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

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 11; pp. 3396 - 3409
• Main Authors: Soares, Marcella A., Lessa, Josane A., Mendes, Isolda C., Da Silva, Jeferson G., dos Santos, Raquel G., Salum, Lívia B., Daghestani, Hikmat, Andricopulo, Adriano D., Day, Billy W., Vogt, Andreas, Pesquero, Jorge L., Rocha, Willian R., Beraldo, Heloisa
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2012; Elsevier
• Subjects: 2-Acetylpyridine thiosemicarbazones; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Death - drug effects; Cell Line, Tumor; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - pathology; Crystallography, X-Ray; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Etoposide - pharmacology; Female; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - pathology; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; hemolysis; Humans; Inhibitory Concentration 50; mechanism of action; Medical sciences; Microtubules - drug effects; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship; structure-activity relationships; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Tubulin; Tubulin - metabolism; Tumor Suppressor Protein p53 - genetics; Cytotoxicity; Breast cancer; Tubulin; 2-Acetylpyridine thiosemicarbazones; Glioblastoma; Antineoplastic agent; Human; Nervous system diseases; Breast disease; Thiosemicarbazone; Malignant tumor; Pyridine derivatives; Malignant glioma; Mammary gland diseases; Structure activity relation; Central nervous system disease; Mammary gland; Mechanism of action; Tumor cell; Cancer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.04.027

N4-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N4-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N4-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N4-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N4-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO2Ph, H2Ac4mNO2Ph, H2Ac4pNO2Ph) 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, 52–0.16nM; T98G, 140–1.0nM; U87, 160–1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10−5M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.