Ring System Research Articles

Couple-close construction of polycyclic rings from diradicals.

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1-3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4-6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7-10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)-C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.

10-Bromo-N,N-di-phenyl-anthracen-9-amine.

In the title compound, C26H18BrN, the dihedral angles between the anthracene ring system and the phenyl rings are 89.51 (14) and 74.03 (15)°. In the extended structure, a weak C-H⋯Br inter-action occurs, which generates [100] chains, but no significant π-π or C-H⋯π inter-actions are observed.

A Review of Cyclic Imines in Shellfish: Worldwide Occurrence, Toxicity and Assessment of the Risk to Consumers.

Cyclic imines are a class of lipophilic shellfish toxins comprising gymnodimines, spirolides, pinnatoxins, portimines, pteriatoxins, prorocentrolides, spiro-prorocentrimine, symbiomines and kabirimine. They are structurally diverse, but all share an imine moiety as part of a bicyclic ring system. These compounds are produced by marine microalgal species and are characterized by the rapid death that they induce when injected into mice. Cyclic imines have been detected in a range of shellfish species collected from all over the world, which raises the question as to whether they present a food safety risk. The European Food Safety Authority (EFSA) considers them to be an emerging food safety issue, and in this review, the risk posed by these toxins to shellfish consumers is assessed by collating all available occurrence and toxicity data. Except for pinnatoxins, the risk posed to human health by the cyclic imines appears low, although this is based on only a limited dataset. For pinnatoxins, two different health-based guidance values have been proposed at which the concentration should not be exceeded in shellfish (268 and 23 µg PnTX/kg shellfish flesh), with the discrepancy caused by the application of different uncertainty factors. Pinnatoxins have been recorded globally in multiple shellfish species at concentrations of up to 54 times higher than the lower guidance figure. Despite this observation, pinnatoxins have not been associated with recorded human illness, so it appears that the lower guidance value may be conservative. However, there is insufficient data to generate a more robust guidance value, so additional occurrence data and toxicity information are needed.

Hyperatins A–D, highly oxidized polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum L. with hypoglycemic potential in liver cells

Hyperatins A–D (1–4), four previously undescribed polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum perforatum L. (St. John's wort). Compound 1 possessed a unique octahydroindeno[1,7a-b]oxirene ring system with a rare 2,7-dioxabicyclo[2.2.1]heptane fragment. Compounds 2–4 had an uncommon decahydrospiro[furan-3,7′-indeno[7,1-bc]furan] ring system. Their structures were established by spectroscopic analyses and X-ray crystallography. Plausible biosynthetic pathways of 1–4 were also proposed. Compounds 1 and 2 exerted promising hypoglycemic activity by inhibiting glycogen synthase kinase 3 expression in liver cells.

Synthesis, molecular modeling, DFT studies, and EPR analysis of 1,4-dihydropyridines as potential calcium channel blockers

1,4-Dihydropyridines (DHPs) are widely recognized as a highly effective class of L-type calcium channel blockers that offer significant therapeutic potential in managing cardiovascular conditions. Furthermore, their ability to target other types of calcium channels makes DHPs attractive candidates for therapeutic applications in neurological and psychiatric disorders. Close examination of the chemical structures of approved DHP-based antihypertensive drugs with a history of over forty years in the market reveals that the C-4 position is the least altered part of this privileged ring system. In the present study, we focused on this position and synthesized two novel compounds (DB1 and DB2) by carrying out chemical modifications on suitable positions of the main scaffold of DA1 (isobutyl 4-(benzo[d][1,3]dioxol-5-yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate) that was previously identified as a DHP-based effective and selective inhibitor of T-type (Cav3.2) over L-type (Cav1.2) calcium channel. Based on whole-cell patch-clamp analysis on Cav1.2 and Cav3.2, DB1 with bromine group on the benzodioxole ring appeared to be a more effective and selective inhibitor of Cav3.2 compared to DB2 with nitro at the same locus. Molecular docking and molecular dynamics (MD) simulations were performed to investigate the binding mode of both DB1 isomers to Cav3.2. Furthermore, density functional theory (DFT) methods were employed to obtain information regarding the stability of the molecules by computing various parameters, such as electric dipole moment, band gap, electronegativity, and global chemical hardness-softness, related to their charge-transfer characteristics. According to DFT studies, DB1 also appeared to be chemically more stable than DB2. Finally, ionizing radiation-induced free radicals of gamma-irradiated DB1 and DB2 in powder form were examined utilizing the electron paramagnetic resonance (EPR) technique and the obtained data demonstrated that radiation sterilization is suitable for the dosage forms including DB1 and DB2.

