Small molecule Son of Sevenless 1 (SOS1) inhibitors: a review of the patent literature.

Introduction: Up to 30% of all human cancers are driven by the overactivation of RAS signaling. Son of Sevenless 1 (SOS1) is a central node in RAS signaling pathways and modulation of SOS1-mediated RAS activation represents a unique opportunity for treating RAS-addicted cancers. Several recent publications and patent documents have demonstrated the ability of small molecules to affect the activation of RAS by SOS1 and have shown their potential for the treatment of cancers driven by RAS mutants.Areas covered: Documents focusing on both small-molecule inhibitors and activators of the SOS1:RAS interaction and their potential use as cancer therapeutics are covered. A total of 10 documents from 4 applicants are evaluated with discussion focusing on structural modifications of these compounds as well as relevant preclinical data.Expert opinion: The last decade has seen a significant increase in research and disclosures in the development of small-molecule SOS1 inhibitors. Considering the promising data that have been disclosed, interest in this area of research will likely remain strong for the foreseeable future. With the first SOS1 inhibitor currently in phase I clinical trials, the outcome of these trials will likely influence future development of SOS1 inhibitors for treatment of RAS-driven cancers.

The Aza-hexadehydro-Diels-Alder Reaction.

The generation of pyridynes from diyne nitriles is reported. These cyano-containing precursors are analogues of the triyne substrates typically used for the hexadehydro-Diels-Alder (HDDA) cycloisomerization reactions that produce ring-fused benzynes. Hence, the new processes described represent aza-HDDA reactions. Depending on the location of the nitrile, either 3,4-pyridynes (from 1,3-diynes containing a tethered cyano group) or 2,3-pyridynes (from 1-cyanoethyne derivatives containing a tethered alkyne) are produced. In situ trapping of these reactive intermediates leads to highly substituted and functionalized pyridine derivatives. In several instances, unprecedented pyridyne trapping reactions are seen. Differences in reaction energetics between the aza-HDDA substrates and that of their analogous HDDA (triyne) substrates are discussed.

Quantification of morphology of canine circumanal gland tumors: a fractal based study.

Circumanal gland tumors are very common neoplasms of dogs. Their classification relies on microscopic examination and is further supported by a few immunohistochemical markers that help indicate their prognosis. However, new additional tests would be highly useful. The purpose of this study was to develop such a test using fractal analysis which is increasingly being applied in science, especially in the field of biomedicine. A total of 53 circumanal gland tumors were chosen from our department archives. After a precise histological classification according to the World Health Organization classification, the number of de novo classified samples was as follows: 15 adenomas, 11 epitheliomas, 21 well differentiated carcinomas, 6 poorly differentiated carcinomas. Ten samples of normal circumanal gland were also included as control. All samples were immunohistochemicaly stained with vimentin. All immunohistochemical reactions were photographed at two different magnifications -100X and 400X and converted to 1 bit in black and white (bitmap) images thus enhancing the positive vimentin reactions. These images were used for the assessment of fractal dimension applying the box counting method and computer software Fractalyse. To determine the significance of results, conventional statistics were performed using Statistica software. The overall vimentin stain score was significantly higher in epitheliomas and carcinomas than in normal circumanal glands (CG) or adenomas. Mean values of fractal dimension estimated at magnification 100X and 400X were as follows: normal CG 1.318 and 1.372, CG adenomas 1.384 and 1.408, CG epitheliomas 1.547 and 1.597, CG well differentiated carcinomas 1.569 and 1.607, CG poorly differentiated carcinomas 1.679 and 1.723. Significant differences (at level of 5%) of these values were observed between individual groups of CG adenomas or normal CG, and epitheliomas or carcinomas. The above results indicate vimentin immunohistochemistry staining and assessment of fractal dimension as an ancillary diagnostic method of choice when discerning between benign and malignant tumors of circumanal glands. Additional development of the method of fractal dimension assesment may yield a possibility for this tool to successfully discern between all of the types of CG tumors.

