In Vitro Anticancer Activity and in Vivo Biodistribution of Rhenium(I) Tricarbonyl Aqua Complexes

Seven
rhenium­(I) complexes of the general formula fac-[Re­(CO)3(NN)­(OH2)]+ where NN =
2,2′-bipyridine (8), 4,4′-dimethyl-2,2′-bipyridine
(9), 4,4′-dimethoxy-2,2′-bipyridine (10), dimethyl 2,2′-bipyridine-4,4′-dicarboxylate
(11), 1,10-phenanthroline (12), 2,9-dimethyl-1,10-phenanthroline
(13), or 4,7-diphenyl-1,10-phenanthroline (14), were synthesized and characterized by 1H NMR spectroscopy,
IR spectroscopy, mass spectrometry, and X-ray crystallography. With
the exception of 11, all complexes exhibited 50% growth
inhibitory concentration (IC50) values that were less than
20 μM in HeLa cells, indicating that these compounds represent
a new potential class of anticancer agents. Complexes 9, 10, and 13 were as effective in cisplatin-resistant
cells as wild-type cells, signifying that they circumvent cisplatin
resistance. The mechanism of action of the most potent complex, 13, was explored further by leveraging its intrinsic luminescence
properties to determine its intracellular localization. These studies
indicated that 13 induces cytoplasmic vacuolization that
is lysosomal in nature. Additional in vitro assays indicated that 13 induces cell death without causing an increase in intracellular
reactive oxygen species or depolarization of the mitochondrial membrane
potential. Further studies revealed that the mode of cell death does
not fall into one of the canonical categories such as apoptosis, necrosis,
paraptosis, and autophagy, suggesting that a novel mode of action
may be operative for this class of rhenium compounds. The in vivo
biodistribution and metabolism of complex 13 and its 99mTc analogue 13* were also evaluated in naı̈ve
mice. Complexes 13 and 13* exhibited comparable
biodistribution profiles with both hepatic and renal excretion. High-performance
liquid chromatography inductively coupled plasma mass-spectrometry
(HPLC-ICP-MS) analysis of mouse blood plasma and urine postadministration
showed considerable metabolic stability of 13, rendering
this potent complex suitable for in vivo applications. These studies
have shown the biological properties of this class of compounds and
demonstrated their potential as promising theranostic anticancer agents
that can circumvent cisplatin resistance.