Preparation of 3-hydroxyquinolines from direct oxidation of dihydroquinolinium salts

A series of functionalized 3,4-dihydroquinolinium salts were prepared from the reaction of aryldiazonium salt with alkene in a nitrile solution. Further oxidation yielding either 3-hydroxyquinoline or quinoline products was investigated. A one-pot process from aryldiazonium salts, alkenes and nitriles leading to 3-hydroxyquinolines was also developed. Furthermore, an intramolecular trapping of an N-arylnitrilium ion with a vinyl group at the ortho position leading to 2-substituted quinolines was revealed.

3-Hydroxyquinoline derivatives can be prepared by a cascade cyclization of aryldiazonium salts with nitriles and alkenes followed by oxygenation.     

Effectiveness of two annual, single-dose mass drug administrations of diethylcarbamazine alone or in combination with albendazole on soil-transmitted helminthiasis in filariasis elimination programme

A longitudinal community-trial on the control of soil-transmitted helminths (STHs), as part of a lymphatic filariasis elimination campaign, was taken up in two revenue blocks of southern India in the years 2001 and 2002 to assess the impact of two annual single-dose mass drug administration (MDA) of diethylcarbamazine (DEC) + albendazole (ALB) with that of DEC alone. The prevalences and intensities of STHs were studied among cross-sectional samples of school children aged 9-10 years by using the Kato-Katz technique at baseline and 11 months after each MDA. The combined drug mass treatment produced a higher reduction in the prevalence (RIP) (51-77%) and the egg reduction rate (ERR) (92-98%) compared with 12-15% RIP and 58-62% ERR of DEC alone mass treatment. The effect of two-drug therapy after two annual treatments was relatively long lasting as shown by RIP and ERR indicating that the reinfection rates were relatively lower in this approach than single-drug therapy. This study demonstrates that mass drug co-administration of DEC + ALB in Global Programme for Elimination of Lymphatic Filariasis (GPELF) targeted at the community had a synergistic and sustainable effect against soil-transmitted helminthiasis and provided considerable 'beyond filariasis' benefits. The additional advantages accrued to the community underscore the importance of scaling-up GPELF to cover the entire population at risk.     

Characterization of a high-affinity galanin receptor in the rat anterior pituitary: absence of biological effect and reduced membrane binding of the antagonist M15 differentiate it from the brain/gut receptor.

Structure-activity studies demonstrate that galanin fragments 1-15 and 2-29 are fully active, whereas fragment 3-29 has been reported to be inactive, in a number of different in vivo models. M15, a chimeric peptide comprising galanin 1-13 and substance P5-11, has recently been found to be a potent galanin antagonist. Direct effects of galanin at the level of the pituitary have been defined, yet, paradoxically, a number of studies have been unable to demonstrate galanin binding to an anterior pituitary receptor. Porcine galanin stimulated prolactin release from dispersed rat anterior pituitary cells up to 180% +/- 12% (mean +/- SEM) of control secretion. The addition of a specific galanin antiserum caused a profound inhibition of basal prolactin release, maximal inhibition being 12% +/- 0.5% of control secretion. Addition of M15 produced no effect on basal or galanin-stimulated prolactin release. Galanin fragment 3-29 was fully active when compared to galanin 1-29. Fragments 5-29 and 8-29 stimulated prolactin release to a lesser extent and galanin 1-15, 10-29, and 20-29 had no significant prolactin-releasing activity. Using [mono(125I)iodo-Tyr26]galanin or porcine 125I-labeled Bolton-Hunter [mono(125I)iodo-Lys25]galanin, no anterior pituitary membrane binding was observed. In contrast, 125I-labeled Bolton-Hunter N-terminally labeled galanin allowed characterization of a single high-affinity anterior pituitary galanin receptor with a Kd of 4.4 +/- 0.34 nM and a Bmax of 79 +/- 8.3 fmol/mg of protein. The IC50 for porcine galanin was 0.51 +/- 0.04 nM but for M15 was in excess of 10 microM. Galanin 3-29 fully displaced the label with an IC50 of 0.96 +/- 0.7 nM. The IC50 for galanin 5-29 was 200 nM, whereas 8-29 and 1-15 were > 1 microM. Galanin 10-29 and 20-29 failed to displace the label. These data suggest the presence of a high-affinity pituitary galanin receptor, designated GAL-R2, in which region 3-10 and amino acid 25 are crucial for membrane binding and biological activity, in contrast to the known gut/brain galanin receptor (designated GAL-R1). A number of tissues known to bind or respond to galanin were screened. GAL-R2 would appear to be expressed only in the anterior pituitary and hypothalamus.     

Successful treatment of pulmonary artery aneurysms secondary to possible Behçet's disease

Pulmonary artery aneurysm (PAA) secondary to Beh?et's disease (BD) is a rare condition. The commonest presentation is hemoptysis, which can be fatal. Though the classical triad of recurrent oral and genital ulcers and relapsing iritis is present in most patients of BD, isolated pulmonary artery involvement termed as incomplete BD has been reported. Prompt diagnosis and immunosuppressive therapy can cause regression of aneurysm and prevent fatal hemoptysis. We report a case of PAA due to BD who presented with hemoptysis and responded to steroid therapy.     

Cardiovascular disease in patients with chronic human immunodeficiency virus infection

In 2012, the United Nations estimated that globally, 34 million people were living with human immunodeficiency virus (HIV) infection at the end of 2011.     