Diels-Alder Reactions of Furans with Itaconic Anhydride: Overcoming Unfavorable Thermodynamics.

Unfavorable thermodynamics often render furans reluctant to engage in high-yielding Diels-Alder (DA) cycloaddition reactions. Here, we report the highly efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl alcohol (FA) to a single DA adduct. The free energy advantages provided by anhydride ring opening and crystal lattice energy of the product overcome the loss of aromaticity of the furanoid diene. Detailed (1)H NMR studies provided valuable insights about relevant kinetic and thermodynamic features.

The pentadehydro-Diels-Alder reaction.

In the classic Diels-Alder [4 + 2] cycloaddition reaction, the overall degree of unsaturation (or oxidation state) of the 4π (diene) and 2π (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic Diels-Alder reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the number of hydrogen atoms in the reactant pair and in the resulting product is reduced by, for example, four in the tetradehydro-Diels-Alder (TDDA) and by six in the hexadehydro-Diels-Alder (HDDA) reactions. Any oxidation state higher than tetradehydro (that is, lacking more than four hydrogens) leads to the production of a reactive intermediate that is more highly oxidized than benzene. This increases the power of the overall process substantially, because trapping of the reactive intermediate can be used to increase the structural complexity of the final product in a controllable and versatile manner. Here we report an unprecedented overall 4π + 2π cycloaddition reaction that generates a different, highly reactive intermediate known as an α,3-dehydrotoluene. This species is in the same oxidation state as a benzyne. Like benzynes, α,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization process a pentadehydro-Diels-Alder (PDDA) reaction-a nomenclature chosen for chemical taxonomic reasons rather than mechanistic ones. In addition to alkynes, nitriles (RC≡N), although non-participants in aza-HDDA reactions, readily function as the 2π component in PDDA cyclizations to produce, via trapping of the α,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.

Supramolecular gels based on boronate esters and imidazolyl donors.

Dative boron-nitrogen bonds can be used for the controlled assembly of boronate esters and N-donor ligands. So far, most investigations have focused on crystalline assemblies. In contrast, there are very few reports about soft materials based on dative B-N bonds. Here, we describe the formation of gels by aggregation of diboronate esters and ditopic bisimidazolyl donor ligands. Analyses of low molecular weight model compounds by NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography reveal that imidazolyl ligands form particularly strong dative bonds with boronate esters. The strong interaction allows gel formation in competitive polar solvents such as THF and acetone. In less polar solvents, very low critical gel concentrations of down to 0.02 wt% are observed. By using a diboronate ester linked by an azobenzene group, it is possible to form a photoresponsive gel.

Tissue fatty acid composition and estimated ∆ desaturase activity after castration in chicken broilers fed with linseed or sunflower oil.

The aims of this study were to investigate the influence of the short-term addition of sunflower and linseed oil and castration on fatty acid composition and desaturation indexes in chicken broilers. Forty-eight male Ross 308 chicken broilers were supplemented with 5% of sunflower or linseed oil. The four experimental groups were linseed oil supplementation and castration (LC), linseed oil without castration (LN), sunflower oil and castration (SC) and sunflower oil without castration (SN). There was no significant influence of castration or oil supplement on live weights, weight gain, feed intake or feed conversion. Castration resulted in an increase in polyunsaturated fatty acids (PUFA), total n3, n6, measured desaturation indexes and a decrease in the saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) content of abdominal fat. In breast muscle, castration increased PUFA and 18:3n3 values, while in the liver tissue, castration did not influence the parameters measured. Linseed oil supplementation significantly increased 18:3n3, n3 long chain polyunsaturated fatty acids (LC PUFA), total n3 and decreased total n6, n6/n3 ratio, and 20:4n6 content. Values for 20:4n6 were the highest in SC and the lowest in the LC group. Linseed oil also significantly decreased ∆5 and ∆4 desaturation indexes in the thighs and ∆5 and ∆5, 6 in abdominal fat and the liver. These results suggest that short-term supplementation of basal diet with 5% of linseed oil could significantly increase n3 LC PUFA and decrease n6/n3 ratio content in the edible tissues of chicken broilers, without adverse effects on growth performance. Meanwhile, castration only improved fatty acid profile in abdominal fat, which is not nutritionally important. The interactions observed between basal diet, supplemented oil, sex hormones and other non-nutritional factors must be elucidated in future trials in order to correctly predict the nutritional value of linseed-fed poultry.

