Control over Anion Coordination on Pd(II), Cu(I), and Ag(I) with Regioisomeric Phosphine-Carboxylate Ligands.

The coordination of anionic donors is involved at various stages of catalytic cycles in transition-metal catalysis, but control over the spatial positioning of anions around a metal center is a challenge in coordination chemistry. Here we show that regioisomeric phosphine-carboxylate ligands provide spatial anion control on palladium(II) centers by favoring either κ2, cis-κ1, or trans-κ1 coordination of the carboxylate donor. Additionally, the palladium(II) carboxylates, which contain a methyl donor, upon protonation, deliver metal-alkyl complexes that feature a coordinated carboxylic acid. Such complexes can be considered as models for the minima that follow the concerted metalation-deprotonation transition state for C-H activation. The predictability of the coordination modes is further demonstrated on silver(I) and copper(I) centers, for which less common structures of mononuclear and dinuclear complexes can be obtained by using spatial anion control. Our results demonstrate the potential for spatial control over carboxylate anions in coordination chemistry.

Amendment of Altered Immune Response by Curcumin in Drosophila Model of Huntington's Disease.

BACKGROUND: Though primarily classified as a brain disorder, surplus studies direct Huntington's disease (HD) to be a multi-system disorder affecting various tissues and organs, thus affecting overall physiology of host. Recently, we have reported that neuronal expression of mutant huntingtin induces immune dysregulation in Drosophila and may pose chronic threat to challenged individuals. Therefore, we tested the polyphenolic compound curcumin to circumvent the impact of immune dysregulation in Drosophila model of HD. OBJECTIVE: The present study examined the molecular basis underlying immune derangements and immunomodulatory potential of curcumin in HD. METHODS: UAS-GAL4 system was used to imitate the HD symptoms in Drosophila, and the desired female progenies (elav > Httex1pQ25; control and elav > Httex1pQ93; diseased) were cultured on food mixed without and with 10 µM concentration of curcumin since early development. Effect of curcumin supplementation was investigated by monitoring the hemocytes' count and their functional abilities in diseased condition. Reactive oxygen species (ROS) level in cells was assessed by DHE staining and mitochondrial dysfunction was assessed by CMXros red dye. In addition, transcript levels of pro-inflammatory cytokines and anti-microbial peptides were monitored by qRT-PCR. RESULTS: We found that curcumin supplementation commendably reduced higher crystal cell count and phenoloxidase activity in diseased flies. Interestingly, curcumin significantly managed altered plasmatocytes count, improved their phagocytic activity by upregulating the expression of key phagocytic receptors in HD condition. Moreover, substantial alleviation of ROS levels and mitochondria dysfunction was observed in plasmatocytes of diseased flies upon curcumin supplementation. Furthermore, curcumin administration effectively attenuated transcriptional expression of pro-inflammatory cytokines and AMPs in diseased flies. CONCLUSIONS: Our results indicate that curcumin efficiently attenuates immune derangements in HD flies and may prove beneficial in alleviating complexities associated with HD.

Site-Selective C-H Arylation of Diverse Arenes Ortho to Small Alkyl Groups.

Catalytic systems for direct C-H activation of arenes commonly show preference for electronically activated and sterically exposed C-H sites. Here we show that a range of functionally rich and pharmaceutically relevant arene classes can undergo site-selective C-H arylation ortho to small alkyl substituents, preferably endocyclic methylene groups. The C-H activation is experimentally supported as being the selectivity-determining step, while computational studies of the transition state models indicate the relevance of non-covalent interactions between the catalyst and the methylene group of the substrate. Our results suggest that preference for C(sp2 )-H activation next to alkyl groups could be a general selectivity mode, distinct from common steric and electronic factors.

Pan-neuronal expression of human mutant huntingtin protein in Drosophila impairs immune response of hemocytes.

