title: N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia.
abstract: Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.
authors.affiliation: Laboratório de Química Medicinal e Computacional, Universidade de São Paulo, São Carlos, SP 13560-590, Brazil.
authors.forename: Lívia B
authors.initials: LB
authors.lastname: Salum
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.affiliation: Centro Infantil Boldrini, Campinas, SP 13083-210, Brazil.
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Canevarolo
authors.affiliation: Laboratório de Química Medicinal e Computacional, Universidade de São Paulo, São Carlos, SP 13560-590, Brazil.
authors.forename: Wanessa F
authors.initials: WF
authors.lastname: Altei
authors.affiliation: Centro Infantil Boldrini, Campinas, SP 13083-210, Brazil.
authors.forename: Angelo B A
authors.initials: AB
authors.lastname: Laranjeira
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Patrícia D
authors.initials: PD
authors.lastname: Neuenfeldt
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Taisa R
authors.initials: TR
authors.lastname: Stumpf
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Louise D
authors.initials: LD
authors.lastname: Chiaradia-Delatorre
authors.affiliation: Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Vollmer
authors.affiliation: Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Hikmat N
authors.initials: HN
authors.lastname: Daghestani
authors.affiliation: Centro Infantil Boldrini, Campinas, SP 13083-210, Brazil.
authors.forename: Carolina P
authors.initials: CP
authors.lastname: de Souza Melo
authors.affiliation: Centro Infantil Boldrini, Campinas, SP 13083-210, Brazil.
authors.forename: André B
authors.initials: AB
authors.lastname: Silveira
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Leal
authors.affiliation: Laboratório de Neurobiologia da Dor e Inflamação, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Marisa J S
authors.initials: MJ
authors.lastname: Frederico
authors.affiliation: Laboratório de Neurobiologia da Dor e Inflamação, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: do Nascimento
authors.affiliation: Laboratório de Neurobiologia da Dor e Inflamação, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
authors.affiliation: Laboratório de Química Medicinal e Computacional, Universidade de São Paulo, São Carlos, SP 13560-590, Brazil.
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors.forename: Rosendo A
authors.initials: RA
authors.lastname: Yunes
authors.affiliation: Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Centro Infantil Boldrini, Campinas, SP 13083-210, Brazil. Electronic address: andres@boldrini.org.br.
authors.forename: José A
authors.initials: JA
authors.lastname: Yunes
authors.affiliation: Laboratório Estrutura e Atividade, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil. Electronic address: nunesricardoj@gmail.com.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Nunes
mesh_terms: D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000840:Anisoles; D000970:Antineoplastic Agents; D006835:Hydrazones; C000604903:N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide; D014404:Tubulin
keywords: Acylhydrazones; Cancer; Cell migration; Colchicine; Leukemia; Microtubule assembly; Tubulin