Modulating anti-inflammatory and anticancer properties by designing a family of metal-complexes based on 5-nitropicolinic acid.

A new family of six complexes based on 5-nitropicolinic acid (5-npic) and transition metals has been obtained: [M(5-npic)2]n (MII = Mn (1) and Cd (2)), [Cu(5-npic)2]n (3), and [M(5-npic)2(H2O)2] (MII = Co (4), Ni (5), and Zn (6)), which display 1D, 2D, and mononuclear structures, respectively, thanks to different coordination modes of 5-npic. After their physicochemical characterization by single-crystal X-ray diffraction (SCXRD), elemental analyses (EA), and spectroscopic techniques, quantum chemical calculations using Time-Dependent Density Functional Theory (TD-DFT) were performed to further study the luminescence properties of compounds 2 and 6. The potential anticancer activity of all complexes was tested against three tumor cell lines, B16-F10, HT29, and HepG2, which are models widely used for studying melanoma, colon cancer, and liver cancer, respectively. The best results were found for compounds 2 and 4 against B16-F10 (IC50 = 26.94 and 45.10 µg mL-1, respectively). In addition, anti-inflammatory studies using RAW 264.7 cells exhibited promising activity for 2, 3, and 6 (IC50 NO = 5.38, 24.10, and 17.63 µg mL-1, respectively). This multidisciplinary study points to complex 2, based on CdII, as a promising anticancer and anti-inflammatory material.

Gut microbiome-derived bacterial extracellular vesicles in patients with solid tumours.

INTRODUCTION: Gut microbiome-derived nanoparticles, known as bacterial extracellular vesicles (bEVs), have garnered interest as promising tools for studying the link between the gut microbiome and human health. The diverse composition of bEVs, including their proteins, mRNAs, metabolites, and lipids, makes them useful for investigating diseases such as cancer. However, conventional approaches for studying gut microbiome composition alone may not be accurate in deciphering host-gut microbiome communication. In clinical microbiome research, there is a gap in the knowledge on the role of bEVs in solid tumor patients. OBJECTIVES: Analyzing the functionality of bEVs using (meta)genomics and proteomics could highlight the unique aspects of host-gut microbiome interactions in solid tumor patients. Therefore, we performed a comparative analysis of the proteome and microbiota composition of gut microbiome-derived bEVs isolated from patients with solid tumors and healthy controls. METHODS: After isolating bEVs from the feces of solid tumor patients and healthy controls, we performed spectrometry analysis of their proteomes and next-generation sequencing (NGS) of the 16S gene. We also investigated the gut microbiomes of feces from patients and controls using 16S sequencing and used machine learning to classify the samples into patients and controls based on their bEVs and fecal microbiomes. RESULTS: Solid tumor patients showed decreased microbiota richness and diversity in both the bEVs and feces. However, the bEV proteomes were more diverse in patients than in the controls and were enriched with proteins associated with the metabolism of amino acids and carbohydrates, nucleotide binding, and oxidoreductase activity. Metadata classification of samples was more accurate using fecal bEVs (100%) compared with fecal samples (93%). CONCLUSION: Our findings suggest that bEVs are unique functional entities. There is a need to explore bEVs together with conventional gut microbiome analysis in functional cancer research to decipher the potential of bEVs as cancer diagnostic or therapeutic biomarkers.

Synthesis of Tricyclic Pterolobirin H Analogue: Evaluation of Anticancer and Anti-Inflammatory Activities and Molecular Docking Investigations.

Pterolobirin H (3), a cassane diterpene isolated from the roots of Pterolobium macropterum, exhibits important anti-inflammatory and anticancer properties. However, its relatively complex tetracyclic structure makes it difficult to obtain by chemical synthesis, thus limiting the studies of its biological activities. Therefore, we present here a short route to obtain a rational simplification of pterolobirin H (3) and some intermediates. The anti-inflammatory activity of these compounds was assayed in LPS-stimulated RAW 264.7 macrophages. All compounds showed potent inhibition of NO production, with percentages between 54 to 100% at sub-cytotoxic concentrations. The highest anti-inflammatory effect was shown for compounds 15 and 16. The simplified analog 16 revealed potential NO inhibition properties, being 2.34 higher than that of natural cassane pterolobirin H (3). On the other hand, hydroxyphenol 15 was also demonstrated to be the strongest NO inhibitor in RAW 264.7 macrophages (IC50 NO = 0.62 ± 0.21 µg/mL), with an IC50NO value 28.3 times lower than that of pterolobirin H (3). Moreover, the anticancer potential of these compounds was evaluated in three cancer cell lines: HT29 colon cancer cells, Hep-G2 hepatoma cells, and B16-F10 murine melanoma cells. Intermediate 15 was the most active against all the selected tumor cell lines. Compound 15 revealed the highest cytotoxic effect with the lowest IC50 value (IC50 = 2.45 ± 0.29 µg/mL in HT29 cells) and displayed an important apoptotic effect through an extrinsic pathway, as evidenced in the flow cytometry analysis. Furthermore, the Hoechst staining assay showed that analog 15 triggered morphological changes, including nuclear fragmentation and chromatin condensation, in treated HT29 cells. Finally, the in silico studies demonstrated that cassane analogs exhibit promising binding affinities and docking performance with iNOS and caspase 8, which confirms the obtained experimental results.

