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: Marcella A Soares, 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
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 11 Pg. 3396-409 (Jun 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22564383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• TP53 protein, human
• Thiosemicarbazones
• Tubulin
• Tumor Suppressor Protein p53
• 2-acetylpyridine thiosemicarbazone
• Etoposide

Topics

• Adenocarcinoma (drug therapy, pathology)
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Central Nervous System Neoplasms (drug therapy, pathology)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Etoposide (pharmacology)
• Female
• Glioblastoma (drug therapy, genetics, pathology)
• Glioma (drug therapy, genetics, pathology)
• Humans
• Inhibitory Concentration 50
• Microtubules (drug effects)
• Molecular Structure
• Structure-Activity Relationship
• Thiosemicarbazones (chemistry, pharmacology)
• Tubulin (metabolism)
• Tumor Suppressor Protein p53 (genetics)