title: N⁴-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: cytotoxicity against human tumor cells, structure-activity relationship studies and investigation on the mechanism of action.
abstract: N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.
authors.affiliation: Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Marcella A
authors.initials: MA
authors.lastname: Soares
authors.forename: Josane A
authors.initials: JA
authors.lastname: Lessa
authors.forename: Isolda C
authors.initials: IC
authors.lastname: Mendes
authors.forename: Jeferson G
authors.initials: JG
authors.lastname: Da Silva
authors.forename: Raquel G
authors.initials: RG
authors.lastname: Dos Santos
authors.forename: Lívia B
authors.initials: LB
authors.lastname: Salum
authors.forename: Hikmat
authors.initials: H
authors.lastname: Daghestani
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Pesquero
authors.forename: Willian R
authors.initials: WR
authors.lastname: Rocha
authors.forename: Heloisa
authors.initials: H
authors.lastname: Beraldo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000473:pathology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D013882:Thiosemicarbazones; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C033836:2-acetylpyridine thiosemicarbazone; D005047:Etoposide