Ring Junction Research Articles

Crystal structure of [(1,2,3,4,11,12-η)-anthracene]tris-(tri-methyl-stann-yl)cobalt(III).

The asymmetric unit of the title structure, [Co(η(6)-C14H10){Sn(CH3)3}3], contains two independent mol-ecules. Each anthracene ligand is η(6)-coordinating to a Co(III) cation and is nearly planar [fold angles of 5.4 (3) and 9.7 (3)°], as would be expected for its behaving almost entirely as a donor to a high-oxidation-state metal center. The slight fold in each anthracene ligand gives rise to slightly longer Co-C bond lengths to the ring junction carbon atoms than to the other four. Each Co(III) cation is further coordinated by three Sn(CH3)3 ligands, giving each mol-ecule a three-legged piano-stool geometry. In each of the two independent mol-ecules, the trio of SnMe3 ligands are modeled as disordered over two positions, rotated by approximately 30%, such that the C atoms nearly overlap. In one mol-ecule, the disorder ratio refined to 0.9365 (8):0.0635 (8), while that for the other refined to 0.9686 (8):0.0314 (8). The mol-ecules are well separated, and thus no significant inter-molecular inter-actions are observed. The compound is of inter-est as the first structure report of an η(6)-anthracene cobalt(III) complex.

Gram‐Scale Enantioselective Formal Synthesis of Morphine through an ortho–para Oxidative Phenolic Coupling Strategy

AbstractA gram‐scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho–para oxidative phenolic coupling and a highly diastereoselective “desymmetrization” of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.

Gram-scale enantioselective formal synthesis of morphine through an ortho-para oxidative phenolic coupling strategy.

A gram-scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho-para oxidative phenolic coupling and a highly diastereoselective "desymmetrization" of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.

Crystal structure of 4-amino-pyridinium 5-(5-chloro-2,4-dinitrophenyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate hemihydrate.

The title mol-ecular salt, C5H7N2 (+)·C12H8ClN4O7 (-)·0.5H2O, crystallizes as a hemihydrate. The two rings in the barbiturate anion are not coplanar but make a dihedral angle of 43.17 (16)°. The two nitro groups deviate from the ring to which they are attached; the nitro group ortho with respect to the ring junction is more deviated [39.3 (4)°] than that in the para position [4.2 (5)°], probably to overcome steric hindrance. As a result of this, the latter nitro group is more involved in delocalizing the negative charge of the anion than the former nitro group. In the crystal, the cations and anions are linked via N-H⋯O hydrogen bonds forming zigzag chains along [10-1]. The chains are linked by O-H⋯O and C-H⋯O hydrogen bonds, forming slabs lying parallel to (10-1). Further C-H⋯O hydrogen bonds link the slabs, forming a three-dimensional structure.