Development and clinical impact assessment of a machine-learning model for early prediction of late-onset sepsis.

BACKGROUND AND AIM: Preterm infants are prone to neonatal infections such as late-onset sepsis (LOS). The consequences of LOS can be severe and potentially life-threatening. Unfortunately, LOS often presents with unspecific symptoms, and early screening laboratory tests have limited diagnostic value and are often late. This study aimed to build a predictive algorithm to aid doctors in the early detection of LOS in very preterm infants. METHODS: In a retrospective cohort study, all consecutively admitted preterm infants (GA ≤ 32 weeks) from 2008 until 2019 were included. They were classified as LOS or control according to blood culture results, currently the gold standard. To generate features, routine and continuously measured oxygen saturation and heart rate data with a minute-by-minute sampling rate were extracted from electronic medical records. Care was taken not to include variables indicative of existing LOS suspicion. The timing of a positive blood culture served as a proxy for LOS-onset. An equivalent timestamp was generated in gestational-age-matched control patients without a positive blood culture. Three machine learning (ML) techniques (generalized additive models, logistic regression, and XGBoost) were used to build a classification algorithm. To simulate the performance of the algorithm in clinical practice, a simulation using multiple alarm thresholds was performed on hourly predictions for the total hospitalization period. RESULTS: 292 infants with LOS were matched to 1497 controls. The median gestational age before matching was 28.1 and 30.3 weeks, respectively. Evaluation of the overall discriminative power of the LR algorithm yielded an AUC of 0.73 (p < 0.05) at the moment of clinical suspicion (t = 0). In the longitudinal simulation, our algorithm detects LOS in at least 47% of the patients before clinical suspicion without exceeding the alarm fatigue threshold of 3 alarms per day. Furthermore, medical experts evaluated the algorithm as clinically relevant regarding the feature contributions in the model explanations. CONCLUSIONS: An ML algorithm was trained for the early detection of LOS. Performance was evaluated on both prediction horizons and in a clinical impact simulation. To the best of our knowledge, our assessment of clinical impact with a retrospective simulation on longitudinal data is the most extensive in the literature on LOS prediction to date. The clinically relevant algorithm, based on routinely collected data, can potentially accelerate clinical decisions in the early detection of LOS, even with limited inputs.

Maslinic acid solid lipid nanoparticles as hydrophobic anticancer drug carriers: Formulation, in vitro activity and in vivo biodistribution.

Maslinic acid (MA) is a natural pentacyclic triterpenoid with inherent antitumor activity which has a very low solubility in water. MA solid lipid nanoparticles (SLNs) were prepared using Poloxamer 407 and Dicarboxylic acid-Poloxamer 407 as surfactants. Both MA SLNs are monodisperse, with sizes around 130 nm, and stable. Curcumin has been encapsulated in both types of nanoparticles without altering their colloidal properties. Moreover, SLNs greatly improve the solubility of MA and Curcumin. The cytotoxicity of MA and SLNs has been evaluated in BxPC3 human pancreatic cancer cells, MCF7 human breast cancer cells, and in a human fibroblast primary cell line. MA shows higher cytotoxic effect in BxPC3 and MCF7 cancer cells than in human primary fibroblasts. Nile Red loaded MA SLNs are quickly uptaken by BxPC3 and MCF7 cells, and show different cytoplasmic distributions depending on the cellular line. The oral or intravenous administration of MA SLNs in mice does not report any toxic effect, and the intravenous administration of fluorescent MA SLNs shows a homogeneous distribution in mice, without site-specific accumulation. Results suggest the great potential of MA SLNs as nanocarriers of anticancer drugs and as promising targeted theranostic nanodevices.

