Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1.

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19 and 20 were designed for an AS assay. Structure-based optimization led to compounds 30 and 31 with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

Three Weeks of Pulmonary Rehabilitation Do Not Influence Oscillometry Parameters in Postoperative Lung Cancer Patients.

Background: Thoracic surgery is a recommended treatment option for non-small cell lung cancer patients. An important part of a patient's therapy, which helps to prevent postoperative complications and improve quality of life, is pulmonary rehabilitation (PR). The aim of this study was to assess whether the implementation of physical activity has an influence on forced oscillation technique (FOT) values in patients after thoracic surgery due to lung cancer. Methods: In this observational study, we enrolled 54 patients after thoracic surgery due to lung cancer, 49 patients with idiopathic interstitial fibrosis (IPF), and 54 patients with chronic obstructive pulmonary disease/asthma−COPD overlap (COPD/ACO). All patients were subjected to three weeks of in-hospital PR and assessed at the baseline as well as after completing PR by FOT, spirometry, grip strength measurement, and the 6-min walk test (6MWT). Results: We observed differences between FOT values under the influence of physical activity in studied groups, mostly between patients after thoracic surgery and COPD/ACO patients; however, no significant improvement after completing PR among FOT parameters was noticed in any group of patients. Improvements in the 6MWT distance, left hand strength, and right hand strength after PR were noticed (p < 0.001, 0.002, and 0.012, respectively). Conclusions: Three weeks of pulmonary rehabilitation had no impact on FOT values in patients after thoracic surgery due to lung cancer. Instead, we observed improvements in the 6MWT distance and the strength of both hands. Similarly, no FOT changes were observed in IPF and COPD/ACO patients after completing PR.

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase.

Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.

Enantioconvergent Alkylations of Amines by Alkyl Electrophiles: Copper-Catalyzed Nucleophilic Substitutions of Racemic α-Halolactams by Indoles.

Transition-metal catalysis has the potential to address shortcomings in the classic SN2 reaction of an amine with an alkyl electrophile, both with respect to reactivity and to enantioselectivity. In this study, we describe the development of a user-friendly method (reaction at room temperature, with commercially available catalyst components) for the enantioconvergent nucleophilic substitution of racemic secondary alkyl halides (α-iodolactams) by indoles. Mechanistic studies are consistent with the formation of a copper(I)-indolyl complex that reacts at different rates with the two enantiomers of the electrophile, which interconvert under the reaction conditions (dynamic kinetic resolution). This investigation complements earlier work on photoinduced enantioconvergent N-alkylation, supporting the premise that this important challenge can be addressed by a range of strategies.

Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases.

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.

Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase.

This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models.

Effect of Pregnancy and Stage of Lactation on Energy Processes in Isolated Blood Cells of Dairy Cows.

INTRODUCTION: The transition period is the most challenging time for dairy cattle, which is characterised not only by negative energy balance but also by fatty tissue mobilisation. MATERIAL AND METHODS: The efficiency of energy pathways, ß-oxidation in WBC and glycolysis in RBC (based on deoxyglucose transmembrane transport) were estimated. Insulin in blood plasma was determined using ELISA. RESULTS: After calving and up to one month after delivery, a significant drop in blood plasma level was noticed, simultaneously with a rise in ß-oxidation from 18.93 ±3.64 to 30.32 ±5.28 pmol/min/mg protein in WBC. A strong negative correlation between these two indices (r = -0.68) was found. During the period of transition to lactation an increase in glucose cross-membrane transportation from 41.44 ±4.92 to 50.49 ±6.41 µmol/h/g Hb was observed. A strong positive correlation between glucose transportation in RBC and ß-oxidation in WBC (r = 0.71) was noticed. These data are in agreement with results of studies on dairy cows using liver slices from dairy cows in late pregnancy and different stages of lactation, in which changes in gene expression were analysed. CONCLUSION: It seems that measuring fatty acids oxidation and glycolysis using isolated blood cells may be an adequate and relatively simple method for energy state analysis to estimate the state of dairy cow metabolism and animal health.

Asymmetric copper-catalyzed C-N cross-couplings induced by visible light.

