Abstract
In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline–piperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline–piperazine hybrids L1–3 were prepared in situ and isolated as six ruthenium and osmium complexes [(η6-p-cymene)M(L1–3)Cl]Cl, where L1 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-2-N-amine, M = Ru ([1a]Cl), Os ([1b]Cl), L2 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-4-N-amine, M = Ru ([2a]Cl), Os ([2b]Cl), L3 = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-8-N-amine, M = Ru ([3a]Cl), Os ([3b]Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV–vis spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [1a,b]Cl–[3a,b]Cl was examined in vitro and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([2a]Cl and [2b]Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure–activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline–piperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents.
Highlights
The search for more effective ruthenium complexes and organoruthenium compounds as chemotherapeutic agents with fewer side effects than currently clinically applied platinum compounds continues to attract attention.[1−8] the use of biologically active ligands in combination with ruthenium is an option to achieve synergistic effects.[9]
The results provide important insight into the structure−activity relationships of ruthenium- and osmium-arene complexes with indoloquinoline−piperazine hybrid ligands
The ruthenium and osmium complexes were assembled in situ by reacting the corresponding indoloquinoline−piperazine hybrid precursors 7a−c containing an amino group at the 2, 4, or 8position of the indoloquinoline scaffold with 2-pyridinecarboxaldehyde
Summary
The search for more effective ruthenium complexes and organoruthenium compounds as chemotherapeutic agents with fewer side effects than currently clinically applied platinum compounds continues to attract attention.[1−8] the use of biologically active ligands in combination with ruthenium is an option to achieve synergistic effects.[9]. It was of interest to vary the metal-binding unit position and to study the effect of these changes on the aqueous solubility and antiproliferative activity of the ruthenium- and osmium-arene complexes. We report the in situ synthesis and characterization of three isomeric indoloquinoline−methyl-piperazine conjugates with the location of the metal-binding site at position 2, 4, or 8 of the indoloquinoline scaffold These compounds were isolated as six water-soluble ruthenium- or osmium-arene complexes of the general formulas [(η6-p-cymene)M(L1−3)Cl]+. Chloridoruthenium(II) Chloride, [3a]Cl. The compound was synthesized by following the general synthetic procedure (A) starting from 8-amino-6-(4-methylpiperazin-1-yl)-indolo[3,2-c]quinoline (0.15 g, 0.45 mmol), [RuCl(μ-Cl)(η6-p-cymene)]2 (0.13 g, 0.20 mmol), and 2-pyridinecarboxaldehyde (39 μL, 0.41 mmol) in dry ethanol (3 mL). ANOVA with a Bonferroni posthoc test and were considered statistically significant when p < 0.05
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