RESUMEN
Seven heptacoordinate titanium(IV) complexes were synthesized based on the concept of hetero-bis-chelate stabilization of salan (ONNO) and thiosalan (OSSO) titanium(IV)alkoxides with 2,6-pyridinedicarboxylic acid (dipic) and derivatives thereof. The resulting compounds were investigated in a solid by X-ray diffraction and in solution by NMR spectroscopy. A thiosalan (OSSO) titanium(IV) complex could be isolated and its conformational stabilization by dipic was shown by (1)H NMR spectroscopy to lead to nonfluxional behavior even at room temperature. The stability of selected complexes was assessed at pH 1.9, 6.8, and 12.1 by an UV-vis monitored hydrolysis study with >5 Mio. equivalents of water. Even at pH 12.1 [L(1)Ti(dipic)(1)] showed t1/2 of more than 2 days. The cytotoxicity of all compounds was investigated in two human carcinoma cell lines. IC50-values in the range of cisplatin were achieved by all tested compounds except for [L(4)Ti(dipic)(1)], which was proven to be nontoxic. The functionalization of dipic was thus well tolerated and did neither interfere with the stability nor the cytotoxicity of the heteroleptic complexes.
RESUMEN
The synthesis, biochemical evaluation, and hydrolysis studies of a wide selection of alkyl- and halogen-substituted titanium salan alkoxides are presented herein. A systematic change in the employed alkoxides revealed that both the bulk of the salan ligands and the steric demand of the labile ligands are of great importance for the obtained biological activity. Surprisingly, these two factors are not independent from each other; lowering the steric demand of the alkoxide of a hitherto nontoxic complex renders it cytotoxic. Therefore, our data suggest that the overall size of the complex exerts a strong influence on its biological activity. To decide whether the correlation between the cytotoxicity and the steric demand of the whole complex is merely based on an altered hydrolysis or on the interaction with biomolecules, the behavior of selected complexes under hydrolytic conditions and the influence of transferrin were investigated. Complexes differing only in their labile alkoxy ligands gave the same hydrolysis products with similar hydrolysis rates but displayed cytotoxicities that differed in the range of one order of magnitude. Thus, it seems that the hydrolysis product is not the active species but rather that the unhydrolysed complex is important for the first interaction with a biomolecule. This promoted the idea of hydrolysis being a detoxification pathway. In accordance with the above conclusion, chloro-substituted complex [Ti(Ph(Cl)N(Me))(2)(O(iPr))(2)] displayed a high cytotoxicity (IC(50) approximately 5 microM) and surprisingly high hydrolytic stability (t(1/2)=108 h). These findings, together with the observed cytotoxicity in a cisplatin-resistant cell line, make halo-substituted salan complexes an interesting target for further studies.
Asunto(s)
Alcoholes/química , Antineoplásicos/química , Complejos de Coordinación/química , Ligandos , Titanio/química , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Cristalografía por Rayos X , Semivida , Células HeLa , Células Hep G2 , Humanos , Hidrólisis , Isomerismo , Espectroscopía de Resonancia Magnética , Conformación Molecular , Compuestos Organometálicos/química , Relación Estructura-ActividadRESUMEN
Titanocene difluorides can be obtained by halide metathesis of the respective titanocene dichlorides with trimethyltin fluoride (Me(3)SnF), giving access to a new class of cytotoxic active substances. Furthermore, an improved method for the synthesis of diaryl-substituted titanocene dichlorides is presented.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Concentración 50 Inhibidora , Neoplasias Renales/tratamiento farmacológico , Células LLC-PK1 , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2 , Relación Estructura-Actividad , PorcinosRESUMEN
Controlled hydrolysis of donor-substituted titanium-salan complexes led to the formation of well-defined dinuclear complexes. Structure determination by means of X-ray and NMR-studies revealed the presence of a single µ-oxo bridge and one labile alkoxide ligand per titanium center. Concomitant cytotoxicity assays of the isolated dinuclear complexes showed cytotoxicities in the low micro-molar region, surpassing in this respect even their monomeric ancestors, thus making them possible highly active metabolites of titanium-salan anti-cancer drugs.
Asunto(s)
Antineoplásicos/química , Compuestos Organometálicos/química , Titanio/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacologíaRESUMEN
Chelate stabilization of a titanium(IV)-salan alkoxide by ligand exchange with 2,6-pyridinedicarboxylic acid (dipic) resulted in heptacoordinate complex 3 which is not redox-active, stable on silica gel and has increased aqueous stability. 3 is highly toxic in HeLa S3 and Hep G2 and has enhanced antitumor efficacy in a mouse cervical-cancer model.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/química , Titanio/química , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/uso terapéutico , Complejos de Coordinación/toxicidad , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Femenino , Células HeLa , Células Hep G2 , Humanos , Ligandos , Ratones , Conformación Molecular , Gel de Sílice/química , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
The anticancer activity of titanium complexes has been known since the groundbreaking studies of Köpf and Köpf-Maier on titanocen dichloride. Unfortunately, possibly due to their fast hydrolysis, derivatives of titanocen dichloride failed in clinical studies. Recently, the new family of titanium salan complexes containing tetradentate ONNO ligands with anti-cancer properties has been discovered. These salan complexes are much more stabile in aqueous media. In this study we describe the biological activity of two titanium salan complexes in a mouse model of cervical cancer. High efficiency of this promising complex family was demonstrated for the first time in vivo. From these data we conclude that titanium salan complexes display very strong antitumor properties exhibiting only minor side effects. Our results may influence the chemotherapy with metallo therapeutics in the future.
Asunto(s)
Antineoplásicos/química , Titanio/química , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Concentración 50 Inhibidora , RatonesRESUMEN
To discover chemical probes to further under-stand the function of individual DNA polymerases, we established a generally applicable high-throughput screening. By applying this technique we discovered three novel inhibitor classes of human DNA polymerase λ (DNA Pol λ), a key enzyme to maintain the genetic integrity of the genome. The rhodanines, classified as an excellent drug scaffold, were found to be the most potent inhibitors for DNA Pol λ. Importantly, they are up to 10 times less active against the highly similar DNA polymerase ß. We investigated basic structure activity relationships. Furthermore, the rhodanines showed pharmacological activity in two human cancer cell lines. So the here reported small molecules could serve as useful DNA Pol λ probes and might serve as starting point to develop novel therapeutic agents.
Asunto(s)
ADN Polimerasa beta/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Rodanina/farmacología , Antineoplásicos/farmacología , Supervivencia Celular , ADN Polimerasa beta/genética , ADN Polimerasa beta/metabolismo , Femenino , Células HeLa , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Relación Estructura-Actividad Cuantitativa , Rodanina/análogos & derivadosRESUMEN
Reaction of the known titanocene Y 2 with methyl lithium at -15 degrees C yields bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dimethyl (dimethyl titanocene Y, 3), a hitherto unknown, surprisingly robust titanium (IV) dimethyl species. Dimethyl titanocene Y was utilized in the preparation of several bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dicarboxylates by the reaction with the free carboxylic acids in fair to good yields. Cytotoxicity of all new compounds has been estimated in Hela S3 cells.