Synthesis, Optical Properties, and Antiproliferative Evaluation of NBD-Triterpene Fluorescent Probes.

A fluorescent labeling protocol for hydroxylated natural compounds with promising antitumor properties has been used to synthesize, in yields of 72-86%, 12 derivatives having fluorescent properties and biological activity. The reagent used for the synthesis of these fluorescent derivatives was 7-nitrobenzo-2-oxa-1,3-diazole chloride (NBD-Cl). The linkers employed to bind the NBD-Cl reagent to the natural compounds were ω-amino acids (Aa) of different chain lengths. The natural triterpene compounds chosen were oleanolic and maslinic acid, as their corresponding 28-benzylated derivatives. Thus, 12 NBD-Aa-triterpene conjugates have been studied for their optical fluorescence properties and their biological activities against cell proliferation in three cancer cell lines (B16-F10, HT-29, and HepG2), compared with three nontumor cell lines (HPF, IEC-18, and WRL68) from different tissues. The results of the fluorescence study have shown that the best fluorescent labels are those in which the ω-amino acid chain is shorter, and the carboxylic group is not benzylated. Analysis by confocal microscopy showed that these compounds were rapidly incorporated into cells in all three cancer cell lines, with these same derivatives showing the highest toxicity against the cancer cell lines tested. Then, the fluorescent labeling of these NBD-Aa-triterpene conjugates enabled their uptake and subcellular distribution to be followed in order to probe in detail their biological properties at the cellular and molecular level.

Semisynthesis and Evaluation of Anti-Inflammatory Activity of the Cassane-Type Diterpenoid Taepeenin F and of Some Synthetic Intermediates.

A new strategy for the semisynthesis of the aromatic cassane-type diterpene taepeenin F (6) is reported. The introduction of the methyl group at C-14, characteristic of the target compound, was achieved via dienone 13, easily prepared from abietic acid (10), the major compound in renewable rosin. Biological assays of selected compounds are reported. The antiproliferative activity against HT29, B16-F10, and HepG2 tumor cell lines has been investigated. Salicylaldehyde 21 was the most active compound (IC50 = 7.72 µM). Products 16 and 21 displayed apoptotic effects in B16-F10 cells, with total apoptosis rates of 46 and 38.4%, respectively. This apoptotic process involves a significant arrest of the B16-F10 cell cycle, blocking the G0/G1 phase. Dienone 16 did not cause any loss of the mitochondrial membrane potential (MMP), while salicylaldehyde 21 caused a partial loss of the MMP. The anti-inflammatory activity of the selected compounds was investigated with the LPS-stimulated RAW 264.7 macrophages. All compounds showed potent NO inhibition, with percentages between 80 and 99% at subcytotoxic concentrations. Dienone 16 inhibited LPS-induced differentiation of RAW 264.7 cells, by increasing the proportion of cells in the S phase. In addition, salicylaldehyde 21 had effects on the cell cycle, recovering the cells from the G0/G1 full arrest produced in response to LPS action.

Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds.

A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 ± 0.04 µg/mL and 5.71 ± 0.14 µg/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 µg/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.

Mecanismos patogénicos de infección por SARS-CoV-2 y enfermedad renal: una perspectiva clínico-molecular / Pathogenic mechanisms of SARS-CoV-2 infection and kidney disease: a clinical and molecular perspective

La infección por SARS-CoV-2 se ha convertido en unproblema mundial de salud pública. Su presentaciónclínica es variada, desde benigna hasta un síndrome dedistrés respiratorio agudo, afectación sistémica y fallomultiorgánico. La severidad del cuadro clínico depen-de de factores biológicos del virus y del huésped y decomorbilidades como la enfermedad renal. Además, lainteracción entre el virus, la enzima convertidora deangiotensina 2 y la respuesta inmunológica exacerbadapodría conducir al desarrollo de lesión renal aguda. Sinembargo, las implicaciones de la infección por SARS-CoV-2 sobre las células renales, las repercusiones pro-nósticas en los pacientes con enfermedad renal crónicay su efecto a largo plazo sobre la función renal no estándel todo claras. El objetivo es revisar el papel del SARS-CoV-2 en la enfermedad renal aguda y crónica, y sus po-sibles mecanismos patogénicos en la afectación renal.

