title: Synthesis and biological evaluation of truncated α-tubulin-binding pironetin analogues lacking alkyl pendants in the side chain or the dihydropyrone ring.
abstract: The preparation of several new truncated analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the suppression of some of the alkyl pendants in either the side chain or the dihydropyrone ring. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that all analogues are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, thus strongly suggesting that, like natural pironetin, they also display a covalent mechanism of action. Their cytotoxicity is, however, lower than that of the parent compound. This indicates that all alkyl pendants are necessary for the full biological activity, with the ethyl group at C-4 seemingly being particularly relevant. Most likely, the alkyl groups cause a restriction in the conformational mobility of the molecule and reduce the number of available conformations. This makes it more probable that the molecule preferentially adopts a shape which fits better into the binding point in α-tubulin.
authors.affiliation: Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, E-12071 Castellón, Spain. jmurga@qio.uji.es.
authors.forename: Julián
authors.initials: J
authors.lastname: Paños
authors.forename: Santiago
authors.initials: S
authors.lastname: Díaz-Oltra
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Peris
authors.forename: Jorge
authors.initials: J
authors.lastname: García-Pla
authors.forename: Juan
authors.initials: J
authors.lastname: Murga
authors.forename: Eva
authors.initials: E
authors.lastname: Falomir
authors.forename: Miguel
authors.initials: M
authors.lastname: Carda
authors.forename: Mariano
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Marco
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011753:Pyrones; D014404:Tubulin; D050257:Tubulin Modulators; C088446:pironetin