👤 Ribeiro GH

Ruthenium(II) complexes (Ru1-Ru5), with the general formula [Ru(N-S)(dppe)₂]PF₆, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC₅₀ values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru(dmp)(dppe)₂]PF₆ (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1-Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests. Show less

In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF₆ (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by ¹H-³¹P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent. Show less

The rational design of anticancer agents that acts in specific biological targets is one of the most effective strategies for developing chemotherapeutic agents. Aiming at obtaining new ruthenium (II) compounds with good cytotoxicity against tumor cells, a series of new complexes of general formula [RuCl(PPh₃)(Hdpa)(NN)]Cl [PPh₃ = triphenylphosphine, N-N = 2,2'-dipyridylamine (Hdpa) (1), 1,2-diaminoethane (en) (2), 2,2'-bipyridine (bipy) (3), 5,5'-dimethyl-2,2'-bipyridine (dmbipy) (4), 1,10-phenanthroline (phen) (5) and 4,7-diphenyl-1,10-phenanthroline (dphphen) (6)] were synthesized. The complexes were characterized by elemental analysis and spectroscopic techniques (IR, UV/Visible, and 1D and 2D NMR) and three of their X-ray structures were determined: [RuCl(PPh₃)(Hdpa)₂]Cl, [RuCl(PPh₃)(Hdpa)(en)]Cl and [RuCl(PPh₃)(Hdpa)(dmbipy)]Cl. All the complexes are more cytotoxic against the cancer cell line than against the non-tumor cell line, highlighting complexes 1 and 5, which have an index selectivity of 18 and 15, respectively. The binding constants of compounds 1-6 with human serum albumin (HSA) were determined by tryptophan fluorescence quenching, indicating moderate to strong interactions. The binding mode of the complexes to calf thymus (CT) DNA was explored by several techniques, which reveal that only the dphphen compound 6 causes distortions in the secondary and tertiary structures of DNA. The studies demonstrated that the nature of the NN co-ligand and the presence of the PPh₃ and Hdpa ligands are features that can influence the binding affinity of the complexes by the biomolecules and in the cytotoxic activity of the complexes. Overall, the complexes with diimine co-ligand are much more cytotoxic than compound 2 with the aliphatic diamine. Show less

PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC₅₀ > 100 μM) to HepG2 cells, but the value decreased by 387-fold to 0.36 μM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development. Show less

Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasma membrane. Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47(phox)-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCδ, p47(phox) and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCδ, p47(phox) or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKCδ/p47(phox)/NOX1 for ROS generation and consequent malignant cellular transformation. Show less