N⁴-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: cytotoxicity against human tumor cells, structure-activity relationship studies and investigation on the mechanism of action

  • Bioorg Med Chem. 2012 Jun 1;20(11):3396-409. doi: 10.1016/j.bmc.2012.04.027.
Marcella A Soares  1 ,  Josane A Lessa ,  Isolda C Mendes ,  Jeferson G Da Silva ,  Raquel G Dos Santos ,  Lívia B Salum ,  Hikmat Daghestani ,  Adriano D Andricopulo ,  Billy W Day ,  Andreas Vogt ,  Jorge L Pesquero ,  Willian R Rocha ,  Heloisa Beraldo
Affiliations
  • 1. Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
PMID: 22564383 DOI: 10.1016/j.bmc.2012.04.027
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.