Two New Diterpenoids from Thuja orientalis and Their Cytotoxicity

Thuja orientalis L. [= Biota orientalis (L.) Endl., Platycladus orientalis (L.) Franco] (Cupressaceae) is an evergreen arbor widely distributed throughout Korea and China. This plant has been used in the traditional medicine for the treatment of hemorrhoids and hypertension. Previous chemical investigations on this plant reported the isolation of terpenoids, flavonoids and lignans. The extract and some constituents of this plant were reported to exhibit anti-inflammatory, cytotoxic, and neuroprotective activities. We investigated the constituents of the leaves of T. orientalis as part of our continuing search for cytotoxic secondary metabolites from Korean medicinal plants and reported about cytotoxic diterpenoids. Further we isolated two new stereoisomers (12) and seven known compounds (3-9) (Figure 1). The chemical structures of 1-2 were determined by spectroscopic methods, including 1D and 2D NMR (H and C NMR, DEPT, H-H COSY, HMQC, HMBC, and NOESY). Previously, 3 was reported with incomplete stereochemistry, and now we reported the complete stereostructure of 3. Compounds 1, 2 and 4-9 were evaluated for their cytotoxicity against A549 (non small cell lung adenocarcinoma), SK-OV-3 (ovarian cancer cells), A498 (renal cell carcinoma) and HCT-15 (colon cancer cells) human tumor cell lines using an in vitro sulforhodamine B (SRB) assay. Compound 1 was obtained as a colorless gum. The molecular formula C22H34O5 was determined from the ion peak [M + Na] at m/z 401.2300 (calcd for C22H34NaO5, 401.2304) in positive ion HRFABMS. The H NMR spectrum showed the presence of signals due to three olefinic [δ 5.65, 4.86, and 4.50 (each brs)], two acetalic [δ 5.54 and 5.42 (each brs)], two methoxyl [δ 3.42 and 3.38 (each s)], and two tertiary methyl [δ 1.23 and 0.61 (each s)] protons. The C NMR spectrum showed 22 carbon signals which were attributed to four methyl, eight methylene, and five methine groups, as well as five quaternary carbons, including one carbonyl carbon (δ 182.7), four olefinic carbons (δ 147.8, 146.3, 123.7 and 106.7), and two acetalic carbons (δ 107.9 and 107.1), determined by the analysis of the DEPT and HMQC spectra. These spectroscopic data of 1 were closely resembled to those of 3 with the exception that H12a and H-12b signals of 1 (δ 2.25 and 2.02, respectively) were slightly shifted (δ 2.35 and 1.88, respectively, 3) in the H NMR spectrum, indicating that 1 may be a stereoisomer of 3. The planar structure of 1 was confirmed by the DEPT, H-H COSY, HMQC and HMBC spectra (Figure 2). A trans-fused A/B ring junction was inferred from the absence of NOESY correlation of H-5/H-20 and the NOESY crosspeaks of H-5/H-9 and H-18 and H-11/H-20 confirmed the relative stereochemistry at A and B rings (Figure 3). The H14, H-15, and H-16 signals in H NMR (δ 5.65, 5.54, and 5.42, respectively) were very similar to those of the cis-form of the 1,4-dihydro-1,4-dimethoxy furan ring (δ 5.64, 5.50 and 5.35), not to those of the trans-form (δ 5.80-5.70 and 5.68-5.60), indicating the H-15 and H-16 of 1 were in the

Surgical anatomy of the aortic root: Implication for valve-sparing reimplantation and aortic valve annuloplasty

BackgroundTo enhance the reproducibility of aortic valve–sparing reimplantation and annuloplasty, we analyzed the topographic relationship between the ventriculoaortic junction (VAJ), basal ring (BR), and sinotubular junction (STJ). The root base thickness is also quantified. MethodFifty-eight fresh human aortic valves were analyzed. The root was dissected to the limit where the aortic wall terminates into the cardiac structures (VAJ). Root height was measured externally from the STJ to the VAJ and internally from the STJ to the BR defined as the plane passing through the cusps nadir. The root base thickness was measured at the BR and orthogonal to the internal wall; except at the right coronary sinus, where it was measured between the BR internally and the VAJ externally. Measurements were taken at the middle of the 3 sinuses and commissures. ResultsThe VAJ is at the same level as the BR from the noncoronary sinus (−0.1 ± 0.9 mm) to the left coronary sinus (0.5 ± 1.3 mm); it is above the BR from the left/right commissure (4.6 ± 1.4 mm) to the right/non commissure (2.5 ± 1.6 mm). The external root height was highest at the non/left commissure (21.5 ± 2.6 mm) followed by the right/non commissure (19.2 ± 2.3 mm) then the left/right commissure (15.7 ± 2.2 mm) (P < .05). The mean root base thickness was 3.2 mm, ranging from 1 ± 0 mm at the left/non commissure to 6.2 ± 1.2 mm at the right coronary sinus (P < .001). ConclusionsThe VAJ is not planar; it is above the level of the BR from the left/right to the right/non commissure. As a consequence, the external height of the non/left commissure is greater than the other 2 commissures. These findings should be taken into consideration when performing aortic valve–sparing reimplantation or external annuloplasty.

Stitched α-helical peptides via bis ring-closing metathesis.

Conformationally stabilized α-helical peptides are capable of inhibiting disease-relevant intracellular or extracellular protein-protein interactions in vivo. We have previously reported that the employment of ring-closing metathesis to introduce a single all-hydrocarbon staple along one face of an α-helical peptide greatly increases α-helical content, binding affinity to a target protein, cell penetration through active transport, and resistance to proteolytic degradation. In an effort to improve upon this technology for stabilizing a peptide in a bioactive α-helical conformation, we report the discovery of an efficient and selective bis ring-closing metathesis reaction leading to peptides bearing multiple contiguous staples connected by a central spiro ring junction. Circular dichroism spectroscopy, NMR, and computational analyses have been used to investigate the conformation of these "stitched" peptides, which are shown to exhibit remarkable thermal stabilities. Likewise, trypsin proteolysis assays confirm the achievement of a structural rigidity unmatched by peptides bearing a single staple. Furthermore, fluorescence-activated cell sorting (FACS) and confocal microscopy assays demonstrate that stitched peptides display superior cell penetrating ability compared to their stapled counterparts, suggesting that this technology may be useful not only in the context of enhancing the drug-like properties of α-helical peptides but also in producing potent agents for the intracellular delivery of proteins and oligonucleotides.

