Platinum(IV) combo prodrugs containing cyclohexane-1R,2R-diamine, valproic acid, and perillic acid as a multiaction chemotherapeutic platform for colon cancer.

The complex [PtCl2(cyclohexane-1R,2R-diamine)] has been combined in a Pt(IV) molecule with two different bioactive molecules (i.e., the histone deacetylase inhibitor 2-propylpentanoic acid or valproic acid, VPA, and the potential antimetastatic molecule 4-isopropenylcyclohexene-1-carboxylic acid or perillic acid, PA) in order to obtain a set of multiaction or multitarget antiproliferative agents. In addition to traditional thermal synthetic procedures, microwave-assisted heating was used to speed up their preparation. All Pt(IV) complexes showed antiproliferative activity on four human colon cancer cell lines (namely HCT116, HCT8, RKO and HT29) in the nanomolar range, considerably better than those of [PtCl2(cyclohexane-1R,2R-diamine)], VPA, PA, and the reference drug oxaliplatin. The synthesized complexes showed pro-apoptotic and pro-necrotic effects and the ability to induce cell cycle alterations. Moreover, the downregulation of histone deacetylase activity, leading to an increase in histone H3 and H4 levels, and the antimigratory activity, indicated by the reduction of the levels of matrix metalloproteinases MMP2 and MMP9, demonstrated the multiaction nature of the complexes, which showed biological properties similar to or better than those of VPA and PA, but at lower concentrations, probably due to the lipophilicity of the combo molecule that increases the intracellular concentration of the single components (i.e., [PtCl2(cyclohexane-1R,2R-diamine)], VPA and PA).

A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells.

Diamine ligands are effective structural scaffolds for tuning the reactivity of transition-metal complexes for catalytic, materials, and phosphorescent applications and have been leveraged for biological use. In this work, we report the synthesis and characterization of a novel class of cyclometalated [C^N] Au(III) complexes bearing secondary diamines including a norbornane backbone, (2R,3S)-N2,N3-dibenzylbicyclo[2.2.1]heptane-2,3-diamine, or a cyclohexane backbone, (1R,2R)-N1,N2-dibenzylcyclohexane-1,2-diamine. X-ray crystallography confirms the square-planar geometry and chirality at nitrogen. The electronic character of the conformationally restricted norbornane backbone influences the electrochemical behavior with redox potentials of -0.8 to -1.1 V, atypical for Au(III) complexes. These compounds demonstrate promising anticancer activity, particularly, complex 1, which bears a benzylpyridine organogold framework, and supported by the bicyclic conformationally restricted diaminonorbornane, shows good potency in A2780 cells. We further show that a cellular response to 1 evokes reactive oxygen species (ROS) production and does not induce mitochondrial dysfunction. This class of complexes provides significant stability and reactivity for different applications in protein modification, catalysis, and therapeutics.

Structural, vibrational spectroscopy, molecular docking, DFT studies and antibacterial activity of (E)-N1-(3-chlorobenzylidene)benzene-1,4-diamine.

In this work, (E)-N1-(3-chlorobenzylidene)benzene-1,4-diamine (CBD) compound was synthesized with good yield. The spectral studies were recorded by FT-IR, FT-Raman, NMR and UV-Vis to determine structural parameters. The geometrical parameters were optimized using DFT calculations at 6-311++G(d,p) basis set. The calculated structural parameters of the molecule were in line with the experimental data. The molecular orbitals of the compound were investigated through highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) analysis. The hyper conjugative interaction energy E(2) along with donor, acceptor electron densities (EDs) were determined by natural bond orbital (NBO) analysis. The molecular electrostatic potential (MEP), mulliken atomic charges, non-linear optical (NLO) properties and potential energy surface (PES) scan were also calculated. The 1H and 13C NMR chemical shifts calculated using Gauge invariant atomic orbital (GIAO) method were compared with the experimental NMR chemical shifts. Thermogravimetry (TG) and Differential Scanning Calorimetry (DSC) were carried out to characterise the thermal behaviour and stability of CBD molecule. In addition, PreADMET tool was also used to estimate ADME and Toxicity of CBD compound. The compound screened against four pathogens two gram positive and two gram negative had shown good anti-bacterial behaviour. The molecular docking studies executed against anti-bacterial target topoisomerase DNA gyrase enzyme (2XCT) emphasized good binding behaviour over the standard drug.Communicated by Ramaswamy H. Sarma.

