Following our strategy of coupling cyclin-dependent kinase (Cdk) inhibitors with organometallic moieties to improve their physicochemical properties and bioavailability, five organoruthenium complexes (1c-5c) of the general formula [RuCl(η(6)-arene)(L)]Cl have been synthesized in which the arene is 4-formylphenoxyacetyl-η(6)-benzylamide and L is a Cdk inhibitor [3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) and indolo[3,2-d]benzazepines (L4 and L5)]. All of the compounds were characterized by spectroscopic and analytical methods. Upon prolonged standing (2-3 months) at room temperature, the dimethyl sulfoxide (DMSO) solutions of 1c and 2c(-HCl) afforded residues, which after recrystallization from EtOH and EtOH/H(2)O, respectively, were shown by X-ray diffraction to be cis,cis-[Ru(II)Cl(2)(DMSO)(2)(L1)]·H(2)O and mer-[Ru(II)Cl(DMSO)(3)(L2-H)]·H(2)O. Compound 5c, with a coordinated amidine unit, undergoes E/Z isomerization in solution. The antiproliferative activities and effects on the cell cycle of the new compounds were evaluated. Complexes 1c-5c are moderately cytotoxic to cancer cells (CH1, SW480, A549, A2780, and A2780cisR cell lines). Therefore, in order to improve their antiproliferative effects, as well as their drug targeting and delivery to cancer cells, 1c-5c were conjugated to recombinant human serum albumin, potentially exploiting the so-called "enhanced permeability and retention" effect that results in the accumulation of macromolecules in tumors. Notably, a marked increase in cytotoxicity of the albumin conjugates was observed in all cases.
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"Afterwards, the protein mixture solution is desalted and restored in PBS (phosphate buffered saline). MALDI-TOF-MS analysis showed that the obtained samples correspond most likely to the presence of about two bound ruthenium moieties per protein. "
"rHA was selected due to its significant role in the pharmacokinetic availability of a wide range of drugs, including metallodrugs and consequentially in determining their bioavailability and toxicology . It is also observed to accumulate in solid tumors and, consequently, has been exploited as a drug-delivery system . In addition, it can also play a divergent role, either in delivery of metal-based anticancer drugs to their cellular targets or in deactivating them even before reaching the target(s) . "
[Show abstract][Hide abstract] ABSTRACT: In cancer chemotherapy, metal-based complexes have been recognized as the most promising means of inhibiting cancer growth due to the successful application of cis-platin and its derivatives above many of the existing organic anticancer agents. The limitations in their rational design can be traced to the complexity of the mechanism of their operations, lack of proper knowledge of their targets and lack of force fields in docking packages to appropriately define the metal centre of the organometallic complexes. In this paper, some of the promising anticancer complexes of Ru(II) such as the rapta-based complexes formulated as [Ru(η6-p-cymene)L2(pta)] and those with unusual ligands are considered. CatB and kinases which have been experimentally confirmed as possible targets of the complexes are also predicted by the three methods as one of the most targeted receptors while TopII and HDAC7 are predicted by two and one of the methods as best targets. The interesting features of the binding of the complexes show that some of the complexes preferentially target specific macromolecules than the others, which is an indication of their specificity and possibility of their therapeutic combination without severe side effects that may come from competition for the same target. Also, introduction of unusual ligands is found to significantly improve the activities of most of the complexes studied. Strong correlations are observed for the predicted binding sites and the orientation of the complexes within the binding site by the three methods of docking. However there are disparities in the ranking of the complexes by the three method of docking, especially that of Glide.
[Show abstract][Hide abstract] ABSTRACT: The present work was aimed that in vitro antioxidant activity of some novel synthetic mononuclear Ruthenium (II) compounds namely, Ru (1, 10-phenanthroline) 2 (2-nitro Phenyl thiosemicarbazone)Cl 2 (compound R 1) and Ru (1, 10-phenanthroline) 2 (2-hydroxy-phenyl thiosemicarbazone)Cl 2 (compound R 2) using [2, 29-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)] (ABTS), Ferric reducing antioxidant power (FRAP), N, N-dimethyl-p-phenylenediamine (DMPD), 1, 1-diphenyl-2-picryl hydrazine (DPPH) and Nitro blue tetrazolium (NBT) assays. The results concluded that both the compounds (R 1 &R 2) exhibited a significant antioxidant activity. But compared to reference standards, R 1 was found to be better free radical scavenging activity than R 2 .
Full-text · Article · May 2012 · Letters in Drug Design & Discovery