Synthesis, characterization and cytotoxic activity of gallium(III) complexes anchored by tridentate pyrazole-based ligands.
Reactions of GaCl(3) with pyrazole-containing ligands of the pyrazole-imine-phenol (HL(1)-HL(3)) or pyrazole-amine-phenol (HL(4)-HL(6)) types led to the synthesis of well-defined [GaL(2)](+) homoleptic complexes (1-6). Complexes 1-6 were characterized by elemental analysis, ESI-MS (electrospray ionization-mass spectrometry), IR and NMR spectroscopies, and in the case of Complex 1 also by X-ray diffraction analysis. In complexes 1-3, the pyrazole-imine-phenolate ligands act as monoanionic chelators that coordinate to the metal in a meridional fashion, while 4-6 contain monoanionic and facially coordinated pyrazole-amine-phenolate ligands. Complexes 1-3 have a greater stability in solution compared to 4-6, which have shown a more pronounced tendency to release the respective ancillary ligands. The cytotoxicity of 1-6 and of the respective ligands (HL(1)-HL(6)) was evaluated against human prostate cancer cells PC-3 and human breast cancer cells MCF-7. The substituents of the phenolate rings strongly influenced the cytotoxicity of the compounds. Complexes 3 and 6 that contain chloride substituents at the phenolate rings have shown the highest cytotoxicity, including in the cisplatin-resistant PC-3 cell line. The cytotoxic profile of 3 and 6 is very similar to the one displayed by the respective anchor ligands, respectively HL(1) and HL(6). The cytotoxic activity of 3 and 6 is slightly increased by the presence of transferrin, and both complexes provoke cell death mainly by induction of apoptotic pathways.
Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
Francisco
F
Silva
Fernanda
F
Marques
I C
IC
Santos
António
A
Paulo
António Sebastião
AS
Rodrigues
José
J
Rueff
Isabel
I
Santos
D001943:Breast Neoplasms; D045744:Cell Line, Tumor / Q000187:drug effects*; D002614:Chelating Agents / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005708:Gallium / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011471:Prostatic Neoplasms; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism; D014961:X-Ray Diffraction
D002614:Chelating Agents; D008024:Ligands; D011720:Pyrazoles; D014168:Transferrin; C031280:pyrazole; D005708:Gallium