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ABSTRACTIntroduction: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.

Copyright of Deep South Magazine is the property of Deep South Media, LLC and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Deep South Magazine is the property of Deep South Media, LLC and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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.

Ein definitiver kurativer Therapieansatz ist mit einer operativen Tumorentfernung bisher nur für das lokal begrenzte Nierenzellkarzinom (NZK) vorhanden. Die Prognose beim metastasierten Nierenzellkarzinom (mNZK) ist vergleichsweise reduziert. Mit Einführung der zielgerichteten Therapie 2006 konnte eine deutliche Verbesserung des Gesamtüberlebens (OS) und des progressionsfreien Überlebens (PFS) erreicht werden. 2016 wurde mit der Zulassung des PD-1-Inhibitors Nivolumab das Therapiespektrum der Zweitlinie beim mNZK um eine neue Wirkstoffklasse erweitert. Zur Systemtherapie besteht weiterhin ein hoher therapeutischer Bedarf für zusätzliche Behandlungsoptionen, die einen relevanten Überlebensvorteil sowie ein anhaltendes und verbessertes Therapieansprechen ermöglichen. Die Systemtherapie für das mNZK umfasst aktuell insgesamt 11 verschiedene zielgerichtete Wirkstoffe aus 4 unterschiedlichen Substanzklassen. A definitive curative treatment exists only for localized renal cell carcinoma (RCC) by surgical resection. The prognosis for metastatic renal cell carcinoma (mRCC) is still comparatively limited. With the introduction of the targeted therapy in 2006, a significant improvement in overall survival (OS) and progression-free survival (PFS) was achieved. In 2016 the approval of the PD-1 inhibitor nivolumab enhanced the therapy spectrum of second-line treatment with a new class of active substances. For first-line treatment there is still a high therapeutic need for additional treatment options to achieve a relevant survival benefit and a sustained and improved response to treatment. The systemic therapy of mRCC currently comprises a total of 11 different targeted drugs from 4 different substance classes.

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.

Abstract: During the 10-year survey (1996–2005), a total of 868 blood samples from different game species in Croatia were analyzed for the presence of leptospiral antibodies. The specific antibodies (AB) were detected in 242 samples (27.88%). According to the species in red deer (Cervus elaphus), the antibodies against six different leptospiral serovars were found in 43 of 226 analyzed sera (19.02%). The most frequent antigen serovars in the deer population were Pomona and Ballum (with the same frequency of 23.6%), whereas the highest titer was recorded for serovar Sejroe (1:800). In the analyzed roe deer (Capreolus capreolus) serum samples, a low level of leptospiral antibodies (6.07%) was determined, with just two AB for antigen serovars—Australis and Sejroe. In wild boar (Sus scrofa), leptospiral antibodies were detected in 151 of 431 samples analyzed (35.03%), with AB for nine antigen serovars. The serovars most frequently found were Australis (48.70%) and Pomona (22.70%), and these serovars also recorded the highest titer (1:3,200). Among brown bear (Ursus arctos) samples, leptospiral antibodies were detected in 25.00% of the samples, with four AB for antigen serovars, of which the most frequent was Icterohaemorrhagiae (>40%). This serovar had the highest recorded titer (1:400). From 112 analyzed red fox (Vulpes vulpes) samples, leptospiral antibodies were found in 35 samples (31.25%). The determined antibodies were specific for four antigen serovars, of which the most frequent (46.2%) and with highest titer (1:1600) was serovar Australis. No antibodies (28/0) were recorded in mouflon (Ovis musimon). The most important game species from an epizootiological point of view in the studied area were certainly wild boar and red foxes. With strong serological reactions, these two species could be emphasized as important hosts for Leptospira interrogans sv. Australis in Croatia, but for their declaration as ‘maintaining hosts,’ isolation of sv. Australis is needed. According to aerial distribution, the highest number of positive samples from different game species was recorded in the central and eastern parts of Croatia, known as the ‘historical natural foci’ of leptospirosis—the regions of Posavina, Podravina, Slavonija, and Baranja. In contrast, the areas of Kordun and Gorski Kotar are declared as leptospira low-risk regions for the game species studied.

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. magnain 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.

The hypothesis that elemental composition of otoliths of the eel (Anguilla spp.) changes with life stage and growth habitat was tested in the present study. The minor elements Cl, Na, K, Mg, Ca, Sr and P in otoliths of European eels (Anguilla anguilla) were examined by using an Electron Probe Microanalyser (EPMA) equipped with wavelength dispersive spectrometers (Cameca SX-50). Yellow-stage eels were collected from coastal waters and lakes of Sweden in 1987, 1988, 1991, and 1994, with ages ranging from 5 to 18 years old. Strontium maps and profiles of Sr:Ca ratio, as well as the elver check in otoliths, were used to classify life history stages of the eels as leptocephalus, and freshwater- and seawater-resident yellow eels. Canonical score plots of the otolith elemental compositions of the freshwater-resident yellow eel were completely separated from those of leptocephalus and seawater-resident yellow eel, but the latter two partially overlapped. Strontium is the primary component in determining the discrimination, but the nutrient-related (S and P), and the physiologically controlled elements (Na and Cl), may also play an important role in the discrimination. These results indicate that multiple-elemental information can provide additional insight into the migratory environmental history of diadromous fishes.

