ABSTRACT
New anticancer ruthenium(II/III) complexes [RuCl2(DMSO)2(Hapbim)] (1) and [RuCl3(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been synthesized and characterized, and their chemotherapeutic potential evaluated. The interaction of the compounds with DNA was studied by both UV-Visible and fluorescence spectroscopies, revealing intercalation of both the Hapbim ligand and the Ru complexes. The in vitro cytotoxicity of the compounds was tested on human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2), with compound (2) the most potent against cancer cells. The cytotoxic effect of (2) is shown to correlate with the ability of the Ru(III) complex to induce apoptosis and to cause cell-cycle arrest in the G2/M phase. Notably, both compounds were inactive in the noncancerous cell line. The anticancer effect of (2) has also been studied in an EAC (Ehrlich Ascites Carcinoma) mouse model. Significantly, the activity of the complex was more pronounced in vivo, with removal of the cancer burden at doses that resulted in only low levels of hepatotoxicity and nephrotoxicity. An apoptosis mechanism was determined by the observation of increased Bax and caspase 3 and decreased Bcl2 expression. Furthermore, (2) decreased oxidative stress and increased the levels of antioxidant enzymes, especially SOD, suggesting the enhancement of normal cell repair. Overall, compound (2) shows great potential as a chemotherapeutic candidate, with promising activity and low levels of side effects.
Subject(s)
Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Ruthenium/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/metabolism , Apoptosis/drug effects , Benzimidazoles/chemistry , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/pathology , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Dimethyl Sulfoxide/chemistry , Disease Models, Animal , Drug Screening Assays, Antitumor , Female , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Mice , Proto-Oncogene Proteins c-bcl-2/metabolism , Up-Regulation/drug effects , bcl-2-Associated X Protein/metabolismABSTRACT
Organometallic Ru(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal MIII/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC50 values correlated quantitatively with the Fc+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC50 values indicate that linking of the Ru and Fc centers promotes antioxidant activity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Organometallic Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Bacillus subtilis/drug effects , Biphenyl Compounds/chemistry , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Ferrous Compounds/chemistry , Ferrous Compounds/pharmacology , HT29 Cells , Humans , Metallocenes/chemistry , Metallocenes/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Oxidation-Reduction , Picrates/chemistry , Ruthenium/chemistry , Ruthenium/pharmacologyABSTRACT
Low aqueous solubility is a major barrier to the clinical application of otherwise promising drug candidates. We demonstrate that this issue can be resolved in medicinal molecules containing potential ligating groups, through the addition of labile transition-metal ions. Incubation of the chemotherapeutic CX5461 with Cu2+ or Zn2+ enables solubilization at neutral pH but does not affect intrinsic cytotoxicity. Spectroscopic and computational studies demonstrate that this arises from coordination to the pyrazine functionality of CX5461 and may involve bidentate coordination at physiological pH.
Subject(s)
Benzothiazoles/pharmacology , Copper/chemistry , Naphthyridines/pharmacology , RNA Polymerase I/antagonists & inhibitors , Zinc/chemistry , Biological Availability , IonsABSTRACT
A new condensation polymerization route leading to alternating polystannanes is presented. The stoichiometric reaction of tin dihydrides and tin diamides in diethyl ether or toluene under mild reaction conditions afforded three new moderate molecular weight alternating polystannanes, -[Ph2Sn-alt-Sn(n-Bu)2]n-, -[Ph2Sn-alt-SnMe2]n-, -[Me2Sn-alt-Sn(n-Bu)2]n-, in addition to a known homopolymer, -[(n-Bu)2]n-.
ABSTRACT
In the title mol-ecule, C13H12N2, all non-H atoms, except for those of the pyridine ring, are essentially coplanar, with an r.m.s. deviation of 0.025â Å. The mean plane of these atoms forms a dihedral angle of 80.98â (4)° with the pyridine ring. In the crystal, weak C-Hâ¯π inter-actions link the mol-ecules, forming a three-dimensional network.
