title: Design and synthesis of pironetin analogue/colchicine hybrids and study of their cytotoxic activity and mechanisms of interaction with tubulin.
abstract: We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an ester-amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated. Relations between the structure and activity are discussed. Since the spacer is not long enough to permit a simultaneous binding of the hybrid molecules to the colchicine and pironetin sites on tubulin, a further feature investigated was whether these molecules would interact with the latter through the pironetin end (irreversible covalent binding) or through the colchicine end (reversible noncovalent binding). It has been found that binding to tubulin may take place preferentially at either of these ends depending on the length of the connecting spacer.
authors.affiliation: Departament de Química Inorgànica i Orgànica, Universitat Jaume I , E-12071 Castellón de la Plana, Castellón, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Vilanova
authors.forename: Santiago
authors.initials: S
authors.lastname: Díaz-Oltra
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* / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects*; D003078:Colchicine / Q000737:chemistry*; D015195:Drug Design; D005455:Fluorescent Antibody Technique; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011753:Pyrones / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011753:Pyrones; D014404:Tubulin; C088446:pironetin; D003078:Colchicine