Iodine-mediated C–N and N–N bond formation: a facile one-pot synthetic approach to 1,2,3-triazoles under metal-free and azide-free conditions

A novel strategy towards the synthesis of 1,4-disubstituted 1,2,3-triazoles via C–N and N–N bond formation has been demonstrated under transition metal-free and azide-free conditions. These 1,2,3-triazoles were obtained in a regioselective manner from commercially available anilines, aryl alkenes/aryl alkynes and N-tosylhydrazines using I₂ under O₂ atmosphere. Broad substrate scope, milder reaction conditions, good to moderate yields and clean protocol are the notable features of the method. Moreover, this protocol is amenable for the generation of a library of medicinally important key building blocks.

A novel strategy towards the synthesis of 1,4-disubstituted 1,2,3-triazoles via C–N and N–N bond formation has been demonstrated under transition metal-free and azide-free conditions.     

From the Cover: Trypanosomal TAC40 constitutes a novel subclass of mitochondrial β-barrel proteins specialized in mitochondrial genome inheritance

Mitochondria cannot form de novo but require mechanisms allowing their inheritance to daughter cells. In contrast to most other eukaryotes Trypanosoma brucei has a single mitochondrion whose single-unit genome is physically connected to the flagellum. Here we identify a β-barrel mitochondrial outer membrane protein, termed tripartite attachment complex 40 (TAC40), that localizes to this connection. TAC40 is essential for mitochondrial DNA inheritance and belongs to the mitochondrial porin protein family. However, it is not specifically related to any of the three subclasses of mitochondrial porins represented by the metabolite transporter voltage-dependent anion channel (VDAC), the protein translocator of the outer membrane 40 (TOM40), or the fungi-specific MDM10, a component of the endoplasmic reticulum–mitochondria encounter structure (ERMES). MDM10 and TAC40 mediate cellular architecture and participate in transmembrane complexes that are essential for mitochondrial DNA inheritance. In yeast MDM10, in the context of the ERMES, is postulated to connect the mitochondrial genomes to actin filaments, whereas in trypanosomes TAC40 mediates the linkage of the mitochondrial DNA to the basal body of the flagellum. However, TAC40 does not colocalize with trypanosomal orthologs of ERMES components and, unlike MDM10, it regulates neither mitochondrial morphology nor the assembly of the protein translocase. TAC40 therefore defines a novel subclass of mitochondrial porins that is distinct from VDAC, TOM40, and MDM10. However, whereas the architecture of the TAC40-containing complex in trypanosomes and the MDM10-containing ERMES in yeast is very different, both are organized around a β-barrel protein of the mitochondrial porin family that mediates a DNA–cytoskeleton linkage that is essential for mitochondrial DNA inheritance.Mitochondria are a hallmark of all eukaroytic cells. They derive from an endosymbiontic event between a free-living bacterium and a presumably prokaryotic host cell. More than 1.5 billion years of evolution resulted in a great diversification of mitochondria. As a consequence, the shape and number of organelles per cell as well as size, content, copy number, and organization of their genomes vary greatly between different taxons (1). However, all eukaryotes must be able to faithfully transmit mitochondria to their offspring (2, 3).Unlike most other eukaryotes, the parasitic protozoa Trypanosoma brucei has a single mitochondrion throughout its life and its cell cycle. Due to the single-unit nature of the mitochondrion, its duplication must be coordinated with the duplication of the nucleus (4). The mitochondrial genome of T. brucei, termed kinetoplast DNA (kDNA), is essential for growth of both the procyclic insect stage and the bloodstream form of the parasite (5). It consists of a disk-shaped single-unit kDNA network that localizes to a distinct region within the mitochondrial matrix (6). The kDNA is physically connected with the cytosolic basal body, the organizing center of the eukaryotic flagellum, via a high-order transmembrane structure termed tripartite attachment complex (TAC) (7) of which only few components have been identified (8–10). Replication of the kDNA network occurs at a defined stage of the cell cycle shortly before the onset of the nuclear S phase. After replication, the kDNA networks need to be correctly positioned so that during cell and mitochondrial division each daughter cell receives a single organelle with a single kDNA network. This process requires an intact TAC and is mediated by the movement of the basal body: one kDNA network remains connected to the basal body of the old flagellum whereas the other one segregates with the basal body of the new flagellum (7, 11).Unlike trypanosomes, Saccharomyces cerevisiae propagates by budding and contains highly dynamic mitochondria that constantly divide and fuse (12, 13). Mitochondrial inheritance in budding yeast therefore requires a mechanism to move mitochondria and their genomes from the mother cell into the growing bud. The protein-associated mitochondrial genomes of S. cerevisiae, termed nucleoids, localize to dozens of globular foci that are distributed all over the organelles. Most actively replicating nucleoids are associated with a protein complex that includes the outer membrane (OM) protein MDM10 as a central unit, as well as the proteins MDM12, MDM34, and MMM1 (14–16). The protein complex forms the endoplasmic reticulum (ER)–mitochondria encounter structure (ERMES) tethering the ER to the mitochondrion (17). The ERMES has also been suggested to connect to cytosolic actin fibers that mediate the movement of mitochondria to the bud of dividing yeast cells (14, 18, 19). Besides its role in mitochondrial inheritance, the ERMES has been implicated in maintenance of mitochondrial morphology and in phospholipid and calcium exchange as well as in the assembly of the protein translocase of the mitochondrial OM (TOM) (20, 21). Some of the proposed ERMES functions are controversial and there is evidence that some of them might be due to secondary effects caused by the drastically altered mitochondrial morphology (22).The central ERMES subunit, the β-barrel protein MDM10 belongs to the mitochondrial porin superfamily, which comprises the three members voltage-dependent anion channel (VDAC), Tom40, and MDM10. Whereas VDAC and Tom40 have so far been found in all eukaryotes, including T. brucei (23, 24), MDM10 is specific to the fungal clade.In this study we identify a mitochondrial OM protein of T. brucei as a novel component of the TAC. We show that the protein defines a novel subclass of the mitochondrial porin superfamily that is specialized in mitochondrial DNA inheritance.