Despite a well-developed and growing body of work in copper catalysis, the potential of copper to serve as a photocatalyst remains underexplored. Here we describe a photoinduced copper-catalyzed method for coupling readily available racemic tertiary alkyl chloride electrophiles with amines to generate fully substituted stereocenters with high enantioselectivity. The reaction proceeds at -40°C under excitation by a blue light-emitting diode and benefits from the use of a single, Earth-abundant transition metal acting as both the photocatalyst and the source of asymmetric induction. An enantioconvergent mechanism transforms the racemic starting material into a single product enantiomer.

Enantioselective synthesis of alcohols and amines by iridium-catalyzed hydrogenation, transfer hydrogenation, and related processes.

The preparation of chiral alcohols and amines by using iridium catalysis is reviewed. The methods presented include the reduction of ketones or imines by using hydrogen (hydrogenations), isopropanol, formic acid, or formate (transfer hydrogenations). Also dynamic and oxidative kinetic resolutions leading to chiral alcohols and amines are included. Selected literature reports from early contributions to December 2012 are discussed.

[Pulmonary rehabilitation in patients with lung cancer]. / Rehabilitacja oddechowa chorych na raka pluca.

The paper presents current news on the possibilities of conducting rehabilitation of patients suffering from lung cancer. It presents the principles of conducting and contraindications for pulmonary rehabilitation for these patients according to current guidelines of American College of Sport Medicine. The methods of measuring exercise capacity for patients with lung cancer have been discussed. The value of ergospirometrial test with maximum oxygen consumption (VO(2peak)) in predicting not only the survival of patients with lung cancer, but also assessing the possibility of pulmonary rehabilitation programs has been highlighted. In the part devoted to physical training for patients before a surgery for lung cancer, current research results have been presented- these show that even a short, high intensity program of pulmonary rehabilitation for patients with lung cancer before surgery is effective and increases the safety of both- the safety of the surgery and extends survival time after operation for lung cancer. The paper describes difficulties in the implementation of rehabilitation programs after surgery conducted on patients with lung cancer resulting from dysfunction of cardiovascular and muscle atrophy - both skeletal and respiratory. The issue of patients with inoperable lung cancer treated with chemotherapy has been discussed so far in only one paper published in 2007. The results shown in it have been discussed as well. The authors demonstrated a significant improvement in the efficiency of respiratory-circulatory system assessed by six-minute walk test, although the rehabilitation program was graduated by small number of patients (44%). It was noted that patients with inoperable lung cancer now account for a large group of patients who use this type of medical intervention and can significantly improve the quality of life and the method shows positive impact on the survival rate.

Ruthenium complexation in an aluminium metal-organic framework and its application in alcohol oxidation catalysis.

A ruthenium trichloride complex has been loaded into an aluminium metal-organic framework (MOF), MOF-253, by post-synthetic modification to give MOF-253-Ru. MOF-253 contains open bipyridine sites that are available to bind with the ruthenium complex. MOF-253-Ru was characterised by elemental analysis, N(2) sorption and X-ray powder diffraction. This is the first time that a Ru complex has been coordinated to a MOF through post-synthetic modification and used as a heterogeneous catalyst. MOF-253-Ru catalysed the oxidation of primary and secondary alcohols, including allylic alcohols, with PhI(OAc)(2) as the oxidant under very mild reaction conditions (ambient temperature to 40 °C). High conversions (up to >99%) were achieved in short reaction times (1-3 h) by using low catalyst loadings (0.5 mol% Ru). In addition, high selectivities (>90%) for aldehydes were obtained at room temperature. MOF-253-Ru can be recycled up to six times with only a moderate decrease in substrate conversion.

A highly active bifunctional iridium complex with an alcohol/alkoxide-tethered N-heterocyclic carbene for alkylation of amines with alcohols.