The SARS-CoV-2 infection has become as a worldwidepublic health emergency. It exhibits a variety of clinicalpresentations, ranging from benign to acute respira-tory distress syndrome, systemic involvement, andmultiorganic failure. The severity of the clinical picturedepends on host and virus biological features and thepresence of comorbidities such as chronic kidney dis-ease. In addition, the interaction between the virus,angiotensin-converting enzyme 2, and the exacerbatedimmune response could lead to the development ofacute kidney injury. However, the implications of SARS-CoV-2 infection on renal cells, the prognosis of patientswith chronic kidney disease, and the long-term behav-ior of renal function are not entirely understood. Thisreview aims to explore the role of SARS-CoV-2 in acuteand chronic kidney disease and the possible pathogen-ic mechanisms of renal involvement.(AU)

[Pathogenic mechanisms of SARS-CoV-2 infection and kidney disease: a clinical and molecular perspective].

The SARS-CoV-2 infection has become as a worldwide public health emergency. It exhibits a variety of clinical presentations, ranging from benign to acute respiratory distress syndrome, systemic involvement, and multiorganic failure. The severity of the clinical picture depends on host and virus biological features and the presence of comorbidities such as chronic kidney disease. In addition, the interaction between the virus, angiotensin-converting enzyme 2, and the exacerbated immune response could lead to the development of acute kidney injury. However, the implications of SARS-CoV-2 infection on renal cells, the prognosis of patients with chronic kidney disease, and the long-term behavior of renal function are not entirely understood. This review aims to explore the role of SARS-CoV-2 in acute and chronic kidney disease and the possible pathogenic mechanisms of renal involvement.

Efficient In Vitro and In Vivo Anti-Inflammatory Activity of a Diamine-PEGylated Oleanolic Acid Derivative.

Recent evidence has shown that inflammation can contribute to all tumorigenic states. We have investigated the anti-inflammatory effects of a diamine-PEGylated derivative of oleanolic acid (OADP), in vitro and in vivo with inflammation models. In addition, we have determined the sub-cytotoxic concentrations for anti-inflammatory assays of OADP in RAW 264.7 cells. The inflammatory process began with incubation with lipopolysaccharide (LPS). Nitric oxide production levels were also determined, exceeding 75% inhibition of NO for a concentration of 1 µg/mL of OADP. Cell-cycle analysis showed a reversal of the arrest in the G0/G1 phase in LPS-stimulated RAW 264.7 cells. Furthermore, through Western blot analysis, we have determined the probable molecular mechanism activated by OADP; the inhibition of the expression of cytokines such as TNF-α, IL-1ß, iNOS, and COX-2; and the blocking of p-IκBα production in LPS-stimulated RAW 264.7 cells. Finally, we have analyzed the anti-inflammatory action of OADP in a mouse acute ear edema, in male BL/6J mice treated with OADP and tetradecanoyl phorbol acetate (TPA). Treatment with OADP induced greater suppression of edema and decreased the ear thickness 14% more than diclofenac. The development of new derivatives such as OADP with powerful anti-inflammatory effects could represent an effective therapeutic strategy against inflammation and tumorigenic processes.

Synthesis and Biological Activity of Triterpene-Coumarin Conjugates.

A set of 12 maslinic acid-coumarin conjugates was synthesized, with 9 being maslinic acid-diamine-coumarin conjugates at the C-28 carboxylic acid group of triterpene acid and the other three being maslinic acid-coumarin conjugates at C-2/C-3 and/or C-28 of the triterpene skeleton. The cytotoxic effects of these 12 triterpene conjugates were evaluated in three cancer cell lines (B16-F10, HT29, and Hep G2) and compared, respectively, with three nontumor cell lines from the same or similar tissue (HPF, IEC-18, and WRL68). The most potent cytotoxic results were achieved by a conjugate with two molecules of coumarin-3-carboxylic acid coupled through the C-2 and C-3 hydroxy groups of maslinic acid. This conjugate showed submicromolar IC50 values in two of the three cancer cell lines tested (0.6, 1.1, and 0.9 µM), being between 110- and 30-fold more effective than its corresponding precursor. Furthermore, this conjugate (10) showed percentages of cell viability for the three nontumor lines of 90%. Four maslinic acid-coumarin conjugates displayed apoptotic effects in the treated cells, with total apoptosis rates of between 40 and 85%, relative to the control. Almost all the compounds assayed caused cell-cycle arrest in all cancer cell lines, increasing the number of these cells in the G0/G1 phase.

