We present here the first comprehensive study on the lipophilicity of ruthenium anticancer agents encompassing compounds with broad structural diversity, ranging from octahedral Ru (azole) through to Ru (arene) complexes. MEEKC was used to determine the capacity factors of the Ru complexes, and after a complex peak was unambiguously assigned using MEEKC-ICP-MS, the results were validated through comparison with the log P determined by octanol/water partitioning experiments. Correlation of the two data sets demonstrated a close relationship despite the limited structural overlap of the compounds studied. The capacity factors found by MEEKC allowed for the clustering of complexes based on their structure and this could be used to rationalize the observed cytotoxicity in the human colon carcinoma HCT116 cell line. It was demonstrated that rather than modification of the mono- or bidentate coordinated ligands much tighter control over a complexes lipophilic properties could be achieved through modification of the Ru(arene) ligand, with minimal detriment to cytotoxicity. This demonstrates the flexibility and potential of the Ru piano-stool scaffold. MEEKC proved to be a highly efficient means of screening the anticancer potential of preclinical ruthenium complex candidates for their lipophilic properties and correlate them with their biological activity and structural properties.
Metal complexes bind to a wide variety of biomolecules and the control of the reactivity is essential when designing anticancer metallodrugs with a specific mode of action in mind. In this study, we used the highly cytotoxic compound [RuII(cym)(8-HQ)Cl] (cym = η6-p-cymene, 8-HQ = 8-hydroxyquinoline), the more inert derivative [RuII(cym)(8-HQ)(PTA)](SO3CF3) (PTA = 1,3,5-triaza-7-phosphaadamantane), and [RuII(cym)(PCA)Cl]Cl (PCA = pyridinecarbothioamide) as a derivative with a different coordination environment about the Ru center and investigated their stability, interactions with proteins and behavior in medium (αMEM) and human serum by capillary zone electrophoresis (CZE). The developed method was found to be robust and provides a quick and low-cost technique to monitor the interactions of such complexes with biomolecules. Each complex was found to behave very differently, emphasizing the importance of the choice of ligands and demonstrating the applicability of the developed method. Additionally, the human serum albumin binding site preference of [RuII(cym)(8-HQ)Cl] was investigated through displacement studies, revealing that the compound was able to bind to both sites I and site II, and the type of adducts formed with transferrin was determined by mass spectrometry.
Using ferrocene-based ligand systems, a series of heterobimetallic
architectures of the general formula [Pd
m
L
n
]
x+ were
designed with the aim of installing an opening and closing mechanism
that would allow the release and binding of guest molecules. Palladium
complex formation was achieved through coordination to pyridyl groups,
and using 2-, 3-, and 4-pyridyl derivatives provided access to defined
PdL, PdL2, and Pd2L4 structures,
respectively. The supramolecular complexes were characterized using
nuclear magnetic resonance (NMR) and infrared spectroscopy, mass spectrometry,
and elemental analysis, and for some examples density functional theory
calculations and single-crystal X-ray diffraction analysis. 1H NMR spectroscopy was used to investigate disassembly and reassembly
of the metallosupramolecular structures. The former was induced by
cleavage of the relatively labile Pd–Npyridyl bonds
with the introduction of the competing ligands N,N′-dimethylaminopyridine (DMAP) and Cl– (using tetrabutylammonium chloride) to yield [Pd(DMAP)4]2+ and [PdCl4]2–, respectively.
The process was found to be reversible for several of the heterodimetallic
compounds, with the addition of H+ or Ag+ triggering
complex reassembly. Guest binding studies with several architectures
revealed interactions with the anionic guests p-toluenesulfonate
and octyl sulfate, but not with neutral molecules. Furthermore, the
release of guests was reversibly induced with Cl– ions as a stimulus.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.