Artemordins A—S, Cadinane‐Type Sesquiterpenoid Dimers from Artemisia ordosica and Their Antihepatoma Activities

Comprehensive SummaryNineteen new cadinane‐involving sesquiterpenoid dimers, artemordins A—S (1—19), together with 13 known SDs (20—32) were isolated from Artemisia ordosica. Their structures and absolute configurations were established by comprehensive spectral analyses, X‐ray single crystal diffraction, theoretical ECD, and NMR calculations. Chemically, artemordins A—F (1—6) were the first examples of two cadinane units constructed by unprecedented C‐3−C‐15′ or C‐3−C‐13′ single bond with an oxido‐rearranged 6/5/6/6 fused ring system; artemordins G—K (7—11) were biogenetically connected by [4 + 2] cycloaddition reaction and artemordins G—J (7—10) possessed a novel 5/6/6/6/6/6/5‐heptacyclic fused ring system. Artemordins L—S (12—19) were formed by esterification, which involved three different types of sesquiterpenoids. Antihepatoma assay suggested that the most active compounds, artemordins B and H (2 and 8), exhibited inhibitory activities on three hepatoma cell lines with IC50 values of 26.9 and 25.1 μmol/L (HepG2), 29.5 and 18.3 μmol/L (Huh7), 19.7 and 15.7 μmol/L (SK‐Hep‐1).

Effect of Volatile-Char Interaction on Biochar Containing N/O-Functional Group During Reburning Denitrification

ABSTRACT The influence of functional groups such as N/O and microcrystalline structure in biochar on NO reduction is critical. The interaction between volatile and char can significantly alter the activity of char, thereby altering its ability to reduce NO. Unfortunately, the impact of this interaction on NO reduction is still unclear. In this study, the effect of this interaction at 900°C on the physicochemical structure of model biochar containing N/O-functional group during reburning denitrification was investigated. This paper simulates the volatile of reactive species containing H and O through pyrolysis of polyethylene and polyethylene glycol, respectively. The results indicate that the H- and O-containing reactive species play distinct roles during the interaction between volatile and char, but both species consume the amorphous carbon structure. The H-containing actives significantly increased the condensation of the aromatic rings and the O and N contents of the char decreased by 1.36% and 0.43% respectively. There were also significant interconversions between the N functional groups, with the content of N-5 increasing by 12% and that of N-6 by 2%. Consequently, the ability of char to reduce NO decreased by 29%. The O-containing reactive species will react with the char to form C-O composite oxides, thus increasing the O content with 1.88% and preventing the carbon structure from being condensed into a large aromatic ring system. Simultaneously, it was found that after the action of O-containing reactive species, the content of N decreased by 0.9%, and the N functional group tended to convert to N-5 (pyrrole or pyridone), increasing its content by 27%. Furthermore, char activity was significantly increased and NO reduction capacity increased by 19%.

Absolute Configuration of Oxabornyl Polyenes Prugosenes A1-A3 and Structural Revision of Prugosene A2.

Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 μM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.

Synthesis, crystal structure and Hirshfeld surface analysis of N-(6-acetyl-1-nitro-naphthalen-2-yl)acetamide.

The title compound, C14H12N2O4, was obtained from 2-acetyl-6-amino-naphthalene through two-step reactions of acetyl-ation and nitration. The mol-ecule comprises the naphthalene ring system consisting of functional systems bearing a acetyl group (C-2), a nitro group (C-5), and an acetyl-amino group (C-6). In the crystal, the mol-ecules are assembled into two-dimensional sheet-like structures by inter-molecular N-H⋯O and C-H⋯O hydrogen-bonding inter-actions. Hirshfeld surface analysis illustrates that the most important contributions to the crystal packing are from O⋯H/H⋯O (43.7%), H⋯H (31.0%), and C⋯H/H⋯C (8.5%) contacts.

