title: Cytotoxic 3,4,5-trimethoxychalcones as mitotic arresters and cell migration inhibitors.
abstract: Based on classical colchicine site ligands and a computational model of the colchicine binding site on beta tubulin, two classes of chalcone derivatives were designed, synthesized and evaluated for inhibition of tubulin assembly and toxicity in human cancer cell lines. Docking studies suggested that the chalcone scaffold could fit the colchicine site on tubulin in an orientation similar to that of the natural product. In particular, a 3,4,5-trimethoxyphenyl ring adjacent to the carbonyl group appeared to benefit the ligand-tubulin interaction, occupying the same subcavity as the corresponding moiety in colchicine. Consistent with modeling predictions, several 3,4,5-trimethoxychalcones showed improved cytotoxicity to murine acute lymphoblastic leukemia cells compared with a previously described parent compound, and inhibited tubulin assembly in vitro as potently as colchicine. The most potent chalcones inhibited the growth of human leukemia cell lines at nanomolar concentrations, caused microtubule destabilization and mitotic arrest in human cervical cancer cells, and inhibited human breast cancer cell migration in scratch wound and Boyden chamber assays.
authors.affiliation: Laboratório de Química Medicinal e Computacional, IFSC - USP, São Carlos, SP, Brazil.
authors.forename: Lívia B
authors.initials: LB
authors.lastname: Salum
authors.forename: Wanessa F
authors.initials: WF
authors.lastname: Altei
authors.forename: Louise D
authors.initials: LD
authors.lastname: Chiaradia
authors.forename: Marlon N S
authors.initials: MN
authors.lastname: Cordeiro
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Canevarolo
authors.forename: Carolina P S
authors.initials: CP
authors.lastname: Melo
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.forename: Bruno
authors.initials: B
authors.lastname: Mattei
authors.forename: Hikmat N
authors.initials: HN
authors.lastname: Daghestani
authors.forename: Maria Cláudia
authors.initials: MC
authors.lastname: Santos-Silva
authors.forename: Tânia B
authors.initials: TB
authors.lastname: Creczynski-Pasa
authors.forename: Rosendo A
authors.initials: RA
authors.lastname: Yunes
authors.forename: José A
authors.initials: JA
authors.lastname: Yunes
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D058105:Polymerization / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
chemical_list: D047188:Chalcones; D014404:Tubulin; C003702:metochalcone