Semi-synthesis of oxygenated dolabellane diterpenes with highly in vitro anti-HIV-1 activity

Research on dolabellane diterpenes of brown algae Dictyota spp. has shown that these diterpenoids have strong anti-HIV-1 activity, but there are not data about antiviral activity of dolabellane diterpenes isolated from octocorals, which are antipodes of those isolated from the brown algae. Dolabellanes 13-keto-1(R),11(S)-dolabella-3(E),7(E),12(18)-triene (1) and β-Araneosene (2) were isolated from the Caribbean octocoral Eunicea laciniata, and both showed low anti-HIV-1 activity and low toxicity. Since it was shown that oxygenated dolabellanes from algae have better anti-HIV-1 activity, in this work some derivatives of the main dolabellane of E. laciniata1 were obtained by epoxidation (3), epoxide opening (4), and allylic oxidation (5). The derivatives showed significant improvement in the anti-HIV-1potency (100-fold), being compounds 3 and 5 the most active ones. Their high antiviral activities, along with their low cytotoxicity, make them promissory antiviral compounds; and it is worth noting that the absolute configuration at the ring junction in the dolabellane skeleton does not seem to be determinant in the antiviral potency of these diterpeneoids.

Synthesis and receptor binding in trans-CD ring-fused A-CD estrogens: Comparison with the cis-fused isomers

Ligands which selectively activate only one of the estrogen receptors, ERα or ERβ, are current pharmaceutical targets. Previously, we have reported on substituted cis A-CD ligands in which the B-ring of the steroidal structure has been removed and cis refers the stereochemistry of the CD ring junction as compared to trans in estradiol. These compounds often showed good potency and selectivity for ERβ. Here we report the synthesis and binding affinities for a similar series of trans A-CD ligands, and compare them to the cis-series. Counterintuitively, trans A-CD ligands, which are structurally more closely related to the natural ligand estradiol, show weaker binding and less β-selectivity than their cis-counterparts.

Larvicidal activities of the stem bark extract and rotenoids of Millettia usaramensis subspecies usaramensis on Aedes aegypti L. (Diptera: Culicidae)

The dichloromethane/methanol (1:1) extract of the stem bark of Millettia usaramensis subspecies usaramensis was tested for its larvicidal activity against the 4th instar Aedes aegypti larvae and demonstrated activity with LC50 value of 50.8±0.06μg/mL at 48h. Compounds isolated from the extract were also tested for their larvicidal activities, and the rotenoid usararotenoid-A (LC50 4.3±0.8μg/mL at 48h) was identified as the most active principle. This compound appears to be the first rotenoid having a trans-B/C ring junction and methylenedioxy group at C-2/C-3 with high larvicidal activity. Related rotenoids with the same configuration at the B/C-ring junction did not show significant activity at 100μg/mL.

Stereospecific cis- and trans-ring fusions arising from common intermediates.

Highly concise and stereospecific routes to cis and trans fusion, carrying various functionality at one of the bridgehead carbons, have been accomplished.

Diterpenes and sesquiterpenes with anti-Coxsackie virus B3 activity from the stems of Illicium jiadifengpi

Seven new diterpenes, jiadifenoic acids J–P (1–7), two new sesquicarane sesquiterpenes, sesquicaranoic acids A and B (8 and 9), and four known compounds, were isolated from the stems of Illicium jiadifengpi. The trans-fused A/B ring junction in diterpenes was deduced from NMR data analysis and confirmed by single-crystal X-ray crystallography of 3. The absolute configurations of compounds 1 and 5 were determined using the Mo2(OAc)4-induced circular dichroism (ICD) method. Compounds 8 and 9 are a pair of C-10 epimers, and their absolute configurations were confirmed by analyzing their CD and ICD data. All of the isolated compounds were evaluated in vitro for their antiviral activities against Coxsackie virus B3 (CVB3). Among the isolated compounds, 4, 5, 7, 10, and 11 exhibited reasonable activity against CVB3, with IC50 values of 7.0–22.2 μmol/mL and selective index values (SI=TC50/IC50) of 49.3, 37.1, 31.3, 45.6 and 40.9, respectively.

