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Direct molecular editing of heteroarene carbon–hydrogen (C–H) bonds through consecutive selective C–H functionalization has the potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry 1 . In contrast to electronically biased heterocyclic C–H bonds 2 – 9 , remote benzocyclic C–H bonds on bicyclic aza-arenes are especially difficult to differentiate because of the lack of intrinsic steric/electronic biases 10 – 12 . Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C–H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C–H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different orders to suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage ‘molecular editing’ strategy to directly modify bicyclic aza-arenes at any given site in different orders. A unified catalytic remote-directing template strategy enabled precise differentiation of remote and adjacent C6–H and C7–H bonds, and similar C3–H and C7–H bonds of a pharmaceutically relevant bicyclic aza-arene scaffold.

We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.

To guarantee accurate measurement of central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP), proper positioning of a reference transducer is a prerequisite. We investigated ideal transducer levels in supine, prone, and sitting position in adults. Chest computed tomography images of 113 patients, taken in supine or prone position were reviewed. For supine position, distances between the back and the uppermost blood level of both atria and their ratios to the largest anteroposterior (AP) diameter of thorax were calculated. For prone position, same distances and ratios were calculated from the anterior chest. For sitting position, distances between the mid-sternoclavicular joint and the most cephalad blood level of both atria and their ratios to the sternal length were calculated. The ratio of the uppermost blood level of right atrium (RA) and left atrium (LA) to the largest AP diameter of thorax was 0.81 ± 0.04 and 0.59 ± 0.03 from the back in supine position. That calculated from the anterior chest in prone position was 0.54 ± 0.03 and 0.46 ± 0.03. The ratio of the most cephalad blood level of RA and LA to the sternal length was 0.70 ± 0.10 and 0.68 ± 0.09 from the mid-sternoclavicular joint in sitting position, which corresponded to the upper border of 4th rib. Optimal CVP transducer levels are at four-fifths of the AP diameter of thorax in supine position, at a half of that in prone position, and at upper border of the 4th sternochondral joint in sitting position. PAOP transducer levels are similar in prone and sitting position, except for supine position which is at three-fifths of the AP diameter of thorax.

Background In this study we investigated whether cerebral ventricle indices based on brain computed tomography (CT) scans are reliable for predicting intracranial pressure (ICP) in hydrocephalic patients. Methods Electronic medical records of 221 patients undergoing ventriculoperitoneal shunt due to hydrocephalus were retrospectively reviewed. Cerebral ventricle indices including Evans' index, third ventricle index, cella media index, and ventricular score were calculated from transverse diameters measured at various levels on preoperative brain CT scans. ICP was considered as CSF opening pressure. Patients were categorized into three groups: communicating hydrocephalus, non-communicating hydrocephalus, and normal pressure hydrocephalus (NPH). The non-communicating hydrocephalus group was further divided according to the obstruction site; aqueduct, fourth ventricle outlet, third ventricle, and the foramen of Monro. The primary endpoint was the extent of the correlation between cerebral ventricle indices and ICP in each hydrocephalus group. Results No cerebral ventricle index correlated with ICP in patients with communicating hydrocephalus ( n  = 113) and NPH ( n  = 62). In the non-communicating hydrocephalus group ( n  = 46), only the third ventricle index revealed moderate negative correlation with ICP ( r  = −0.395, p  < 0.01). In subgroup analyses, the third ventricle index showed a strong negative relationship with ICP only in patients with the third ventricle obstruction ( r  = −0.779, p  < 0.05). Conclusions In this study we showed that although an inverse correlation existed between ICP and the third ventricle index only in patients with non-communicating hydrocephalus due to obstruction of the third ventricle, cerebral ventricle indices based on brain CT scan were non-reliable predictors of ICP in hydrocephalic patients.

The functionalization of C–H bonds in organic molecules is one of the most direct approaches for chemical synthesis. Recent advances in catalysis have allowed native chemical groups such as carboxylic acids, ketones and amines to control and direct C( sp 3 )–H activation 1 – 4 . However, alcohols, among the most common functionalities in organic chemistry 5 , have remained intractable because of their low affinity for late transition-metal catalysts 6 , 7 . Here we describe ligands that enable alcohol-directed arylation of δ -C( sp 3 )–H bonds. We use charge balance and a secondary-coordination-sphere hydrogen-bonding interaction—evidenced by structure–activity relationship studies, computational modelling and crystallographic data—to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C–H cleavage transition state. In contrast to previous studies in C–H activation, in which secondary interactions were used to control selectivity in the context of established reactivity 8 – 13 , this report demonstrates the feasibility of using secondary interactions to enable challenging, previously unknown reactivity by enhancing substrate–catalyst affinity. Ligands enable alcohol-directed arylation of δ-C( sp 3 )–H bonds by stabilizing hydroxyl coordination to palladium through charge balance and hydrogen bonding.