Variability in disease burden and management of rheumatic fever and rheumatic heart disease in two regions of tropical Australia.

BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) contribute to Aboriginal Australian and Torres Strait Islander health disadvantage. At the time of this study, specialist ARF/RHD care in the Kimberley region of Western Australia was delivered by a broad range of providers. In contrast, in Far North Queensland (FNQ), a single-provider model was used as part of a coordinated RHD control programme. AIMS: To review ARF/RHD management in the Kimberley and FNQ to ascertain whether differing models of service delivery are associated with different disease burden and patient care. METHODS: An audit of ARF/RHD management. Classification and clinical management data were abstracted from health records, specialist letters, echocardiograms and regional registers using a standardised data collection tool. RESULTS: Four hundred and seven patients were identified, with 99% being Aboriginal and/or Torres Strait Islanders. ARF without RHD was seen in 0.4% of Aboriginal and/or Torres Strait Islander residents and RHD in 1.1%. The prevalence of RHD was similar in both regions but with more severe disease in the Kimberley. More FNQ RHD patients had specialist review within recommended time frames (67% vs 45%, χ(2) , P < 0.001). Of patients recommended benzathine penicillin secondary prophylaxis, 17.7% received ≥80% of scheduled doses in the preceding 12 months. Prescription and delivery of secondary prophylaxis was greater in FNQ. CONCLUSIONS: FNQ's single-provider model of specialist care and centralised RHD control programme were associated with improved patient care and may partly account for the fewer cases of severe disease and reduced surgical procedures and other interventions observed in this region.

Liver enzymes and blood metabolites in a population of free-ranging red deer (Cervus elaphus) naturally infected with Fascioloides magna.

We investigated the effects of Fascioloides magna infection on the serum biochemistry values of the naturally infected red deer population in eastern Croatia. The investigation was performed on 47 red deer with F. magna infection confirmed patho-anatomically in 27 animals (57.4%). Fibrous capsules and migratory lesions were found in 14 deer while only fibrous capsules without migratory lesions were found in 13 deer. In 13 deer both immature and mature flukes were found, in 5 deer only immature flukes were found and in 9 deer only mature flukes were found. Fascioloides magna infected deer with fibrous capsules and migratory lesions had significantly higher values for lactate dehydrogenase (LDH), glutamate dehydrogenase (GLDH) and globulin, and lower values for albumin/globulin ratio and glucose compared to uninfected deer. Fascioloides magna infected deer with fibrous capsules without the presence of migratory lesions had higher values for alanine aminotransferase (ALT) and globulin, and lower values for albumin/globulin ratio and glucose, than the uninfected deer. The number of immature flukes was positively correlated with values of aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), LDH, GLDH, urea and triglycerides. The number of migratory lesions was positively correlated with GGT, GLDH, globulin and urea values. The creatinine value was positively correlated with the number of mature flukes. The trial showed that F. magna infection causes significant changes in serum biochemistry. Moreover, these changes do not completely resemble changes following F. hepatica infection. Further investigation of changes in liver enzymes and other serum metabolites in controlled, experimentally induced fascioloidosis in red deer is needed to better understand the pathogenesis of F. magna.

Hematological and biochemical changes in organically farmed sheep naturally infected with Fasciola hepatica.

