With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.
authors.affiliation: R&D, Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30.400, 00040 Pomezia, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alloatti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Isabella
authors.initials: I
authors.lastname: Lustrati
authors.forename: Mauro
authors.initials: M
authors.lastname: Marzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciacci
authors.forename: Grazia
authors.initials: G
authors.lastname: Gallo
authors.forename: M Ornella
authors.initials: MO
authors.lastname: Tinti
authors.forename: Marcella
authors.initials: M
authors.lastname: Marcellini
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.forename: Mario B
authors.initials: MB
authors.lastname: Guglielmi
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005461:Fluorine; D006801:Humans; D008833:Microcirculation / Q000166:cytology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D001704:Biopolymers; D013267:Stilbenes; D014404:Tubulin; D005461:Fluorine; C040105:combretastatin