The functionalization of C-H bonds in organic molecules is one of the most direct ways of chemical synthesis. Recent advances in catalysis have made native chemical groups such as carboxylic acids, ketones, and amines amenable to C(sp3)–H activation1–4. However, alcohols, among the most common functionalities in organic chemistry5, have remained intractable due to their low affinity for transition-metal catalysts6,7. Here, we describe ligands which enable alcohol-directed arylation of δ-C(sp3)–H bonds. Our strategy employs charge balance and a secondary-coordination-sphere H-bonding interaction—evidenced by SAR studies, computational modelling, and crystallographic data—to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C–H cleavage transition state. In contrast to prior studies in C–H activation, where secondary interactions were used to control selectivity in the context of established reactivity8–13, this report demonstrates the feasibility of employing secondary interactions to enable challenging, novel reactivity by enhancing substrate-catalyst affinity.

Direct molecular editing of heteroarene carbon-hydrogen (C–H) bonds through consecutive selective C–H functionalization has the potential to grant rapid access into diverse chemical space; a valuable but often challenging venture to achieve in medicinal chemistry1. Contrasting with electronically-biased heterocyclic C–H bonds2-9, remote benzocyclic C–H bonds on bicyclic aza-arenes are especially difficult to differentiate due to lack of intrinsic steric/electronic biases10-12. We herein report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 vs. C7) and positionally-similar positions (C3 vs. C7) on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C–H olefination, alkynylation, and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative, and late-stage C–H editing of quinoline-containing pharmacophores can be modularly performed in different orders to suit bespoke synthetic applications. This report, in combination with previously reported complementary methods, now fully establishes a unified late-stage ‘molecular editing’ strategy to directly modify bicyclic aza-arenes at any given site in different orders.

This thesis documents the development of several palladium(II)-catalyzed diverse C–H functionalization of abundant carbonyl compounds ranging from ketones, carboxylic acids and native amides. The key to achieving these diverse transformations is the design of deliberately tuned directing groups and a novel pyridone based bidentate ligand. In chapter 1, a brief overview on key advanced of ligand and directing group design is provided. In chapter 2, the first example of C(sp3)–H olefination of ketone is described. Building on our previous reports on ketone C–H activation, newly developed L,X-type imino-amide bidentate directing group enabled the γ-C(sp3)–H olefination of ketones. Chapter 2 also contains the ligand enabled γ-C(sp3)–H olefination of carboxylic acids without installation of directing groups providing an expedient route to access various d- lactone products. Chapter 3 illustrates the development of β-C(sp3)–H nitrooxylation of ketones and native amides. For the β-C(sp3)–H nitrooxylation of ketones the use of the powerful and robust L,X-type bidentate directing group allowed the incorporation of practical iron nitrate as the sole oxidant as well as the nitrate(–ONO2) source. In the same chapter, the β-C(sp3)–H nitrooxylation of neutral amides is described. Rational reaction design of using additional bystanding oxidant along with the nitrate source enabled the formation of C(sp3)–H oxidation of weakly coordinating amide substrates. In the last chapter 4, we have designed a new X,X-type bidentate pyridone-carboxylic acid ligand (PyriCarbox) which enables the room-temperature C(sp2)–H hydroxylation of a wide range of phenylacetic acids and benzoic acids. Low-cost hydrogen peroxide aqueous solution is used as the oxidant. The low palladium loading, and scalability features the practicality of this chemistry.

The ability to employ a wide range of native substrates is essential for the broad application of transition-metal-catalyzed C–H activation. Recent advances have made native carboxylic acids, ketones, and amines amenable to C(sp3)–H activation, but alcohols, perhaps the most common functionality in organic chemistry, have remained intractable due to their low affinity for late-transition-metal catalysts. Herein we describe the rational development of ligands to overcome this challenge and enable alcohol-directed -C(sp3)–H arylation reactions. Our ligand design strategy employs charge balance and a secondary-coordination-sphere H-bonding interaction—evidenced by SAR studies, computational modelling, and crystallographic data—to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C–H cleavage transition state. In contrast to prior studies in C–H activation, where secondary interactions were used to control selectivity in the context of established reactivity, this report demonstrates the feasibility of employing secondary interactions to enable challenging novel reactivity by enhancing substrate-catalyst affinity.