ABSTRACT
Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3)·3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para-fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2-acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para-nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gallium/chemistry , Thiosemicarbazones/chemistry , Tubulin/chemistry , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Cell Cycle Checkpoints/drug effects , Cell Shape/drug effects , Coordination Complexes/chemistry , Crystallography, X-Ray , Erythrocytes/drug effects , HeLa Cells , Humans , Inhibitory Concentration 50 , Kinetics , MCF-7 Cells , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Protein Multimerization/drug effects , Pseudomonas aeruginosa/drug effects , Pyridines/chemistry , Staphylococcus aureus/drug effects , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Apoptosis/drug effects , 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 , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Etoposide/pharmacology , Female , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Humans , Inhibitory Concentration 50 , Microtubules/drug effects , Molecular Structure , Structure-Activity Relationship , Tubulin/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
2-acetylpyridine N(4)-phenyl thiosemicarbazone (H2Ac4Ph), and its N(4)-ortho-tolyl (H2Ac4oT), N(4)-meta-tolyl (H2Ac4mT), N(4)-para-tolyl (H2Ac4pT), N(4)-ortho-chlorophenyl (H2Ac4oClPh), N(4)-meta-chlorophenyl (H2Ac4mClPh) and N(4)-para-chlorophenyl (H2Ac4pClPh) derivatives were assayed for their cytotoxicity against RT2 (expressing p53 protein) and against T98 (expressing mutant p53 protein) glioma cells. The compounds were highly cytotoxic against RT2 (IC50=24-1.4 nM) and T98 cells (IC50=50-1.0 nM). IC50 for cisplatin=5 (RT2) and 17 µM (T98). The thiosemicarbazones presented haemolytic activity with IC50>10(-3)M, indicating a very good therapeutic index. SAR studies suggested that stereo properties are critical to define the potential activity of the studied compounds against the RT2 cell line, while electronic properties seem to be important for interaction with the biological target in T98 cells.