Huntington's disease (HD) is a late-onset; progressive, dominantly inherited neurological disorder marked by an abnormal expansion of polyglutamine (poly Q) repeats in Huntingtin (HTT) protein. The pathological effects of mutant Huntingtin (mHTT) are not restricted to the nervous system but systemic abnormalities including immune dysregulation have been evidenced in clinical and experimental settings of HD. Indeed, mHTT is ubiquitously expressed and could induce cellular toxicity by directly acting on immune cells. However, it is still unclear if selective expression of mHTT exon1 in neurons could induce immune responses and hemocytes' function. In the present study, we intended to monitor perturbations in the hemocytes' population and their physiological functions in Drosophila, caused by pan-neuronal expression of mHTT protein. A measure of hemocyte count and their physiological activities caused by pan-neuronal expression of mHTT protein highlighted the extent of immune dysregulation occurring with disease progression. We found that pan-neuronal expression of mHTT significantly alters crystal cells and plasmatocyte count in larvae and adults with disease progression. Interestingly, plasmatocytes isolated from diseased conditions exhibit a gradual decline in phagocytic activity ex vivo at progressive stages of the disease as compared to age-matched control groups. In addition, diseased flies displayed elevated reactive oxygen species (ROS) in circulating plasmatocytes at the larval stage and in sessile plasmatocytes of hematopoietic pockets at terminal stages of disease. These findings strongly implicate that neuronal expression of mHTT alone is sufficient to induce non-cell-autonomous immune dysregulation in vivo.

Direct C-H Arylation.

Bonds between hydrogen and carbon atoms are the most frequent type of bonds in organic molecules. The ability to replace hydrogen atoms by making other types of bonds to carbon atoms can enable simpler access to complex organic molecules by substituting multistep synthetic sequences. The use of transition metal catalysts to activate C-H bonds is particularly attractive as it offers control over the reactivity and selectivity through catalyst design. However, such functionalization includes the difficult breaking of strong C-H bonds that are not activated by the presence of other groups. Additionally, the common presence of a number of C-H bonds in a molecule raises the issue of site-selectivity because differentiation of C-H bonds that are in sterically and electronically similar environments is a challenge. We discuss selected recent developments that are a part of the long-term research interest in mild and selective C-H activation reactions with a focus on the replacement of C-H bonds with C-aryl groups and an emphasis on the work of our group.

Spatial Anion Control on Palladium for Mild C-H Arylation of Arenes.

C-H arylation of arenes without the use of directing groups is a challenge, even for simple molecules, such as benzene. We describe spatial anion control as a concept for the design of catalytic sites for C-H bond activation, thereby enabling nondirected C-H arylation of arenes at ambient temperature. The mild conditions enable late-stage structural diversification of biologically relevant small molecules, and site-selectivity complementary to that obtained with other methods of arene functionalization can be achieved. These results reveal the potential of spatial anion control in transition-metal catalysis for the functionalization of C-H bonds under mild conditions.

An interplay between immune response and neurodegenerative disease progression: An assessment using Drosophila as a model.

Neurodegeneration, the slow and progressive loss of neurons in the central nervous system has become a major challenge to public health worldwide particularly with elderly people. Until recently, the brain and immune system were studied exclusively, independent of each other representing two distinct systems. Recent studies ensue crosstalk between these two systems to maintain homeostasis. Though the progressive loss of specific neuronal subsets is a hallmark of neurodegenerative disease, emerging evidences indicate that immune response also plays a critical role in disease progression. Due to conservation of mechanisms that govern neural development and innate immune activation in flies and humans, and availability of powerful genetic tools, the fruit fly Drosophila melanogaster is one of the best model organisms to investigate the immune response in neurodegenerative disease. Owing to significant homology between human and Drosophila immune system and recent reports on interplay between immune system and neurodegenerative disease progression, the main focus of the review is to develop a comprehensive understanding of how neuro-immune interactions contribute to neurodegeneration using Drosophila as a model system.