New photoswitchable platinum(ii) azobenzene complexes as potential anticancer drugs
- Autores: Katia Ghannadzadeh Samper
- Directores de la Tesis: Mercè Capdevila Vidal (dir. tes.), Òscar Palacios Bonilla (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: José Ruiz López (presid.), Fernando Novio Vázquez (secret.), Olga Iranzo (voc.)
- Programa de doctorado: Programa de Doctorado en Química por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Since the serendipitous discovery of the anticancer activity of cisplatin, platinum-based complexes have become some of the most important anticancer drugs used in clinic therapies. Although new promising complexes have been developed, they have not yet been able to match the efficacy of cisplatin. However, the disadvantages of cisplatin, such as toxic side effects and drug resistance, require the development of novel platinum-drugs with improved tumor selectivity. Moreover, the interaction of platinum drugs with proteins may be related to their toxic side effects.
Photoactivatable Chemotherapy (PACT) is a potential alternative to the conventional platinum-drugs. The use of light to modulate biological activity of complexes is a goal that is actively being pursued by researchers worldwide. Although several studies show the different behavior of the active and non-active complexes, the in situ activation by irradiation of the complex performed by the modification of the complexes’ structure is still under study. Azobenzenes are on such photoreactive groups that can be switched between trans and cis isomers with UV-vis light. This configurational change can provoke a strong modification of the azobenzene-metallic complexes formed. While azobenzenes isomerization is widely studied, the isomerization of platinum(II)-complexes with azobenzene as ligand is a promising research direction that has not been pursued. Tuning the functionalization of such azobenzene ligands may be crucial to modulate the reactivity of the drug.
Here we present six platinum(II)-complexes bearing azobenzene-derivative molecules acting as monodentate, bidentate and bridging ligands. The photoisomerization of the platinum(II)-complexes bearing bidentate azobenzene ligands was inhibited because of their six-membered chelate rings with the azobenzene. However, the photoisomerization of the platinum(II)-complexes bearing monodentate and bridging ligands showed an increase of the half-life time of the cis-azobenzenes if compared with the azobenzene molecule.
On one hand, the anticancer activity of platinum(II)-complexes bearing monodentate azobenzene ligands is kinetically more reactive than cisplatin, improving its IC50 values and showing high amount of platinum inside the cell for short times of incubation. On the other hand, the anticancer activity of platinum(II)-complexes bearing bidentate ligands in wild-type and cisplatin-resistant ovarian cancer cells is reflected by IC50 values below 10 μM. They display similar activity in both cell lines, indicating that they are not cross-resistant with cisplatin. Moreover, the study of the interactions of these complexes with DNA shows that an alternative mechanism of action to that known for cisplatin can be postulated. The interaction of these platinum-complexes with some proteins is also evaluated by ESI-MS, showing different behavior for each complex.
