👤 de Oliveira TD

Chemical screens across hundreds of cell lines have shown that the drug sensitivities of human cancers can vary by genotype or lineage. However, most drug discovery studies have relied on culture media that poorly reflect metabolite levels in human blood. Here, we perform drug screens in traditional and Human Plasma-Like Medium (HPLM). Sets of compounds that show conditional anticancer activity span different phases of global development and include non-oncology drugs. Comparisons of the synthetic and serum-derived components that comprise typical media trace sets of conditional phenotypes to nucleotide synthesis substrates. We also characterize a unique dual mechanism for brivudine, a compound approved for antiviral use. Brivudine selectively impairs cell growth in low folate conditions by targeting two enzymes involved in one-carbon metabolism. Cataloged gene essentiality data further suggest that conditional phenotypes for other compounds are linked to off-target effects. Our findings establish general strategies for identifying drug-nutrient interactions and mechanisms of action by exploiting conditional lethality in cancer cells. Show less

Title: Increasing the π-Expansive Ligands in Ruthenium(II) Polypyridyl Complexes: Synthesis, Characterization, and Biological Evaluation for Photodynamic Therapy Applications. Abstract: Lack of selectivity is one of the main issues with currently used chemotherapies, causing damage not only to altered cells but also to healthy cells. Over the last decades, photodynamic therapy (PDT) has increased as a promising therapeutic tool due to its potential to treat diseases like cancer or bacterial infections with a high spatiotemporal control. Ruthenium(II) polypyridyl compounds are gaining attention for their application as photosensitizers (PSs) since they are generally nontoxic in dark conditions, while they show remarkable toxicity after light irradiation. In this work, four Ru(II) polypyridyl compounds with sterically expansive ligands were studied as PDT agents. The Ru(II) complexes were synthesized using an alternative route to those described in the literature, which resulted in an improvement of the synthesis yields. Solid-state structures of compounds [Ru(DIP)2phen]Cl2 and [Ru(dppz)2phen](PF6)2 have also been obtained. It is well-known that compound [Ru(dppz)(phen)2]Cl2 binds to DNA by intercalation. Therefore, we used [Ru(dppz)2phen]Cl2 as a model for DNA interaction studies, showing that it stabilized two different sequences of duplex DNA. Most of the synthesized Ru(II) derivatives showed very promising singlet oxygen quantum yields, together with noteworthy photocytotoxic properties against two different cancer cell lines, with IC50 in the micro- or even nanomolar range (0.06-7 μM). Confocal microscopy studies showed that [Ru(DIP)2phen]Cl2 and [Ru(DIP)2TAP]Cl2 accumulate preferentially in mitochondria, while no mitochondrial internalization was observed for the other compounds. Although [Ru(dppn)2phen](PF6)2 did not accumulate in mitochondria, it interestingly triggered an impairment in mitochondrial respiration after light irradiation. Among others, [Ru(dppn)2phen](PF6)2 stands out for its very good IC50 values, correlated with a very high singlet oxygen quantum yield and mitochondrial respiration disruption. Show less

We report here on three new ruthenium(II) complexes, [Ru(DPEPhos)(mtz)(bipy)]PF₆ (Ru1), [Ru(DPEPhos)(mmi)(bipy)]PF₆ (Ru2) and [Ru(DPEPhos)(dmp)(bipy)]PF₆ (Ru3). DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2-mercaptopyrimidine and bipy = 2,2'-bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 - Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC₅₀ values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC₅₀ value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 - Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies. Show less

Title: Ruthenium(II)-diphosphine complexes containing acylthiourea ligands are effective against lung and breast cancers. Abstract: We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 μM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment. 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

Five new complexes with general formula [Ru(L_n)(PP)(bipy)]PF₆, where L_n = N,N'-dimethyl-N-Acyl thiourea, and P-P: 1,2-bis(diphenylphosphino)ethane (dppe) or 1,4-bis(diphenylphosphino)butane (dppb)) were synthesized and characterized by elemental analysis, molar conductivity, cyclic voltammetry, IR, NMR (¹H, ¹³C{¹H} and ³¹P{¹H}), and single crystal X-ray diffractometry. The cytotoxicity of compounds against lung and breast tumor cell lines was significant, where two complexes, [Ru(L₃)(bipy)(dppe)]PF₆ (3) and [Ru(L₃)(bipy)(dppb)]PF₆ (6), were selected to evaluate changes in morphology, inhibition of migration and cell death in the MDA-MB-231 lineage. The complexes caused alterations in the cell morphology and were able to inhibit cell migration at the concentrations evaluated, induce the cell cycle arrested in the Sub-G1 phase, and induced cell death by apoptosis. All the complexes presented interaction with HSA, and the interaction studies with DNA suggested weak interactions, probably by the minor groove. Show less

In this study, half-sandwich Ru(II) complexes containing acylthiourea ligands of the general type [Ru(η⁶-p-cymene)(PPh₃)(S)Cl]PF₆ (1m-6m) and [Ru(η⁶-p-cymene)(PPh₃)(S-O)]PF₆ (1b-6b) where S/S-O = N',N'-disubstituted acylthiourea were synthesized and characterized (via elemental analyses, IR spectroscopy, ¹H NMR spectroscopy, ¹³C{¹H} NMR spectroscopy, and X-ray diffractometry), and their cytotoxic activity was evaluated. The different coordination modes of the acylthiourea ligands, monodentately via S (1m-6m) and bidentately via S,O (1b-6b), to ruthenium were modulated from different synthetic routes. The cytotoxicity of the complexes was evaluated in five human cell lines (DU-145, A549, MDA-MB-231, MRC-5, and MCF-10A) by MTT assay. The IC₅₀ values for prostate cancer cells (2.89-7.47 μM) indicated that the complexes inhibited cell growth, but that they were less cytotoxic than cisplatin (2.00 μM). Unlike for breast cancer cells (IC₅₀ = 0.28-0.74 μM) and lung cancer cells (IC₅₀ = 0.51-1.83 μM), the complexes were notably more active than the reference drug, and a remarkable selectivity index (SI 4.66-19.34) was observed for breast cancer cells. Based on both the activity and selectivity, complexes 5b and 6b, as well as their respective analogous complexes in the monodentate coordination 5m and 6m, were chosen for further investigation in the MDA-MB-231 cell line. These complexes not only induced morphology changes but also were able to inhibit colony formation and migration. In addition, the complexes promoted cell cycle arrest at the sub-G₁ phase inducing apoptosis. Interaction studies by viscosity measurements, gel electrophoresis, and fluorescence spectroscopy indicated that the complexes interact with the DNA minor groove and exhibit an HSA binding affinity. Show less