A naturally occurring outbreak of fasciolosis in a group of 20 Merinolandschaf (German Merino) sheep was studied. Hematological and blood biochemical values in sheep spontaneously infected with liver fluke Fasciola hepatica were compared with equivalent values in 20 parasite-free sheep from organically farmed flock. Investigated animals were kept in outdoor system, on pastures covered with swamps, which remain flooded after rainy season. Significantly lower red blood cell (RBC) count, lymphocytes, hemoglobin (Hb), packed cell volume (PCV), mean corpuscular hemoglobin concentration (MCHC), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, and albumin were recorded in sheep from the infected herd, whereas white blood cell (WBC) count, eosinophil, segmented and band neutrophil count, mean corpuscular volume (MCV), gamma-glutamyl transferase (GGT), concentrations of glucose, and globulins were significantly higher than in the parasite free herd. No significant correlation between the investigated blood parameters and the number of F. hepatica eggs in the feces was detected. This study shows that hematological and biochemical values can be useful in early diagnosis and prognosis of sheep fasciolosis.

Evolution of the snow area index of the subarctic snowpack in central Alaska over a whole season. consequences for the air to snow transfer of pollutants.

The detailed physical characteristics of the subarctic snowpack must be known to quantify the exchange of adsorbed pollutants between the atmosphere and the snow cover. For the first time, the combined evolutions of specific surface area (SSA), snow stratigraphy, temperature, and density were monitored throughout winter in central Alaska. We define the snow area index (SAI) as the vertically integrated surface area of snow crystals, and this variable is used to quantify pollutants' adsorption. Intense metamorphism generated by strong temperature gradients formed a thick depth hoar layer with low SSA (90 cm(2) g-1) and density (200 kg m(-3)), resulting in a low SAI. After snowpack buildup in autumn, the winter SAI remained around 1000 m(2)/m(2) of ground, much lower than the SAI of the Arctic snowpack, 2500 m(2) m-(2). With the example of PCBs 28 and 180, we calculate that the subarctic snowpack is a smaller reservoir of adsorbed pollutants than the Arctic snowpack and less efficiently transfers adsorbed pollutants from the atmosphere to ecosystems. The difference is greater for the more volatile PCB 28. With climate change, snowpack structure will be modified, and the snowpack's ability to transfer adsorbed pollutants from the atmosphere to ecosystems may be reduced, especially for the more volatile pollutants.

Monitoring and treatment of Fascioloides magna in semi-farm red deer husbandry in Croatia.

The presence of American liver fluke (Fascioloides magna) in Croatian wild ruminant species was detected for the first time in January 2000. At the same time, the problem of adequate parasitological monitoring and treatment appeared in the captive deer population. Quarantine and health screening protocols, as well as migration and transportation influence had to be evaluated in red deer husbandry. Non-invasive methods were introduced to estimate the prevalence of F. magna in the semi-farm rearing system. Coprological analysis has been performed on 264 faecal samples. The most effective antiparasitic treatment was implemented on herd and individual treatment. Treatment was extended to the free-ranging population of deer in the same region.

Dioxin concentration in milk and tissues of cows and sheep related to feed and soil contamination.

If cows or sheep are grazing on areas known for a higher dioxin level of the soil, respectively, dry cows are fed with feedstuffs produced on such areas, the dioxin concentration in food, in this case in cows' milk and livers of sheep could reach or exceed maximum levels. Furthermore large amounts of polychlorinated dibenzo-p-dioxins/polychlorinated dibenzo-p-furans (PCDD/F) can be excreted with the faeces. But there are chances for farmers to prevent or at least to minimize the dioxin load of feed and with it of food (including the harvesting technique and the feeding strategy).

A ruthenium porphyrin catalyst immobilized in a highly cross-linked polymer.

An immobilized Ru(meso-tetraarylporphyrin) complex was shown to be a very efficient catalyst for the epoxidation of olefins. In the presence of HBr, alcohols and even alkanes could be converted to the corresponding ketones. For the latter reactions the polymeric catalyst displayed a significantly enhanced activity when compared to that of the homogeneous version.[reaction: see text]

Self-assembled organometallic [12]metallacrown-3 complexes.

