A Unique and Stable Polyproline I Helix Sorted out from Conformational Equilibrium by Solvent Polarity.

Polyproline I helical structures are often considered as the hidden face of their most famous geminal sibling, Polyproline II, as PPI is generally spotted only within a conformational equilibrium. We designed and synthesized a stable Polyproline I structure exploiting the striking tendency of (S)-indoline-2-carboxylic acid to drive the peptide bond conformation toward the cis amide isomer, when dissolved in polar solvents. The cooperative effect of only four amino acidic units is sufficient to form a preferential structure in solution. We shed light on this rare secondary structure with a thorough analysis of the spectroscopic and chiroptical properties of the tetramer, supported by X-ray crystallography and computational studies.

New camptothecin derivatives for generalized oncological chemotherapy: Synthesis, stereochemistry and biology.

Derivatives of SN38 were synthesized that were either monosubstituted at C-5 or C-9 or disubstituted at both C-5 and C-9. Substitution to C-5 led to the generation of pairs of diastereomers (2c-2 h) in a one-pot reaction and was readily separable by HPLC. The absolute configurations of C-5 were established by electronic circular dichroism experiments. Compounds were tested in vitro against human cancer cell lines as well as a normal cell line. The impact of compounds 2a-2j on cancer cells is significant and the IC50 values against the normal cell line are several times higher than that of SN38. Using the Mannich reaction we obtained a new innovative group of derivatives with unique biological properties that preserves the high cytotoxicity in cancer cells and eliminates the acute toxicity to non-neoplastic cells, which can be considered a breakthrough in chemotherapy with the use of topoisomerase I inhibitors from the camptothecin family.

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus.

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved.

Higginsianins D and E, Cytotoxic Diterpenoids Produced by Colletotrichum higginsianum.

Two new diterpenoids with tetrasubstituted 3-oxodihydrofuran substituents, named higginsianins D (1) and E (2), were isolated from the mycelium of the fungus Colletotrichum higginsianum grown in liquid culture. They were characterized as methyl 2-[6-hydroxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)-decahydronaphthalen-1-ylmethyl]-4,5-dimethyl-3-oxo-2,3-dihydrofuran-2-carboxylate and its 21-epimer by using NMR, HRESIMS, and chemical methods. The relative configurations of higginsianins D and E, which did not afford crystals suitable for X-ray analysis, were determined by NOESY experiments and by comparison with NMR data of higginsianin B. The absolute configuration was established by comparison of experimental and calculated electronic circular dichroism data. The evaluation of 1 and 2 for antiproliferative activity against human A431 cells derived from epidermoid carcinoma and H1299 non-small-cell lung carcinoma cells revealed that 2 exhibited higher cytotoxic activity than 1, with an IC50 value of 1.0 µM against A431 cells. Remarkably, both 1 and 2 were almost ineffective against immortalized keratinocytes, used as a preneoplastic cell line model.

Finite Element Analysis of the Stability of a Sinusoidal Web in Steel and Composite Steel­Concrete Girders.

This paper presents the results of numerical investigations into the behavior of a sinusoidal web loaded in shear due to buckling in the period from the onset of buckling until failure, as well as the impact of a reinforced concrete slab on the stability of the web. The analysis concerned steel girders and composite girders with the top flange bonded to a reinforced concrete slab. Nonlinear analyses were performed using the finite element method. The results of the investigations support the conclusion that the appearance and propagation of shear stresses in the sinusoidal web of the composite steel-concrete beam are the same as those in an identical non­composite steel beam, but the bracing of the top flanges improves the shear strength and, at the same time, affects the location of initial stresses. In addition, it was found that, despite the three types of buckling, the predominant failure of the sinusoidal webs, regardless of the presence of the concrete slab, is global buckling. It occurs diagonally through several folds at the same time, including deformation of the web over its entire height.

Experimental Investigation of Impact Concrete Slab on the Bending Behavior of Composite Bridge Girders with Sinusoidal Steel Web.