A series of new iridium(III) complexes containing bidentate N-heterocyclic carbenes (NHC) functionalized with an alcohol or ether group (NHC-OR, R = H, Me) were prepared. The complexes catalyzed the alkylation of anilines with alcohols as latent electrophiles. In particular, biscationic Ir(III) complexes of the type [Cp*(NHC-OH)Ir(MeCN)](2+)2[BF(4)(-)] afforded higher-order amine products with very high efficiency; up to >99% yield using a 1:1 ratio of reactants and 1-2.5 mol % of Ir, in short reaction times (2-16 h) and under base-free conditions. Quantitative yields were also obtained at 50 °C, although longer reaction times (48-60 h) were needed. A large variety of aromatic amines have been alkylated with primary and secondary alcohols. The reactivity of structurally related iridium(III) complexes was also compared to obtain insights into the mechanism and into the structure of possible catalytic intermediates. The Ir(III) complexes were stable towards oxygen and moisture, and were characterized by NMR, HRMS, single-crystal X-ray diffraction, and elemental analyses.

Allylic alcohols as synthetic enolate equivalents: isomerisation and tandem reactions catalysed by transition metal complexes.

Allylic alcohols can be isomerised into carbonyl compounds by transition metal complexes. In the last few years, catalyst design and development have resulted in highly efficient isomerisations under mild reaction conditions, including enantioselective versions. In addition, the isomerisation of allylic alcohols has been combined with C-C bond forming reactions when electrophiles such as aldehydes or imines were present in the reaction mixture. Also, C-F bonds can be formed when electrophilic fluorinating reagents are used. Thus, allylic alcohols can be treated as latent enol(ate)s. In this article, we highlight the latest developments concerning the isomerisation of allylic alcohols into carbonyl compounds, focusing in particular on tandem isomerisation/C-C or C-heteroatom bond formation processes. Significant attention is given to the mechanistic aspects of the reactions.

Microporous aluminoborates with large channels: structural and catalytic properties.

Channel zapping: PKU-1 and newly synthesized PKU-2 (Al(2)B(5)O(9)(OH)(3)⋅n H(2)O; see picture) possess microporous structures with 18-ring and 24-ring channels, respectively. They show high reactivity and size selectivity in the cyanosilylation of aldehydes as heterogeneous Lewis acid catalysts. The different channel sizes determine the substrate selectivity. These examples demonstrate the potential of octahedron-based aluminoborate channels in catalysis.

Building molecular complexity via tandem Ru-catalyzed isomerization/C-H activation.

A tandem isomerization/C-H activation of allylic alcohols was performed using a catalytic amount of RuCl(2)(PPh(3))(3). A variety of ortho alkylated ketones have been obtained in excellent yields. This tandem process relies on an in situ generation of a carbonyl functional group that directs the ortho C-H bond activation.

Synthesis of nucleoside phosphorothio-, phosphorodithio- and phosphoroselenoate diesters via oxidative esterification of the corresponding H-phosphonate analogues.

It was found that nucleoside H-phosphonothioate, H-phosphonodithioate, and H-phosphonoselenoate monoesters in the presence of iodine underwent rapid oxidative esterification with various hydroxylic components to produce in "one pot" reactions the corresponding nucleoside phosphorothioate, nucleoside phosphorodithioate and nucleoside phosphoroselenoate diesters in good yields. The transformation represents a novel alternative method for the synthesis of internucleotide phosphate bridge, bearing sulfur or selenium atoms. Mechanistic studies have revealed metaphosphate analogues as the probable intermediates, involved in the reactions.

The case for the intermediacy of monomeric metaphosphate analogues during oxidation of H-phosphonothioate, H-phosphonodithioate, and H-phosphonoselenoate monoesters: mechanistic and synthetic studies.

Studies on the reaction of H-phosphonothioate, H-phosphonodithioate, and H-phosphonoselenoate monoesters with iodine in the presence of a base led to identification of a unique oxidation pathway, which consists of the initial oxidation of the sulfur or selenium atom in these compounds, followed by oxidative elimination of hydrogen iodide to generate the corresponding metaphosphate analogues. The intermediacy of the latter species during oxidation of the investigated H-phosphonate monoester derivatives with iodine was supported by various diagnostic experiments. The scope and limitation of these oxidative transformations for the purpose of the synthesis of nucleoside phosphorothioate, nucleoside phosphorodithioate, and nucleoside phosphoroselenoate diesters was also investigated.