Anti-cancer and anti-inflammatory activities of a new family of coordination compounds based on divalent transition metal ions and indazole-3-carboxylic acid.

A new family of mononuclear coordination compounds has been synthetized and characterized: [M(3-ind)2(H2O)2] (M = Co (1), Ni (2), Zn (3), Fe (4), Mn (5); 3-ind = indazole-3-carboxylate). These materials are mononuclear coordination compounds that possess strong hydrogen bond interactions. The anti-inflammatory effects of these compounds were assayed in lipopolysaccharide activated RAW 264.7 macrophages by inhibition of NO production. Moreover, the cytotoxicity of the complexes and the ligand in RAW 264.7 cells were determined for the first time. The most significant results were obtained for the compounds 4 and 5 reaching values of NO inhibition close to 80% at 48 h, and above to 90% at 72 h of treatment. The highest inhibitory effects on NO production were showed at the range 7-23 µg/mL for compounds 4 and 5. As a consequence, compounds 4 and 5 could be potential drugs due to the interesting anti-inflammatory properties showed. The anti-cancer potential of these compounds has been also tested against different tumor cell lines. The cytotoxicity of the ligand and of compounds 2 and 3 were assayed in three cell lines: HT29, colon cancer cells, Hep-G2, hepatoma cells and B16-F10 melanoma cells. The best results have been achieved with compound 2 in HepG2 and B16-F10 cell lines, being between 1.5 and 2 times more effective that the ligand in HepG2 cells, and B16-F10 cells. All in all, indazole-3-carboxylic acid is a promising ligand for the formation of coordination compounds with biochemical properties.

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.

The presence of microcystins in the coastal waters of Nigeria, from the Bights of Bonny and Benin, Gulf of Guinea.

Microcystins (MCs) are the most studied toxins of cyanobacteria in freshwater bodies worldwide. However, they are poorly documented in coastal waters in several parts of the world. In this study, we investigated the composition of cyanobacteria and the presence of microcystins (MCs) in several coastal aquatic ecosystems of Nigeria. Direct morphological analysis revealed that members of the genus Oscillatoria were dominant with five species, followed by Trichodesmium with two species in Nigerian coastal waters. Oso Ibanilo had the highest cyanobacterial biomass (998 × 103 cells/L), followed by Rivers Ocean (156 × 103 cells/L). Except for the Cross River Ocean, cyanobacteria were present in all the investigated aquatic ecosystems. Ten (10) out of twenty water bodies examined had detectable levels of MCs. Furthermore, genomic DNA analysis for the mcyE gene of microcystin synthetase (mcy) cluster showed identities higher than 86% (query coverage > 96%) with toxic strains of cyanobacteria in all the samples analyzed. Also, the sequences of samples matched those of uncultured cyanobacteria from recreational lakes in Southern Germany. Our findings indicate that the presence of toxic cyanobacteria in coastal waters of Nigeria is of public and environmental health concern.

Designing Single-Molecule Magnets as Drugs with Dual Anti-Inflammatory and Anti-Diabetic Effects.

We have designed and synthesized two novel cobalt coordination compounds using bumetanide (bum) and indomethacin (ind) therapeutic agents. The anti-inflammatory effects of cobalt metal complexes with ind and bum were assayed in lipopolysaccharide stimulated RAW 264.7 macrophages by inhibition of nitric oxide production. Firstly, we determined the cytotoxicity and the anti-inflammatory potential of the cobalt compounds and ind and bum ligands in RAW 264.7 cells. Indomethacin-based metal complex was able to inhibit the NO production up to 35% in a concentration-dependent manner without showing cytotoxicity, showing around 6-37 times more effective than indomethacin. Cell cycle analysis showed that the inhibition of NO production was accompanied by a reversion of the differentiation processes in LPS-stimulated RAW 264.7 cells, due to a decreased of cell percentage in G0/G1 phase, with the corresponding increase in the number of cells in S phase. These two materials have mononuclear structures and show slow relaxation of magnetization. Moreover, both compounds show anti-diabetic activity with low in vitro cell toxicities. The formation of metal complexes with bioactive ligands is a new and promising strategy to find new compounds with high and enhanced biochemical properties and promises to be a field of great interest.

5-Aminopyridine-2-carboxylic acid as appropriate ligand for constructing coordination polymers with luminescence, slow magnetic relaxation and anti-cancer properties.

