Targeting of G‐quadruplex DNA with 99mTc(I)/Re(I) Tricarbonyl Complexes Carrying Pyridostatin Derivatives
Makaleler > Tam Makale · 2024
Yazarlar: Elisa Palma, Çiğdem İÇHEDEF, Celia Fernandes, Ana Belchior, Paula Raposinho, Lurdes Gano, Andre Miranda, David Moreira, Pedro Lourenco, Carla Cruz, Ana Salome Pires, Maria Filomena Botelho, Antonio Paulo
Chemistry – A European Journal, SCI İndekslerine Giren Dergi, Uluslararası, Wos, 2024, cilt 30, ss e202400285-e202400285
Özet
Abstract The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of 99mTc and Re targeting G‐quadruplex structures for the design of new tools for cancer theranostics. 99mTc provides the complexes with the ability to perform single‐photon‐emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural 99mTc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl‐diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4‐binding motif. The interaction of the PDF‐Pz‐Re (8) complex with different G4‐forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET‐melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4‐structures from different DNA or RNA sequences, namely those present on the SRC proto‐oncogene and telomeric RNA (TERRA sequence). PDF‐Pz‐Re (8) showed low to moderate cytotoxicity in PC3 and MCF‐7 cancer cell lines, as typically observed for G4‐binders. Biodistribution studies of the congener PDF‐Pz‐99mTc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high in vitro stability.