The reaction of [(arene)RuCl2]2 (arene = C6H6, cymene, C6H3Et3, or C6Me6) or [Cp*RhCl2]2 with 3-hydroxy-2-pyridone in the presence of Cs2CO3 gives trinuclear metallamacrocyclic complexes. The self-assembly process was shown to be completely diastereoselective, and a racemic mixture of complexes with M(R)M(R)M(R) or MsMsMs (M=Ru, Rh) configuration was obtained. Plausible mononuclear intermediates of the formula [(arene)RuCl(C5H4NO2)] (arene = cymene, C6Me6) have been isolated and characterized. A structurally related trimer was synthesized by using [(cymene)RuCl2]2 and 3-acetamido-2-pyridone instead of 3-hydroxy-2-pyridone. The macrocycles were shown to be highly potent ionophores for Na+ and/or Li+ with negligible affinities for the larger cation K+. The selectivities of the receptors depend on the pi-ligand present: whereas the (C6H6)Ru- and (cymene)Ru complexes bind both Li+ and Na+, the (C6Me6)Ru-, (C6H3Et3)Ru-, and Cp*Rh complexes bind exclusively Li+. For all receptors, the presence of alkali metal ions can be detected electrochemically: the peak potential is shifted by > 300 mV toward anionic potential upon binding. This behavior was utilized to detect Li+ and Na+ colorimetrically. Single crystal X-ray analyses have been carried out on eight complexes, four of which are bound to an alkali metal halide ion pair. Structural parameters, which affect the affinity and selectivity are discussed. A computational study on [[MX][12]crown-3] complexes (M =Li, Na; X=Cl, Br, I) was performed in order to compare relevant bond lengths and angles of the energy-minimized structures with those of the organometallic receptors.

A de novo designed peptide ligase: a mechanistic investigation.

A 33-residue de novo designed peptide ligase is reported which catalyzes the template-directed condensation of suitably activated short peptides with catalytic efficiencies in excess of 10(5) ([k(cat)/K(m)]/k(uncat)). The ligase peptide, derived from natural and designed alpha-helical coiled-coil proteins, presents a surface for substrate assembly via formation of a hydrophobic core at the peptide interface. Charged residues flanking the core provide additional binding specificity through electrostatic complementarity. Addition of the template to an equimolar fragment solution results in up to 4100-fold increases in initial reaction rates. Dramatic decreases in efficiency upon mutation of charged residues or increase in ionic strength establishes the importance of electrostatic recognition to ligase efficiency. Although most of the increase in reaction efficiency is due to entropic gain from binding of substrates in close proximity, mechanistic studies with altered substrates demonstrate that the system is highly sensitive to precise ordering at the point of ligation. Taken together these results represent the first example of a peptide catalyst with designed substrate binding sites which can significantly accelerate a bimolecular reaction and support the general viability of alpha-helical protein assemblies in artificial enzyme design.

Comparative sequence analysis of the core- and NS5-region of hepatitis C virus from tumor and adjacent non-tumor tissue.

The sequence variability within the core- and non-structural 5 (NS5)-region of the hepatitis C virus (HCV) was investigated in tumor and non-tumor tissue of 8 patients with HCV-associated hepatocellular carcinoma (HCC). Analyses of multiple clones containing polymerase chain reaction-amplified HCV sequences revealed a significantly higher variability within the core-region of tumor tissue isolates than of isolates from non-tumor tissue. Mutant sequence diversity ranged from silent mutations, as well as amino acid substitutions, appearance of in frame stop codons and deletions leading to frame-shifts. In contrast, the variability of the NS5-region sequences between isolates from tumor and non-tumor tissue was not significantly different. These observations might have important implications on the pathology of HCV, especially its potential tumorigenicity.

Imprinted polymers with transition metal catalysts.

The microenvironment of immobilized transition metal catalysts can be manipulated using catalyst-substrate conjugates in combination with the technology of molecular imprinting. Recent results have shown that catalysts with a significantly enhanced activity combined with an improved substrate-, regio- and enantioselectivity can be prepared in this way. These artificial systems resemble metalloenzymes because the catalytic transformation is effectively controlled by a well-defined second coordination sphere.