Five new coordination polymers (CPs) constructed of aminopyridine-2-carboxylate (ampy) ligand have been synthesized and fully characterized. Three of them correspond to metal-organic chains built from the coordination of ampy to sodium and lanthanides with formulae [MNa(ampy)4]n (M = terbium (2), erbium (1) and ytterbium (3)) resembling a previously reported dysprosium material which shows anticancer activity. On another level, the reaction of Hampy with cobalt and copper ions ({[CoK(ampy)3(H2O)3](H2O)3}n (4) and [Cu(ampy)2]n (5)) lead to CPs with variable dimensionalities, which gives the opportunity of analyzing the structural properties of this new family. Lanthanide materials display solid state intense photoluminescent emissions in both the visible and near-infrared region and exhibit slow relaxation of magnetization with frequency dependence of the out-of-phase susceptibility. More interestingly, in our search for multifunctional materials, we have carried out antitumor measurements of these compounds. These multidisciplinary studies of metal complexes open up the possibility for further exploring the applications in the fields of metal-based drugs.

Antiparasitic, anti-inflammatory and cytotoxic activities of 2D coordination polymers based on 1H-indazole-5-carboxylic acid.

We report on the formation of two novel multifunctional isomorphous (4,4) square-grid 2D coordination polymers based on 1H-indazole-5-carboxylic acid. To the best of our knowledge, these complexes are the first examples of 2D-coordination polymers constructed with this novel ligand. We have analysed in detail the structural, magnetic and anti-parasitic properties of the resulting materials. In addition, the capability of inhibiting nitric oxide production from macrophage cells has been measured and was used as an indirect measure of the anti-inflammatory response. Finally, the photocatalytic activity was measured with a model pollutant, i.e. vanillic acid (phenolic compound), with the aim of further increasing the functionalities and applicability of the compounds.

Oleanolic Acid Derivatives as Potential Inhibitors of HIV-1 Protease.

Pentacyclic triterpenes, such as oleanolic acid (I), are promising scaffolds for diversification through the use of combinatorial methods to obtain derivatives that improve their biological properties, increasing their bioavailability and enhancing their therapeutic efficacy. The purpose of this study was to evaluate the influence that derivatives of oleanolic acid, conjugated with one or two amino acids and an acyl group, might exert on HIV-1 protease inhibition. The in vitro studies conducted suggested that the presence of a carboxyacyl group generally improves the inhibition of HIV-1 protease, especially when a phthaloyl group is present, with IC50 concentration values below 5 µM. The gain in activity of three 3-phthaloyl derivatives, with sub-micromolar IC50 values, was between 60- and 100-fold more active than oleanolic acid. A molecular docking study has also been performed to elucidate the mode of binding to the protease by these oleanolic acid derivatives. In general, the derivatives that exhibited the highest inhibitory activity of HIV-1 protease also showed the highest binding energies in docking simulations. The overall results suggest that the coupling of one or two amino acids and a phthaloyl group to oleanolic acid improves HIV-1 protease inhibition, implying that these triterpene derivatives may be promising antiviral agents against HIV.

Maslinic acid conjugate with 7-amino-4-methylcoumarin as probe to monitor the temperature dependent conformational changes of human serum albumin by FRET.

Synthesis, characterization and spectroscopic investigation of maslinic acid labeled with fluorescent 7-amino-4-methylcoumarin is reported. It was found that the coumarin-maslinic derivative (MaCo) forms an excellent fluorescence resonance energy transfer (FRET) pair with the tryptophan (Trp) residue of human serum albumin (HSA). This feature allowed for monitoring HSA conformational alterations by measuring the distance between donor (Trp) and acceptor (MaCo) through Förster energy transfer mechanism. Displacement experiments confirmed that MaCo binds to subdomain IIA of HSA with independence of temperature. It was observed that, in the temperature range 35-45 °C, the fluorescence emission maximum of HSA-MaCo complex decreased, whereas in the range 45 °C-65 °C, an increment was detected. The concomitant change in the polarity of environment surrounding Trp was confirmed by red edge excitation shift experiments. Thermal denaturation of HSA was followed by time-resolved fluorescence spectroscopy. Average lifetime of Trp residue decreased with temperature due to the increment of solvent collisions and changes in the solvent exposure of Trp. To discriminate the importance of each effect, lifetime of N-Acetyl-L-tryptophanamide (NATA) at different temperatures was measured. Circular dichroism (CD) studies confirmed the loss of secondary structure of HSA with increasing temperature and showed a different trend in the conformational transformation below and above 45 °C, in agreement with steady-state and time-resolved fluorescence experiments.