Until recently, steel plate girders with corrugated steel members were used primarily as poles and girders in the construction of industrial buildings. Currently, they are also being used in the construction of bridges. Compared to traditional steel and rolled girders, steel plate girders weigh less and are more stiff, while also having a neater appearance. In this paper, the results of an experimental study are present. The aim of the study was to determine the behavior of a bridge girder with sinusoidal web geometry when subjected to a bending moment. The study was focused on a composite steel and concrete structure with pin connections, which is currently the most common solution. Three near-real scale beams were subjected to bending tests. The study found that composite corrugated-web steel beams and non-composite corrugated-web steel beams showed similar forms of failure. A reinforced concrete slab did not prevent web stress concentration at the point of connection with the flange. Furthermore, the study indicates that corrugated steel webs in bridge girders can have a much smaller thickness (less than 8 mm) compared with the traditional solution.

Elusive π-helical peptide foldamers spotted by chiroptical studies.

A series of oligomers containing alternate l-Ala and pGlu (pyroglutamic acid) both in the L and D form have been prepared and conformationally investigated by X-ray, NMR, UV/ECD, IR/VCD and molecular modelling. X-ray diffraction analysis was possible for the shortest oligomers LL-1 and LD-1. Molecular dynamics simulations of the oligomers demonstrated that the energy landscapes of the LL-series are broad. In contrast, the energy landscapes of the LD-series are characterized by well-defined minima corresponding to specific conformational structures. A single well-defined minimum exists in the energy landscape of the largest oligomer LD-8, corresponding to a precise conformation, characterized by i + 5 →i N-HO[double bond, length as m-dash]C hydrogen bonds, typical of a π-helix. ECD and VCD spectra were measured to identify the chiroptical profiles of the oligomers. The most striking element in the ECD spectra of the LD-series is their exceptionally strong intensity, which confirms that these polypeptides attain a high degree of helical order. VCD spectra for the LD-series are well reproduced by frequency calculations when π-helix folds are employed as input structures, suggesting that a symmetrical VCD couplet around 1720 cm-1 can be taken as the VCD signature of π-helices.

Polyoxygenated cyathane diterpenoids from the mushroom Cyathus africanus, and their neurotrophic and anti-neuroinflammatory activities.

In a previous study, we reported ten new polyoxygenated cyathane diterpenoids, neocyathins A-J, and their anti-neuroinflammatory effects from the liquid culture of the medicinal Basidiomycete Cyathus africanus. In the present study, eight new highly polyoxygenated cyathane diterpenoids, named neocyathins K-R (1-8), were isolated from the solid culture of C. africanus cultivated on cooked rice, together with three known congeners (9-11). The structures and the absolute configurations of the new compounds were elucidated through comprehensive NMR and HRESIMS spectroscopic data, electronic circular dichroism (ECD) data, and chemical conversion. Compounds 1 and 2 represent the first reported naturally occurring compounds with 4,9-seco-cyathane carbon skeleton incorporating an unprecedented medium-sized 9/7 fused ring system, while the 3,4-seco-cyathane derivative (3) was isolated from Cyathus species for the first time. All compounds were evaluated for their neurotrophic and anti-neuroinflammatory activity. All the isolates at 1-25 µM displayed differential nerve growth factor (NGF)-induced neurite outgrowth-promoting activity in PC-12 cells, while one of the compounds, allocyathin B2 (11), inhibited NO production in lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. In addition, molecular docking studies showed that compound 11 generated interactions with the inducible nitric oxide synthase (iNOS) protein.

First record of Giardia assemblage D infection in farmed raccoon dogs (Nyctereutes procyonoides).

The presence of Giardia genotypes was investigated in 18 raccoon dogs (Nyctereutes procyonoides) and 80 red foxes (Vulpes vulpes) on one farm. To demonstrate Giardia cysts, fresh and trichrome stained smears were microscopically screened. Two molecular markers were used for Giardia genotyping: a fragment of the beta-giardin gene and a fragment of the glutamate dehydrogenase gene. All faecal samples obtained from red foxes were negative. Giardia cysts were identified only in 2 of the 18 raccoon dogs. The result of genotyping and phylogenetic analysis showed that the G. duodenalis from both raccoon dogs belonged to the D assemblage. This finding of a new animal reservoir of G. duodenalis canids-specific genotypes is important in order to eliminate the risk of infecting other animals bred for fur. Further molecular analyses of Giardia isolates in raccoon dogs are required. The present study represents the first contribution to knowledge of G. duodenalis genotypes in raccoon dogs.