Enantioselective total synthesis of (−)-cyathin B2

Ayer and Lee1 isolated (−)-cyathin B2 (1) (Scheme 1) as a component of various congeners, from Cyathus earlei Lloyd, which is a tropical or subtropical species of bird’s nest fungus (family Nidulariaceae) found in Cuba, Puerto Rico, Mexico and Hawaii. It is a cyathane diterpenoid with a cyathane core as the common scaffold, which features a five–six–seven tricyclic ring system with a trans-[6–7] ring fusion and two all-carbon quaternary stereogenic centers at the ring junctions.

Structural Optimization and Biological Screening of a Steroidal Scaffold Possessing Cucurbitacin‐Like Functionalities as B‐Raf Inhibitors

Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting the commonly occurring mutated B-Raf in melanoma has become a practical method for the development of drugs and drug candidates. In order to expand upon the currently reported structural scaffolds used to target the MAPK pathway, molecular docking studies led to the installation an α,β-unsaturated ketone side chain, related to the cucurbitacin class of natural products, on to an estrone core via an aldol condensation reaction, along with installation of the Δ(9,11) olefin to assemble what has been defined as a pseudo-cis configuration at the B/C ring juncture. Combination of these cucurbitacin-like features resulted in a compound with an enhanced biological profile against the A-375 mutant B-Raf cell line, in regards to their cytotoxicity and inhibitory activity toward phosphorylated extracellular-signal-regulated kinase (ERK).

Organization of the Ectodermal Nervous Structures in Medusae: Cubomedusae

At least two conducting systems are well documented in cubomedusae. A variably diffuse network of large neurons innervates the swim musculature and can be visualized immunohistochemically using antibodies against α- or β-tubulin. Despite the non-specificity of these antibodies, multiple lines of evidence suggest that staining highlights the primary motor networks. These networks exhibit unique neurite distributions among the muscle sheets in that network density is greatest in the perradial frenula, where neurites are oriented in parallel with radial muscle fibers. This highly innervated, buttress-like muscle sheet may serve a critical role in the cubomedusan mechanism of turning. In scyphomedusae, a second subumbrellar network immunoreactive to antibodies against the neuropeptide FMRFamide innervates the swim musculature, but it is absent in cubomedusae. Immunoreactivity to FMRFamide in cubomedusae is mostly limited to a small network of neurons in the pacemaker region of the rhopalia, the pedalial apex at the nerve ring junction, and a few neuron tracts in the nerve ring. However, FMRFamide-immunoreactive networks, as well as tubulin-immunoreactive networks, are nearly ubiquitous outside of the swim muscle sheets in the perradial smooth muscle bands, manubrium, pedalia, and tentacles. Here we describe in detail the peripheral nerve nets of box jellyfish on the basis of immunoreactivity to the antibodies above. Our results offer insight into how the peripheral nerve nets are organized to produce the complex swimming, feeding, and defensive behaviors observed in cubomedusae.

Treatment of unstable pelvic ring injuries with vertebropelvic transpedicular fixation

In the period from 2011 to 2013 in Botkin City Hospital 17 patients with unstable injuries of pelvic ring and lumbosacral junction were operated using the method of transpedicular vertebropelvic fixation. In the preoperative period a comprehensive instrumental examination, including X-rays and CT was performed in all patients. In 11 (64.7 %) patients neurological complications were detected, of which 4 (23.5%) - cauda equina syndrome (patients with transverse fractures of the sacrum). The follow- up of patients was 1.5 years In all cases the X-ray pattern after surgical treatment was regarded as satisfactory. During the observation period the necessary to remove the fixation devices didn’t appear. The regression rate of neurological symptoms in the postoperative period depend on the severity of the initial injury and the intensity of symptoms. In the group of patients with transverse fractures of the sacrum disorders of pelvic organs remained, caused by primary severe damage in the sacral canal zone. In the other groups there was a gradual regression of motor and sensory disorders in the year after surgery. The complications in the early postoperative period: 2 (11.8 %) cases of delayed healing of surgical wounds in the sacral region (secondary healing) and one (5.9%) case of postoperative wound infection that requested the secondary surgical treatment, rehabilitation and installation of the suction-irrigation system. The method of transpedicular vertebropelvic fixation is effective in the treatment of unstable pelvic injuries if braking-down of gemipelvis is necessary and also in the combined damage of low-lumbar spine.