Immunosuppressive steroids quadrilisteroids A−C and derivatives from the terrestrial fungus Aspergillus quadrilineatus

Seven undescribed compounds (1−7) along with six known compounds (8−13) were isolated from Eurotiaceae Aspergillus quadrilineatus. Their structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD calculations. Quadrilisteroids A (1) and B (2) possessed an unprecedented 6/5/6/6/6/5 hexacyclic ring system in conjugation with a highly fused benzene ring, while quadrilisteroid C (3) featured a surprising 6/6/6/5/5-fused carbocyclic skeleton. Quadrilisteroid C (3) exhibited potent inhibitory activity against LPS-induced proliferation of B lymphocyte cells with an IC50 value of 1.03 μM. Compound 4, demonstrated inhibitory activity against Con A-induced proliferation of T lymphocyte cells with IC50 values of 6.42 μM.

Synthesis of the [6-6-7-5-5] Pentacyclic Core of Calyciphylline N.

A new approach for the concise 11-step synthesis of the [6-6-7-5-5] BCDEF pentacyclic core of calyciphylline N is described. A type II [5 + 2] cycloaddition was employed to construct the strained BCD skeleton, which encompasses the challenging bicyclo[2.2.2] and bicyclo[4.3.1] ring systems. With a regio- and diastereoselective Lu's [3 + 2] cycloaddition, followed by intramolecular aldol cyclization and elimination, the desired [5-5]-fused EF ring system has been successfully installed, resulting in the complete carbocyclic skeleton of calyciphylline N.

Mathematical modeling of irregularity indices for adriamycin and their statistical analysis for emetic drugs

Anthracyclines exert cytotoxic effects on cancer cells through genotoxicity, inducing damage to their genetic material and impeding their reproductive capacity. The compound possesses a molecular framework consisting of an anthracycline ring system, which confers its pharmacological activity against cancer. Adriamycin is an anthracycline chemotherapeutic agent characterized by a structurally intricate chemical composition. In this article, we computed irregularity indices like the Albertson index, total irregularity index, Randić irregularity index and other degree-based irregularity indices to estimate the biological and chemical properties of Adriamycin. The findings are illustrated through the use of numerical figures and graphical representations. Further, we proposed the relationship between irregularity indices and the physicochemical properties of emetic drugs. We examined that the irregularity indices showed a statistically significant relationship with Molecular Weight, Monoisotopic Mass, Polar Surface Area, Heavy Atom Count, Complexity, Boiling Point, Enthalpy of Vaporization, Flash Point, Molar Refractivity and Polarizability based on the p-value (<0.5). We proposed multiple linear regression models that will be helpful to estimate the physical properties of those drugs that were not calculated. The numerical results and visual representations of our analyses will be helpful in the advancement of knowledge regarding the structure-property correlations of these drugs.

Activity-Based Protein Profiling Identifies Protein Disulfide-Isomerases as Target Proteins of the Volatile Salinilactones.

The salinilactones, volatile marine natural products secreted from Salinispora arenicola, feature a unique [3.1.0]-lactone ring system and cytotoxic activities through a hitherto unknown mechanism. To find their molecular target, an activity-based protein profiling with a salinilactone-derived probe is applied that disclosed the protein disulfide-isomerases (PDIs) as the dominant mammalian targets of salinilactones, and thioredoxin (TRX1) as secondary target. The inhibition of protein disulfide-isomerase A1 (PDIA1) and TRX1 is confirmed by biochemical assays with recombinant proteins, showing that (1S,5R)-salinilactone B is more potent than its (1R,5S)-configured enantiomer. The salinilactones bound covalently to C53 and C397, the catalytically active cysteines of the isoform PDIA1 according to tandem mass spectrometry. Reactions with a model substrate demonstrated that the cyclopropyl group is opened by an attack of the thiol at C6. Fluorophore labeling experiments showed the cell permeability of a salinilactone-BODIPY (dipyrrometheneboron difluoride) conjugate and its co-localization with PDIs in the endoplasmic reticulum. The study is one of the first to pinpoint a molecular target for a volatile microbial natural product, and it demonstrates that salinilactones can achieve high selectivity despite their small size and intrinsic reactivity.

