Enhancement of Cytotoxicity by Combining Pyrenyl-Dendrimers and Arene Ruthenium Metallacages

Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyrGn) or alcohol (pyrGn-OH) (n = 1–3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, [Ru6(p-cymene) 6 (OO∩OO)3(tpt)2]6+ (OO∩OO = 5,8-dioxydo- 1,4-naphtaquinonato (donq) [1]6+ and 6,11-dioxydo-5,12- naphtacenedionato (dotq) [2]6+; tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host–guest properties of [guestC1]6+ and [guestC2]6+ were studied in solution by NMR and UV–vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water- soluble host–guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

Mononuclear5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (areneisC6H5Me or p-Pr i C6H4Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC50≤20μM), while the mononuclear derivatives were not (IC50≥100μM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5μM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium-DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652nm. At low concentration (5μM), LD50 of the mononuclear derivatives was between 5 and 10J/cm2, while for the tetranuclear derivatives LD50 was approximately 2.5J/cm2 for the [Ru4(η6-arene)4(tetra-4-pp)Cl8] complexes and less than 0.5J/cm2 for the [Ru4(η6-arene)4(tetra-3-pp)Cl8] complexes. Examination of cells under a fluorescence microscope revealed the [Ru4(η6-arene)4(tetra-4-pp)Cl8] complexes as cytoplasmic aggregates, whereas the [Ru4(η6-arene)4(tetra-3-pp)Cl8] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitize

Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(η6- p -MeC6H4Pr i )2Ru2(SC6H4- p -X)3]+: synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential

A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(η6-p-MeC6H4Pr i )2Ru2(SC6H4-p-X)3]+ (1 Xis H, 2 Xis Me, 3 Xis Ph, 4 Xis Br, 5 Xis OH, 6 Xis NO2, 7 Xis OMe, 8 Xis CF3, 9 Xis F, 10 Xis Pr i , 11 Xis Bu t ) have been synthesized from the reaction of [(η6-p-MeC6H4Pr i )RuCl2]2 with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(η6-C6H6)2Ru2(SC6H5)3]+ (12) and [(η6-C6Me6)2Ru2(SC6H5)3]+ (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50% inhibition of cancer cell growth (IC50 values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC50 value of 0.03µM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC50 values and the turnover frequencies at about 50% conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants σ p) and the lipophilicity of the thiols p-XC6H4SH (calculated logP parameters

Protein ruthenation and DNA alkylation: chlorambucil-functionalized RAPTA complexes and their anticancer activity

Chemotherapeutics for the treatment of tumorigenic conditions that feature novel modes of action are highly sought after to overcome the limitations of current chemotherapies. Herein, we report the conjugation of the alkylating agent chlorambucil to the RAPTA scaffold, a well-established pharmacophore. While chlorambucil is known to alkylate DNA, the RAPTA complexes are known to coordinate to amino acid side chains of proteins. Therefore, such a molecule combines DNA and protein targeting properties in a single molecule. Several chlorambucil-tethered RAPTA derivatives were prepared and tested for their cytotoxicity, stability in water and reactivity to protein and DNA substrates. The anticancer activity of the complexes is widely driven by the cytotoxicity of the chlorambucil moiety. However, especially in the cis-platin-resistant A2780R cells, the chlorambucil-functionalized RAPTA derivatives are in general more cytotoxic than chlorambucil and also a mixture of chlorambucil and the parent organoruthenium RAPTA compound. In a proof-of-principle experiment, the cross-linking of DNA and protein fragments by a chlorambucil-RAPTA derivative was observed

Excellent Correlation between Drug Release and Portal Size in Metalla-Cage Drug-Delivery Systems

A series of large cationic hexanuclear metalla-prisms, [Ru6(p-iPrC6H4Me)6(tpt)2(donq)3]6+, [Ru6(p-iPrC6H4Me)6(tpt)2(doaq)3]6+ and [Ru6(p-iPrC6H4Me)6(tpt)2(dotq)3]6+, composed of p-cymene–ruthenium building blocks bridged by OO∩OO ligands (donq=5,8-dioxido-1,4-naphthoquinonato; doaq=5,8-dioxido-1,4-anthraquinonato, dotq=6,11-dioxido-5,12-naphthacenedionato) and connected by two 2,4,6-tripyridin-4-yl-1,3,5-triazine (tpt) panels, which encapsulate the guest molecules 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene and Pd(acac)2, have been prepared. The host–guest properties of these water-soluble delivery systems were studied in solution by NMR and fluorescence spectroscopy, providing the stability constants (K) for these host–guest systems. Moreover, the ability of the hosts to deliver the guests into cancer cells was evaluated and the uptake mechanism studied; the rate of release of the guest molecule was found to depend on the portal size of the host