A closer look at N2,6-substituted 1,3,5-triazine-2,4-diamines: Advances in synthesis and biological activities.

N2,6-Substituted 1,3,5-triazine-2,4-diamines (N2-substituted guanamines) attracted significant interest due to their potential in the development of bioactive molecules. With just two points of diversity, this scaffold is proved to be suitable for constructing compounds targeting various enzymes, receptors, transporters, and nucleic acids with an array of therapeutic applications, particularly in cancer, inflammation, and CNS disorders. This review discusses progress in the synthesis of N2,6-substituted 1,3,5-triazine-2,4-diamines and their biological activities ranging from the inhibition of cancer-related enzymes (e.g. DNA topoisomerase IIα, carbonic anhydrases, ubiquitin-conjugating enzyme 2B, lysophosphatidic acid acyltransferase ß and various kinases) to the binding to CNS-relevant receptors (e.g. histamine H4, serotonin 5-HT6, adenosine A2a, and α7 nicotinic acetylcholine receptors).

Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors.

Inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-κB signaling, with the potential to treat B-cell lymphoma and autoimmune diseases. We describe the discovery and optimization of (1s,4s)-N,N'-diaryl cyclohexane-1,4-diamines, a novel series of allosteric MALT1 inhibitors, resulting in compound 8 with single digit micromolar cell potency. X-ray analysis confirms that this compound binds to an induced allosteric site in MALT1. Compound 8 is highly selective and has an excellent in vivo rat PK profile with low clearance and high oral bioavailability, making it a promising lead for further optimization.

Efficacy of 30% and 38% Silver Diamine Fluoride in Arresting Caries Lesions After Different Application Times: An in Vitro Study

Abstract Objective: To evaluate the efficacy of silver diamine fluoride (SDF) in arresting dentin caries lesions when applied under different concentrations and times. Material and Methods: Forty-two bovine blocks were selected and fixed in 24-well plates. Each well received a mixed bacterial inoculum added to the culture medium with 5% sucrose. The plates were incubated in microaerophilia (7 days) for caries formation, confirmed by micro-CT (M1). SDF was applied over the carious lesions for different times and concentrations (n=6): SDF 30% - immediate removal, 1 minute and 3 minutes; SDF 38%, - immediate removal, 1 minute and 3 minutes. The group without treatment was the control. Then, the samples were again scanned by micro-CT (M2) and submitted to a second cariogenic challenge for 21 days. Then, a final scan was performed (M3). Results: Mean pH at the culture medium and lesion depth were compared using Kruskal-Wallis and Wilcoxon tests. 38% SDF showed the lowest metabolic activity of the biofilm. All 38% groups and 30% 1 and 3 minutes did not show an increase in mean lesion depth comparing M3 with M1. However, only 30% 3 minutes and 38% 1 and 3 minutes showed a significant reduction of lesion depth. Conclusion: The minimum application time of 30% SDF to arrest dentin caries lesion was 1 minute, while 38% SDF arrested with application and immediate removal.

Bivalent ß-Carbolines Inhibit Colorectal Cancer Growth through Inducing Autophagy.

In this study, a series of alkyl diamine linked bivalent ß-carbolines was synthesized and evaluated as antitumor agent. The results demonstrated that most compounds displayed good antiproliferative activities with IC50 value lower than 10 µM against a panel of human tumor cell lines, and compound 8 was found to be the most potent antiproliferative agent with IC50 value of 1.39, 1.96, 1.42, 1.49, 1.32, 1.96 and 1.63 µM against human breast cancer cell line (MCF-7), human adenocarcinoma cell line (769-P), human malighant melanoma cell line (A375), human ovarian cancer cell line (SK-OV-3), human colon carcinoma cell line (HCT-116), human gastric cancer cell line (BGC-823) and human esophageal squamous carcinoma cell line (Eca-109), respectively. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8 inhibited colorectal cancer growth through inducing autophagy.

Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials.

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

Discovery of 2,4-pyrimidinediamine derivatives as potent dual inhibitors of ALK and HDAC.

Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung cancer (NSCLC) naïve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC50 = 2.1 nM) and HDAC1 (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALKL1196M (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALKG1202R (IC50 = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively induce cell death via cell apoptosis and cell cycle arrest. Taken together, these results suggested 10f would be a promising lead compound for the ALK-positive NSCLC treatment, especially the Ceritinib- or Crizotinib-resistant NSCLC.

Development of a SYBR Green-based real-time quantitative polymerase chain reaction assay to detect enzootic nasal tumor virus in goats.

Enzootic nasal adenocarcinoma is a contagious respiratory disease in goats that is caused by the enzootic nasal tumor virus 2 (ENTV-2). In order to increase the number of available detection methods for ENTV-2, we developed a SYBR Green real-time polymerase chain reaction (SGrPCR) assay that targets the gag gene of ENTV-2. The low limit of detection of the assay was 3.68 × 101 copies/µL, a hundredfold more sensitive than conventional PCR. The melt curve showed a single sharp melt peak at 83°C, which indicated that there was no non-specific amplification or primer dimer formation. The intra-assay and inter-assay coefficients of variation were 1.58% and 1.82%, respectively. There was no cross-reactivity with closely related goat viruses (i.e., orf virus, peste des petits ruminants virus, goatpox virus, foot-and-mouth disease virus) and endogenous retroviruses. In conclusion, the SGrPCR assay is specific for the gag gene of ENTV-2 and provides a rapid and sensitive approach for detecting ENTV-2 in clinical samples.

L'adénocarcinome nasal enzootique est une maladie respiratoire contagieuse chez les chèvres qui est causé par le virus de la tumeur nasale enzootique 2 (ENTV-2). Afin d'augmenter le nombre de méthodes de détection disponibles pour ENTV-2, nous avons développé un test de réaction en chaîne par polymérase en temps réel SYBR Green (SGrPCR) qui cible le gène gag de ENTV-2. La limite basse de détection du test était de 3,68 × 101 copies/µL, cent fois plus sensible que la PCR conventionnelle. La courbe de fusion montrait un seul pic de fusion net à 83 °C, ce qui indiquait qu'il n'y avait pas d'amplification non spécifique ou de formation de dimère d'amorce. Les coefficients de variation intra-essai et inter-essai étaient respectivement de 1,58 % et 1,82 %. Il n'y avait pas de réactivité croisée avec les virus caprins étroitement apparentés (c'est-à-dire le virus orf, le virus de la peste des petits ruminants, le virus de la variole caprine, le virus de la fièvre aphteuse) et les rétrovirus endogènes. En conclusion, le test SGrPCR est spécifique du gène gag de l'ENTV-2 et fournit une approche rapide et sensible pour la détection d'ENTV-2 dans des échantillons cliniques.(Traduit par Docteur Serge Messier).

Novel chiral naphthalimide-cycloalkanediamine conjugates: Design, synthesis and antitumor activity.

A novel series of enantiopure naphthalimide-cycloalkanediamine conjugates were designed, synthetized and evaluated for in vitro cytotoxicity against human colon adenocarcinoma (LoVo), human lung adenocarcinoma (A549), human cervical carcinoma (Hela) and human promyelocytic leukemia cell lines (HL-60). The cytotoxicity of the compounds was highly dependent on size and relative stereochemistry of the cycloalkyl ring as well as length of the spacer. By contrast, any kind of enantioselection was observed for each pair of enantiomers. Flow cytometric analysis indicated that compounds 22 and 23 could effectively induce G2/M arrest in the four previous cell lines despite a mild apoptotic effect.

Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.

MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.

Pt(iv) complexes based on cyclohexanediamines and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid: synthesis, characterization, cell penetration properties and antitumor activity.

The Pt(iv) complexes based on (SP-4-2)-dichlorido(cyclohexane-1,4-diamine)platinum(ii) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid (POA) were investigated. Since POA contains a chiral carbon, all the possible Pt(iv) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt(iv) complexes containing the cyclohexane-1R,2R-diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC50), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied. Overall, the two series of Pt(iv) complexes showed similar cell penetration properties, being significantly better than that of the Pt(ii) reference compounds. Finally, a representative compound of the whole set of complexes (i.e., that based on cyclohexane-1R,2R-diamine and racemic POA) was tested in vivo on mice bearing Lewis lung carcinoma, showing good tumor growth inhibition with negligible body weight loss.

Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations.

Clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Here, we identified salicylic diamines as potent agents exhibiting toxicity to murine and human PSCs but not to cardiomyocytes (CMs) derived from them. Half maximal inhibitory concentrations (IC50) of small molecules SM2 and SM6 were, respectively, 9- and 18-fold higher for human than murine PSCs, while the IC50 of SM8 was comparable for both PSC groups. Treatment of murine embryoid bodies in suspension differentiation cultures with the most effective small molecule SM6 significantly reduced PSC and non-PSC contamination and enriched CM populations that would otherwise be eliminated in genetic selection approaches. All tested salicylic diamines exerted their toxicity by inhibiting the oxygen consumption rate (OCR) in PSCs. No or only minimal and reversible effects on OCR, sarcomeric integrity, DNA stability, apoptosis rate, ROS levels or beating frequency were observed in PSC-CMs, although effects on human PSC-CMs seemed to be more deleterious at higher SM-concentrations. Teratoma formation from SM6-treated murine PSC-CMs was abolished or delayed compared to untreated cells. We conclude that salicylic diamines represent promising compounds for PSC removal and enrichment of CMs without the need for other selection strategies.

DNA-Binding Capabilities and Anticancer Activities of Ruthenium(II) Cymene Complexes with (Poly)cyclic Aromatic Diamine Ligands.

Ruthenium(II) arene complexes of the general formula [RuCl(η6-p-cymene)(diamine)]PF6 (diamine = 1,2-diaminobenzene (1), 2,3-diaminonaphthalene (2), 9,10-diaminophenanthrene (3), 2,3-diaminophenazine (4), and 1,2-diaminoanthraquinone (5) were synthesized. Chloro/aqua exchange was evaluated experimentally for complexes 1 and 2. The exchange process was investigated theoretically for all complexes, revealing relatively fast exchange with no significant influence from the polycyclic aromatic diamines. The calf thymus DNA (CT-DNA) binding of the complexes increased dramatically upon extending the aromatic component of the diamines, as evaluated by changes in absorption spectra upon titration with different concentrations of CT-DNA. An intercalation binding mode was established for the complexes using the increase in the relative viscosity of the CT-DNA following addition of complexes 1 and 2. Theoretical studies showed strong preference for replacement of water by guanine for all the complexes, and relatively strong Ru-Nguanine bonds. The plane of the aromatic systems can assume angles that support non-classical interactions with the DNA and covalent binding, leading to higher binding affinities. The ruthenium arenes illustrated in this study have promising anticancer activities, with the half maximal inhibitory concentration (IC50) values comparable to or better than cisplatin against three cell lines.

Antibacterial Functions and Proposed Modes of Action of Novel 1,2,3,4-Tetrahydro-ß-carboline Derivatives that Possess an Attractive 1,3-Diaminopropan-2-ol Pattern against Rice Bacterial Blight, Kiwifruit Bacterial Canker, and Citrus Bacterial Canker.

In recent years, naturally occurring tetrahydro-ß-carboline (THC) alkaloids and their derivatives have been of biological interest. However, few studies and developments have reported the use of such structures in managing plant bacterial diseases. Herein, an array of novel THC derivatives containing an attractive 1,3-diaminopropan-2-ol pattern were prepared to evaluate the antiphytopathogen activity in vitro and in vivo and explore innovative antibacterial frameworks. Notably, target compounds exhibited excellent activities against three rebellious phytopathogens, namely, Pseudomonas syringae pv. actinidiae (Psa), Xanthomonas axonopodis pv. citri, and Xanthomonas oryzae pv. oryzae, at related optimal EC50 values of 2.39 (II9), 2.06 (I23), and 1.69 (II9) µg/mL, respectively. These effects were superior to those of the parent structure 1,2,3,4-THC and positive controls. In vivo assays showed that II9 exhibited excellent control efficiencies of 51.89 and 65.45% at 200 µg/mL against rice bacterial blight and kiwifruit bacterial canker, respectively, and I23 substantially relieved the citrus canker on the leaves. Antibacterial mechanisms indicated that these THC compounds could induce the increment of reactive oxygen species and subsequently endow the tested bacteria with distinct apoptotic behavior. In addition, II9 could alleviate the hypersensitive response and pathogenicity of Psa. Overall, these simple THC derivatives can be further developed as versatile antibacterial agents.