Beyond Point Masses. III. Detecting Haumea’s Nonspherical Gravitational Field

The dwarf planet Haumea is one of the most compelling trans-Neptunian objects to study, hosting two small, dynamically interacting satellites, a family of nearby spectrally unique objects, and a ring system. Haumea itself is extremely oblate due to its 3.9 hr rotation period. Understanding the orbits of Haumea’s satellites, named Hi’iaka and Namaka, requires detailed modeling of both satellite–satellite gravitational interactions and satellite interactions with Haumea’s nonspherical gravitational field (parameterized here as J 2). Understanding both of these effects allows for a detailed probe of the satellites’ masses and Haumea’s J 2 and spin pole. Measuring Haumea’s J 2 provides information about Haumea’s interior, possibly determining the extent of past differentation. In an effort to understand the Haumea system, we have performed detailed non-Keplerian orbit fitting of Haumea’s satellites using a decade of new, ultra-precise observations. Our fits detect Haumea’s J 2 and spin pole at ≳2.5σ confidence. Degeneracies present in the dynamics prevent us from precisely measuring Haumea’s J 2 with the current data, but future observations should enable a precise measurement. Our dynamically determined spin pole shows excellent agreement with past results, illustrating the strength of non-Keplerian orbit fitting. We also explore the spin–orbit dynamics of Haumea and its satellites, showing that axial precession of Hi’iaka may be detectable over decadal timescales. Finally, we present an ephemeris of the Haumea system over the coming decade, enabling high-quality observations of Haumea and its satellites for years to come.

Impact of discontinuous grain size distributions on the spectral energy distribution of debris disks

Context. The collisional evolution of debris disks is expected to cause the characteristic wavy pattern, that is, an under- or overabundance of particles of specific sizes, of grain size distributions. This perturbed grain size distribution potentially leaves characteristic patterns in the spectral energy distribution (SED) of the disk system. Aims. We aim to quantify and understand the specific influence of discontinuous particle size distributions on the appearance of debris disks. For this purpose, we considered dust emission models based on two different grain size distributions, namely, one with a single power law and one with a broken power law. In particular, our study is focused on the impact of an overabundance of small grains and an underabundance of medium-sized grains on the far-IR and (sub-)millimeter regime on the dust reemission radiation and the potential to constrain discontinuities in the grain size distribution from (sub-)millimeter photometric measurements of debris disks. Methods. We compared the spectral index α (Fν ∝ να) in the case of a continuous grain size distribution with that of a discontinuous grain size distribution. We performed this comparison for central stars with different spectral types and two different disk structures (e.g., slim and broad debris dust rings). Results. Within the considered parameter space, we found a characteristic difference between the spectral slopes of the SED in the different scenarios. In particular, the overabundance of small grains resulting from collisional events and thus parameters defining the outcome of disk events in debris disks is potentially observable by comparison with the SED corresponding to a grain size distribution resulting from an ideal collisional cascade. More specifically, the overabundance of small grains leads to a steeper slope in the far-IR and sub-millimeter regime, while the spectral index in the millimeter regime is hardly affected. On the other hand, the underabundance of medium-sized grains results in a slight steepening of the far-IR slope of the SED, but its primary effect is on the millimeter slope of the SED, causing it to become shallower. We also found that the impact of an overabundance of small dust particles is more pronounced than that of an underabundance of medium-sized dust particles. We also found that the difference between the spectral indices for the two different grain size distributions is largest for debris disks around brighter central stars and broader disks. However, the impact of the considered spatial distributions described by the fractional width of the disk system is weak. Our results also show that the dust composition is not the sole physical mechanism responsible for the spectral inversion observed in the far-IR to millimeter part of the SED of debris disk systems. Furthermore, the location of the spectral break is placed at different wavelength regimes if the grain size distribution is considered as a function of blowout size and stellar type.

Ochrolines A-C, three new indole diketopiperazines from cultures of endophytic fungi Bionectria ochroleuca SLJB-2

Three new indole diketopiperazines, ochrolines A-C (1–3), along with three known compounds (4–6), were isolated and identified from the EtOAc extract of the solid fermentation of Bionectria ochroleuca SLJB-2. Notably, compound 1 featured a natural rarely-occurring caged skeleton with a 6/5/6/7 heterotetracyclic bridged ring system. The structures including absolute configurations of 1–3 were fully accomplished by extensive spectroscopic analyses, DFT GIAO 13C NMR and electronic circular dichroism (ECD) calculations. The plausible biogenetic pathways of these new indole diketopiperazines were also proposed. Moreover, the cytotoxic activity screening revealed that compound 2 exhibited moderate inhibitory effect against A549 with inhibition rate of 57.44% at the concentration of 50 μM and compound 1 exhibited mild inhibitory activities against A549, Hela and MCF-7.

