Mono- and dicationic Re(I)/(99m)Tc(I) tricarbonyl complexes for the targeting of energized mitochondria.

Abstract

The enhanced negative mitochondrial membrane potential of tumor cells can increase the cell accumulation of triphenylphosphonium (TPP) derivatives, which prompted us to investigate TPP-containing Re(I)/(99m)Tc organometallic compounds as probes for in vivo targeting of energized mitochondria. Novel compounds (Re1-Re4/Tc1-Tc4) were obtained with bifunctional chelators of the pyrazole-diamine (N,N,N-donors) and pyrazole-aminocarboxylic (N,N,O-donors) type, functionalized with TPP pharmacophores that have been introduced at the central amine of the chelators using different spacers. In this way, dicationic (Re1-Re2, Tc1-Tc2) and monocationic (Re3-Re4, Tc3-Tc4) complexes with variable lipophilicity were synthesized. The (99m)Tc complexes (Tc1-Tc4) are highly stable under physiological conditions and their chemical identification was done by HPLC comparison with the Re congeners (Re1-Re4), which were fully characterized by common analytical techniques (electrospray ionization mass spectrometry (ESI-MS), IR, multinuclear NMR). The in vitro biological evaluation of Tc1-Tc4 was performed in a panel of human tumor cell lines (PC-3, MCF-7 and H69), including cell lines overexpressing P-glycoprotein (MCF-7/MDR1 and H69/Lx4), and in isolated mitochondria. All the tested complexes showed a low to moderate cellular and mitochondrial uptake and did not undergo significant P-glycoprotein (Pgp)-mediated efflux processes. In particular, the dication Tc2 and the monocation Tc4 presented the highest cellular and mitochondrial uptake. Their cellular uptake was shown to depend on the mitochondrial (Δψm) and plasma membrane (Δψp) potentials. Altogether, the biological properties of these compounds suggest that they might be relevant for the design of radioactive metalloprobes for in vivo targeting of mitochondria.

• Authors: Carolina Moura, Filipa Mendes, Lurdes Gano, Isabel Santos, António Paulo
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 123 Pg. 34-45 (Jun 2013) ISSN: 1873-3344 [Electronic] United States
• PMID: 23507077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Organotechnetium Compounds
• Rhenium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Humans
• Mitochondria (drug effects)
• Organotechnetium Compounds (chemical synthesis, chemistry, pharmacology)
• Rhenium (chemistry)