N-4-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: Cytotoxicity against human tumor cells, structure-activity relationship studies and investigation on the mechanism of action

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 (IC50: 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. (C) 2012 Elsevier Ltd. All rights reserved.

CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)

CNEN (Comissao Nacional de Energia Nuclear)

CNEN (Comissao Nacional de Energia Nuclear)

FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)

Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)

INCTINOFAR (Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos)

INCT-INOFAR (Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos) [Proc. CNPq 573.364/2008-6]

INCTMM (Instituto Nacional de Ciencia e Tecnologia de Medicina Molecular)

INCT-MM (Instituto Nacional de Ciencia e Tecnologia de Medicina Molecular) [Proc. FAPEMIG: CBB-APQ-00075-09/CNPq 573646/2008-2]

INCT-Catalise (Instituto Nacional de Ciencia e Tecnologia de Catalise em Sistemas Moleculares e Nanoestruturados)

INCTCatalise (Instituto Nacional de Ciencia e Tecnologia de Catalise em Sistemas Moleculares e Nanoestruturados)

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)

FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)