Holotrichones A and B, potent anti-leukemic lindenane-type sesquiterpene trimers with unprecedented complex carbon skeletons from a rare Chloranthus species

Two lindenane-type sesquiterpene (LDS) trimers with unprecedented carbon skeletons, holotrichones A (1) and B (2), were obtained from the whole plant of Chloranthus holostegius var. trichoneurus by a ultra performance liquid chromatography-photodiode array detector-mass spectrometry (UPLC-PDA-MS)-guided isolation strategy. Compound 1 represents the first LDS trimer incorporating a unique 3/5/6/6-fused framework, in which a lindenane-type monomer and the 2-methylbutyryl substituent of an LDS dimer is bridged by a six-membered ring system. Compound 2 is the first hetero-trimer fused by an LDS dimer with a p-benzoquinone-meroterpenoid, featuring an unusual 3/5/6/6/3/5/6/6/6 nonacyclic system fused by the sesquiterpenoid unit and a 2-geranyl-6-methyl-2,5-cyclohexadien-1,4-dione moiety. In compound 2, the dimeric LDS moiety is equipped with a rare oxaspiro[4.5]decane system. Their structures, including absolute configurations, were established by spectroscopic methods, GIAO NMR calculations and DP4+ probability analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. The plausible biogenetic pathway speculation indicated that hetero- and homo-Diels-Alder additions may dominate the formation of these highly fused polycyclic frameworks. Both compounds 1 and 2 induced the human acute myeloid leukemia MV-4-11 cell death via apoptosis induction, which deserves further investigation on this new chemical class of LDS oligomers for their anti-leukemic potential.

Review on the Discovery of New Benzimidazole Derivatives as Anticancer Agents: Synthesis and Structure-activity Relationship (2010-2022)

Background: Benzimidazole (Benz-fused bicyclic ring system) is the most versatile class of heterocyclic compounds due to its numerous applications in industrial and synthetic organic chemistry because of its many biological actions. Benzimidazole analogs have been used to discover various medical problems, such as cancer, bacterial infections, fungi infections, etc. Researchers are studying nitrogencontaining hybrid heterocyclic compounds because they provide a broad range of therapeutic potential and have minimal side effects. Objective: The current literature review emphasizes recent developments in the design of new benzimidazole derivatives as possible anticancer agents with their relationship between structure and activity, which will give insight into the future design of more active benzimidazole molecules. Results: The present review consists of synthetic protocols for the synthesis of benzimidazole derivatives along with their pharmacological potentials and structure-activity relationship in correlation with synthetic molecules to provide a depth view of the work done on benzimidazole. Conclusion: It would be significant for further research in developing better drug molecules representing a potent derivative of medicinal agents.

The engineering legacy of the FIFA World Cup Qatar 2022TM: the gahfiya-shaped Al Thumama Stadium

The structures of the Al Thumama Stadium could be categorised into four main building components: The permanent bowl structure with the lower and middle tiers are mainly cast-in-place reinforced concrete with precast seating units. Structural steel is utilised for the upper tier stands which is to be dismantled for legacy conversion after FIFA World Cup Qatar 2022™. The roof and façade system utilises steel and cable systems with a unique membrane cladding design derived from the cultural gahfiya symbol. The roof is a self-anchored tension-compression ring system based on the principle of a horizontal spoked wheel with one compression ring along the outer perimeter and two tension rings along the oculus. The façade consists of lightweight double-layered and pre-stressed cable nets spanning between curved vertical beams. A translucent PTFE coated fibreglass membrane with highly transparent mesh inserts form the cladding of the stadium and provide its unique architectural design. This article gives an overview of the entire building structure design and construction methodology.

Sustainable Green Synthesis of Pyrimidine Derivatives: Review on Multicomponent Synthesis, Catalysts and Techniques.

"The founder of green chemistry explains how chemicals manufacturing must change to support a sustainable future." In this review, Green chemistry is considered in the synthesis of heterocycles compounds containing Pyrimidine nuclei using different catalyzes, solvents, and techniques for the synthesis of pyrimidine derivatives that achieve sustainability. The mentioned fused heterocycles are classified according to the type of ring system. The yield of the target molecules reported in the review is given in the reaction's last step.