Sesquiterpene lactone stereochemistry influences herbivore resistance and plant fitness in the field.

Stereochemical variation is widely known to influence the bioactivity of compounds in the context of pharmacology and pesticide science, but our understanding of its importance in mediating plant-herbivore interactions is limited, particularly in field settings. Similarly, sesquiterpene lactones are a broadly distributed class of putative defensive compounds, but little is known about their activities in the field. Natural variation in sesquiterpene lactones of the common cocklebur, Xanthium strumarium (Asteraceae), was used in conjunction with a series of common garden experiments to examine relationships between stereochemical variation, herbivore damage and plant fitness. The stereochemistry of sesquiterpene lactone ring junctions helped to explain variation in plant herbivore resistance. Plants producing cis-fused sesquiterpene lactones experienced significantly higher damage than plants producing trans-fused sesquiterpene lactones. Experiments manipulating herbivore damage above and below ambient levels found that herbivore damage was negatively correlated with plant fitness. This pattern translated into significant fitness differences between chemotypes under ambient levels of herbivore attack, but not when attack was experimentally reduced via pesticide. To our knowledge, this work represents only the second study to examine sesquiterpene lactones as defensive compounds in the field, the first to document herbivore-mediated natural selection on sesquiterpene lactone variation and the first to investigate the ecological significance of the stereochemistry of the lactone ring junction. The results indicate that subtle differences in stereochemistry may be a major determinant of the protective role of secondary metabolites and thus of plant fitness. As stereochemical variation is widespread in many groups of secondary metabolites, these findings suggest the possibility of dynamic evolutionary histories within the Asteraceae and other plant families showing extensive stereochemical variation.

Stereochemistry affects sesquiterpene lactone bioactivity against an herbivorous grasshopper

Sesquiterpene lactones are defensive compounds which protect plants against a variety of herbivores and other natural enemies. Sesquiterpene lactones from higher plants can be divided into two groups based on the stereochemistry of their lactone ring junction, either cis-fused or trans-fused. It is unclear whether and how this variation affects potentially important ecological interactions. To investigate whether stereochemical variation in sesquiterpene lactone ring junctions can influence resistance to herbivorous insects, we performed controlled feeding trials with two pairs of diastereomeric sesquiterpene lactones and examined the deterrent effect of each compound on feeding by the polyphagous grasshopper Schistocerca americana (Drury). Sesquiterpene lactone stereochemistry and concentration significantly influenced feeding behavior with grasshoppers consuming less of the trans-fused compounds than the cis-fused compounds. To our knowledge, this is the first demonstration that sesquiterpene lactone ring junction stereochemistry influences the feeding behavior of herbivores. Because this stereochemical trait polymorphism is widely distributed in nature, it could have substantial consequences for the ecology and evolution of large groups of plants, particularly the Asteraceae.

Methods for the synthesis of xanthine-derived polycyclic fused systems

Abstract Xanthines are a widely known group of alkaloids, commonly used as bronchodilators and psycho and cardiac stimulants. Most of their actions are principally connected with either antagonism of adenosine receptors or phosphodiesterase inhibition; nevertheless, other profiles of their biological activity – antiviral, antitumor or anticancer – are also known. Here, we present a review of the main synthetic methods to obtain xanthine-derived heterocyclic fused systems. The five-, six- or seven-membered heterocyclic ring is attached to the purine-2,6-dione core with one or two bridgehead (ring junction) nitrogen atoms. The biological activity profile of the individual heterocyclic systems is mentioned.

A computational study on azaazulenes

Abstract All possible aza analogs of azulene, containing from one to three nitrogen atoms in the five-membered ring or from one to five nitrogen atoms in the seven-membered ring, have been theoretically considered to obtain information about their stabilities and aromaticities. Total electronic energy and nucleus independent chemical shift (NICS) data have been used to evaluate stability and aromaticity, respectively. The stabilities of the structures are strongly affected by the positions of the nitrogen atoms. Calculations of azaazulenes show that stability is decreased with close proximity of the nitrogen atoms. When nitrogen in the five-membered ring is adjacent to a ring junction, aromaticity of the cyclopentadienyl anion is reduced and that of the tropylium cation is increased. The number of nitrogen atoms affects the aromaticity of the system.