Abstract
Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding.
Highlights
Half-sandwich organometallic compounds are among the most widely studied anticancer complexes of platinum group metals such as Ru, Rh, Os, and Ir [1,2]
We found that ethidium bromide (EB) was released upon binding of the complexes to calf-thymus DNA (ct-DNA); intercalation of the complexes is not suggested; it is more probable that their binding via coordinative bonds to the macromolecule modifies the EB binding capacity of ct-DNA, leading to the liberation of this intercalating agent
All solvents were of analytical grade and used without further purification. [RhCp*(μ-Cl)Cl]2, [Ru(η6p-cymene)(μ-Cl)Cl]2, 5-chloro-8-hydroxyquinoline, D-proline, D-homoproline, aqueous formaldehyde (30% (v/v)), pic, phen, KNO3, HNO3, KOH, n-octanol, CD3OD, D2O, doxorubicin, EB, human serum albumin (HSA) (A8763, essentially globulin free), ct-DNA, DG, 4,4-dimethyl-4-silapentane1-sulfonic acid (DSS) were Sigma-Aldrich
Summary
Half-sandwich organometallic compounds are among the most widely studied anticancer complexes of platinum group metals such as Ru, Rh, Os, and Ir [1,2]. Numerous cytotoxic complexes of HQ ligands formed with rare earth metal ions [20], Pd(II) [21] or Pt(II) [22] are reported. HQ and its derivatives form complexes with Ru(η6-p-cymene) (RuCym) and Rh(η5-C5Me5) (RhCp*) characterized by high solution stability, and many of them were reported to display potent anticancer activity in human cancer cell lines [7,8,9,24,25,26,27]
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