Design and synthesis of a library of C8-substituted sulfamidoadenosines to probe bacterial permeability.

Gram-negative bacteria pose a major challenge in antibiotic drug discovery because their cell envelope presents a permeability barrier that affords high intrinsic resistance to small-molecule drugs. The identification of correlations between chemical structure and Gram-negative permeability would thus enable development of predictive tools to facilitate antibiotic discovery. Toward this end, have advanced a library design paradigm in which various chemical scaffolds are functionalized at different regioisomeric positions using a uniform reagent set. This design enables decoupling of scaffold, regiochemistry, and substituent effects upon Gram-negative permeability of these molecules. Building upon our recent synthesis of a library of C2-substituted sulfamidoadenosines, we have now developed an efficient synthetic route to an analogous library of regioisomeric C8-substituted congeners. The C8 library samples a region of antibiotic-relevant chemical space that is similar to that addressed by the C2 library, but distinct from that sampled by a library of analogously substituted oxazolidinones. Selected molecules were tested for accumulation in Escherichia coli in a pilot analysis, setting the stage for full comparative evaluation of these libraries in the future.

Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling.

The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

Dynamic Catalytic Highly Enantioselective 1,3-Dipolar Cycloadditions.

In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent-bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermodynamically more stable isomers. Notably, enantioselective catalysis of dynamic transformations has not been reported and applied in complex molecule synthesis. We describe the discovery of dynamic covalent enantioselective metal-complex-catalyzed 1,3-dipolar cycloaddition reactions. We have developed a stereodivergent tandem synthesis of structurally and stereochemically complex molecules that generates eight stereocenters with high diastereo- and enantioselectivity through asymmetric reversible bond formation in a dynamic process in two consecutive Ag-catalyzed 1,3-dipolar cycloadditions of azomethine ylides with electron-poor olefins. Time-dependent reversible dynamic covalent-bond formation gives enantiodivergent and diastereodivergent access to structurally complex double cycloadducts with high selectivity from a common set of reagents.

Factors Affecting eGFR Slope of Renal Transplant Patients During the First 2 Years.

PURPOSE: In healthy individuals, glomerular filtration rate decreases by 1 mL/min/y after a peak level of 125.0 mL/min has been reached in adulthood. Any reduction greater than this is a progressive slope (slope more negative than -1 mL/min/y, stable [-1 to +1]), or an improvable slope if it shows more of an increase, that is, greater than +1.0 mL/min/y). The aim of the study was to determine the factors affecting estimated glomerular filtration rate (eGFR) slope during the first 2 years of renal transplant in patients with negative pretransplant panel-reactive antibody. MATERIALS AND METHODS: The characteristics of 59 renal transplant patients, such as age, sex, etiology, and 2 years of laboratory data, were collected retrospectively. For each patient, the eGFR decline rate (slope) (mL/min-1/1.73 m2-1/y-1) was determined by linear regression analysis using all calculated eGFR values over the study period. FINDINGS: Of 59 patients, 7 (11.8%) had a progressive slope, 22 (37.2%) had a stable slope, and 30 (50.8%) had an improvable slope. The first-year mean tacrolimus level was lower in patients with progressive slope than in the patients with stable slope and improvable slope (P < .022). The determinants of eGFR slope in multiple regression analysis were post-transplant hypertension (ß = -0.393; P = .002) and the first-year mean tacrolimus level (ß = 0.320; P = .01), whereas age, serum albumin, and 2-year mean tacrolimus level did not reach the level of significance. CONCLUSION: Keeping tacrolimus levels high in the first year to prevent eGFR declining is important.

The effect of the intercondylar notch width index on anterior cruciate ligament injuries: a study on groups with unilateral and bilateral ACL injury.