A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC50, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74-95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies.

Lighting Silver(I) Complexes for Solution-Processed Organic Light-Emitting Diodes and Biological Applications via Thermally Activated Delayed Fluorescence.

Luminescent coinage metal complexes have shown promising applications as electroluminescent emitters, photocatalysts/photosensitizers, and bioimaging/theranostic agents, rendering them attractive alternatives to transition metal complexes based on iridium, ruthenium, and platinum that have extremely low earth abundance. In comparison to the widely studied Au(I) and Cu(I) complexes, Ag(I) complexes have seldom been explored in this field because of their inferior emission properties. Herein, we report a novel series of [Ag(N^N)(P^P)]PF6 complexes exhibiting highly efficient thermally activated delayed fluorescence by using easily accessible neutral diamine ligands and commercially available ancillary diphosphine chelates. The photoluminescence quantum yields (PLQYs) of the Ag(I) emitters are ≤0.62 in doped films. The high PLQY with a large delayed fluorescence ratio enabled the fabrication of solution-processed organic light-emitting diodes (OLEDs) with a high maximum external quantum efficiency of 8.76%, among the highest values for Ag(I) emitter-based OLEDs. With superior emission properties and an excited state lifetime in the microsecond regime, together with its potent cytotoxicity, the selected Ag(I) complex has been used for simultaneous cell imaging and anticancer treatment in human liver carcinoma HepG2 cells, revealing the potential of luminescent Ag(I) complexes for biological applications such as theranostics.

Synthesis and anti-cancer activity of bis-amino-phosphine ligand and its ruthenium(II) complexes.

The development of both chemotherapeutic drug resistance as well as adverse side effects suggest that the current chemotherapeutic drugs remain ineffective in treating the various types of cancers. The development of new metallodrugs presenting anti-cancer activity is therefore needed. Ruthenium complexes have gained a great deal of interest due to their promising anti-tumour properties and reduced toxicity in vivo. This study highlighted the effective induction of cell death in a malignant melanoma cell by two novel bis-amino-phosphine ruthenium(II) complexes referred to as GA105 and GA113. The IC50 concentrations were determined for both the complexes, the ligand and cisplatin, for comparison. Both complexes GA105 and GA113 displayed a high anti-cancer selectivity profile as they exhibited low IC50 values of 6.72 µM and 8.76 µM respectively, with low toxicity towards a non-malignant human cell line. The IC50 values obtained for both complexes were lower than that of cisplatin. The new complexes were more effective compared to the free ligand, GA103 (IC50 = >20 µM). Morphological studies on treated cells induced apoptotic features, which with further studies could indicate an intrinsic cell death pathway. Additionally, flow cytometric analysis revealed that the mode of cell death of complex GA113 was apoptosis. The outcomes herein give further insight into the potential use of selected Ru(II) complexes as alternative chemotherapeutic drugs in the future.

A light-triggerable formulation to control the stability of pro-angiogenic transcription factor hypoxia inducible factor-1α (HIF-1α).

The control of vascular remodeling mediated by transcription factor HIF-1α is critical in the treatment of several diseases including cancer, retinopathies, chronic wounds, and ischemic heart disease, among others. Gene silencing using a small interfering RNA (siRNA) is a promising therapeutic strategy to regulate HIF-1α; however, the delivery systems developed so far have limited endothelial targeting and efficiency. Herein, we have synthesized a light-triggerable polymeric nanoparticle (NP) library composed of 110 formulations which showed variable morphology, charge and disassembly rates after UV exposure. More than 35% of the formulations of the library were more efficient in gene knockdown than the siRNA delivered by a commercial transfection agent (lipofectamine RNAiMAX). The most efficient siRNA delivery formulations were tested against different cell types to identify one with preferential targeting to endothelial cells. Using a two-step methodology, we have identified a formulation that shows exquisite targeting to endothelial cells and is able to deliver more efficiently the siRNA that modulates HIF-1α than commercial transfection agents. Overall, the strategy reported here increases the specificity for tissue regulation and the efficiency for the intracellular delivery of siRNAs.