An [(arene)RuCl2]2 complex with a methacrylate side chain (2) has been prepared in two steps using commercially available starting materials. This complex reacts with PPh3, pyridine, or toluidine to give the corresponding mononuclear adducts (3−5). The structure of 4 was determined by single-crystal X-ray diffraction. Complex 2 and the PPh3 adduct 3 were immobilized by copolymerization with divinylbenzene (DVB) or ethyleneglycol dimethacrylate (EGDMA). The resulting EGDMA copolymer was tested as a catalyst in asymmetric transfer hydrogenations. Using (1R,2R)-(−)-N-p-tosyl-1,2-diphenylethylenediamine as the chiral ligand and azeotropic NEt3/HCO2H as the reducing agent, aromatic ketones were converted to the corresponding alcohols with selectivities between 87 and 97% ee.

The symmetric chloro-bridged complexes [(Et3P)2PtCl(µ-Cl)]2, [(Et3P)2Pt(µ-Cl)]2²⁺ and [(C3H5)Pd(µ-Cl)]2 and the asymmetric complexes [(C3H5)Pd(µ-Cl)2Pt(PEt3)2]⁺ and [(C3H5)Pd(µ-Cl)2Pt(PEt3)Cl] were studied by means of vibrational spectroscopy (infrared, Raman) and computational chemistry. Assignments of all normal modes associated with skeletal stretching are suggested and their displacement vectors are discussed. Copyright © 2001 John Wiley & Sons, Ltd.

The ubiC gene of Escherichia coli encodes chorismate pyruvatelyase, an enzyme that converts chorismate into 4-hydroxybenzoate (4HB) and is not normally present in plants. The ubiC gene was expressed in Nicotiana tabacum L. plants under control of a constitutive plant promoter. The gene product was targeted into the plastid by fusing it to the sequence for the chloroplast transit peptide of the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. Transgenic plants showed high chorismate pyruvate-lyase activity and accumulated 4HB as beta-glucosides, with the glucose attached to either the hydroxy or the carboxyl function of 4HB. The total content of 4HB glucosides was approximately 0.52% of dry weight, which exceeded the content of untransformed plants by at least a factor of 1000. Feeding experiments with [1,7-13C2]shikimic acid unequivocally proved that the 4HB that was formed in the transgenic plants was not derived from the conventional phenylpropanoid pathway but from the newly introduced chorismate pyruvate-lyase reaction.

Chorismate pyruvate-lyase activity was detected in extracts of Escherichia coli. 4-Hydroxybenzoate was identified as the product of the enzymatic reaction by chemical derivatization and GC-MS analysis. The ubiCgene, coding for the chorismate pyruvate-lyase, was cloned and sequenced. The molecular weight of the gene product was calculated as 18.776 Da and confirmed by expression of the protein in E. coliminicells. The ubiAgene, coding for the 4-hydroxybenzoate octaprenyl transferase, was identified by sequence homology and complementation of a ubiA−strain. It is located directly downstream of ubiCin a typical operon structure.

Summary: The present study reports for the first time on the helminth species occurring in the gastro-intestinal system of fat dormice (Glis glis) in Croatia. Out of 55 dormice, 63.7 % harboured helminths belonging to two species, the nematode Paraheligmonina gracilis (syn. Longistriata elpatievskii) (Heligmonellidae, Trichostrogyloidea) in the prevalence of 52.7 %, and the cestode Hymenolepis sulcata (Hymenolepididae, Cyclophyllidea) in the prevalence of 32.7 %. Concurrent infections of both parasites were found in 12 fat dormice, P. gracilis alone was detected in 17 hosts and H. sulcata alone in 6 samples. No influence of parasitic infestation on animal weight was observed. Glirid helminths do not represent zoonotic pathogens despite the fact that dormice occasionally inhabit cottages and village houses, and are used in human nutrition.

The trinuclear ruthenium complexes [RuCl2-(PAd2Bu)]3 and [RuCl2(P^tBu2Cy)]3 have been obtained by reaction of [(cymene)RuCl2]2 with 2 equiv of the respective phosphine. Crystallographic analyses show that the three metal fragments are connected by strong Ru−Ru bonds and bridging chloro ligands.

A bimetallic complex, in which a RuCl2(η²-C2H4)(PCy3) fragment is connected via three chloro bridges to a (η⁶-p-cymene)RuCl2 fragment, has been synthesized and characterized by single-crystal X-ray crystallography. This complex was used to catalyze the atom transfer radical addition of CCl4 and CHCl3 to olefins at temperatures between 0 and 40 °C. Turnover frequencies of up to 1550 h^-1 were observed, making the new complex one of the most active catalysts for this type of reaction described so far.

A heterobimetallic complex, in which a RuCl2(acetone)(PPh3)2 fragment is connected via three chloro bridges to a (η⁴-C4Ph4CO)RhCl fragment, has been identified as a potent catalyst precursor for the Oppenauer-type oxidation of alcohols. With 0.1−0.5 mol % of this complex and K2CO3 as the cocatalyst, it is possible to oxidize secondary and primary alcohols at room temperature using acetone as the solvent and oxidation agent.

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.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.