BACKGROUND: To evaluate the relationship of the intercondylar notch width with unilateral and bilateral ACL injury by using MR images. MATERIAL AND METHODS: The intercondylar notch width index was measured on the MR images of 18 patients with a bilateral ACL injury, 38 patients with a unilateral ACL injury and 53 healthy subjects with a normal ACL and the results of all groups were compared with each other. RESULTS: The mean NWI values were 0,227 (±0.008) in bilateral injured; 0,245 (±0.009) in unilateral injured and 0,272 (±0.01) in control groups and 0,251(±0.01) in unaffected side of the unilateral group. There were statistically significant differences in intercondylar notch width index (NWI) values between all groups and there was a significant difference between the affected and the unaffected sides in group with unilateral ACL injury. A cutoff value of 0.25 for NWI gave an odds ratio of 26.5 for bilateral and 3.23 for unilateral ACL injuries. CONCLUSIONS: The finding that NWI is significantly narrowed in patients with bilateral and unilateral ACL tears compared with the healthy controls suggest a relationship between a narrow NWI and an increased risk of ACL injury. The patients with a narrow NWI should also be screened contralaterally for assessment of ACL injury risk on the other knee. So, specialized training programmes for the people with narrow NWI can be prepared for preventing ACL injuries.

Evaluation of vertebral artery involvement by Doppler sonography in patients with Behçet disease.

OBJECTIVES: Neurologic lesions in Behçet disease are most frequently observed in areas supplied by the vertebrobasilar system. We aimed to evaluate possible vertebral artery involvement by Doppler sonography in patients with Behçet disease. METHODS: Forty-five patients with Behçet disease and 29 healthy volunteers had Doppler sonography of the vertebral arteries. Patients were grouped according to neurologic examination and magnetic resonance imaging findings as follows: group 1, Behçet disease without neurologic involvement; group 2, neuro-Behçet disease; and group 3, control. Results were assessed with a 95% confidence interval. RESULTS: The main findings of our study were as follows: (1) total vertebral artery volume flow was significantly lower in the patient groups than the control group (P< .05); (2) total volume flow was lower in group 2 than group 1, although the difference was not statistically significant; (3) peak systolic and end-diastolic velocity values were significantly lower in the patient groups than the control group; (4) right and left mean volume values were lower in group 2; and (5) resistive and pulsatility index values for the left vertebral artery were significantly higher in group 2, but no statistically significant differences were found in the resistive and pulsatility index values for the right vertebral artery. CONCLUSIONS: Doppler sonography of the vertebral arteries in Behçet disease shows alterations that may aid in the diagnosis and treatment of this condition.

Assessment of hepatic steatosis on contrast enhanced computed tomography in patients with colorectal cancer.

AIMS: Non-alcoholic fatty liver disease is often seen in patients with colorectal cancer. Insulin resistance and metabolic syndrome are related to increased risk of colorectal cancer. The aim of this study was to quantitatively determine the relationship between non-alcoholic fatty liver disease and colorectal cancer with the examination of routine abdominopelvic computed tomography images taken for staging. METHODS: A retrospective evaluation was made of the colonoscopy and histopathology reports of 1630 patients who presented for a scanning or diagnostic colonoscopy examination. Colorectal cancer was determined histopathologically in 129 cases. Colorectal cancer patients with distant metastasis or additional malignancies were excluded from the study. A total of 105 patients met the criteria and were included in the study. A control group was formed of 94 patients with no history of cancer. The liver density on abdominopelvic computed tomography and serum transaminase values were recorded for the patients and compared with those of the control group. RESULTS: The groups were similar in respect of age, gender and aspartate aminotransferase levels. Although not statistically significant, the alanine aminotransferase levels of the patient group were high compared to the control group. The liver density on computed tomography was statistically significantly lower in the patient group than in the control group. CONCLUSION: The liver density measurement on contrast abdominopelvic computed tomography of colorectal cancer patients was low, which is consistent with non-alcoholic fatty liver disease.

Role of transesophageal echocardiography in diagnosis and management of cardiac hydatid cyst: report of three cases and review of the literature.

Although diagnostic value of transthoracic echocardiography in cardiac echinococcus is well established, the role of transesophageal echocardiography in both the diagnosis and the management of this entity is not well known. We present 3 unusual cases of cardiac hydatid cyst in which transesophageal echocardiography was used. A review of the literature on the subject is also presented.