Ring System Research Articles

Masterpenoids A-D, Four Unprecedented Nortriterpenoids from the Mastic (Pistacia lentiscus) and Their Anti-inflammatory Activity.

Four unprecedented nortriterpenoids, masterpenoids A-D, were isolated and fully elucidated from the resin of the mastic tree (Pistacia lentiscus). Masterpenoids A-C are the first norterpenoids featuring an unprecedented 6/6/6/10 ring system, while masterpenoid D possesses a novel 6/6/6/7/5 ring system. The anti-inflammatory potential of the compounds was meticulously assessed through the establishment of an in vitro model of lipopolysaccharide-induced inflammation in RAW264.7 macrophage cells. Among them, Masterpenoids A and D showed potent inhibition of NO production, with IC50 values of 10.6 ± 0.8 and 8.2 ± 0.9 μM, respectively, compared to positive control dexamethasone (IC50 = 23.2 ± 1.2 μM).

Synthesis and Characterization of a Novel Intrinsically Fluorescent Analog of Cholesterol with Improved Photophysical Properties.

Live-cell imaging of cholesterol trafficking depends on suitable cholesterol analogs. However, existing fluorescent analogs of cholesterol either show very different physicochemical properties compared to cholesterol or demand excitation in the ultraviolet spectral region. We present a strategy to synthesize two novel intrinsically fluorescent sterol probes with a close resemblance of cholesterol. The analogs contain four conjugated double bonds in the ring system and either a keto group (probe 5) or a hydroxy group (probe 6) in the C3 position. The emission of 5 is in the visible range of the spectrum, i.e., red-shifted by 150 nm compared to the widely used dehydroergosterol. Together with its high multiphoton absorption, this allows for imaging of 5 on conventional microscopes, including multicolor 3D and time-lapse microscopy. Molecular dynamics simulations and nuclear magnetic resonance spectroscopy reveal that 5 can condense the fatty acyl chains of phospholipids in model membranes. In giant unilamellar vesicles, 5 partitions equally into the liquid-ordered and disordered phases. In contrast, 6 emits in the ultraviolet range and is unstable in solution, preventing its use in live-cell imaging applications. The good photophysical properties of 5 make it a suitable analogue for improved live-cell imaging of sterol transport.

Structure and Function of Sabinene Synthase, a Monoterpene Cyclase That Generates a Highly Strained [3.1.0] Bicyclic Product.

Sabinene is a plant natural product with a distinctive strained [3.1.0] bicyclic ring system that is used commercially as a spicy and pine-like fragrance with citrus undertones. This unusual monoterpene has also been studied as an antifungal and anti-inflammatory agent as well as a next-generation biofuel. In order to understand the molecular determinants of [3.1.0] bicyclic ring formation in sabinene biosynthesis, we now report three X-ray crystal structures of sabinene synthase from Western red cedar, Thuja plicata (TpSS), with open and partially closed active site conformations at 2.21-2.72 Å resolution. We additionally report the complete biochemical characterization of sabinene synthase, including steady-state kinetics, active site mutagenesis, and product array profiling. The catalytic metal ion requirement is unexpectedly broad for a class I terpene cyclase: optimal catalytic activity was measured using Mn2+ or Co2+, with more modest activity observed using Mg2+ or Ni2+. Kinetic parameters were determined for both full-length TpSS and a deletion variant lacking the putative N-terminal plastidial targeting sequence, designated ΔTpSS. Monoterpene product profiles for both indicated similar product arrays independent of the catalytic metal ion used, with sabinene comprising nearly 90% of the total products generated. Site-directed mutagenesis was utilized to probe the function of active site residues, and several mutants yielded altered product arrays. Most notably, the G458A substitution converted ΔTpSS into a high-activity α-pinene synthase. α-Pinene contains a bicyclic [3.1.1] ring system; structural and mechanistic analyses suggest a molecular rationale for the reprogrammed transannulation reaction, leading to the alternative bicyclic product.

Bioinspired synthesis of cucurbalsaminones B and C.

Cucurbalsaminones B (1) and C (2) are two abeo-cucurbitane triterpenoids with a unique 5/6/3/6/5-fused ring system and exhibited potent multidrug resistance (MDR)-reversing activity. Herein, we report the first synthesis of these two natural products, both of them were accomplished in 14 steps from commercially available inexpensive resource compound lanosterol. Key features of this synthesis include a biomimetic tandem Wagner-Meerwein type lanostane-to-cucurbitane rearrangement followed by a bioinspired photochemical oxa-di-π-methane (ODPM) rearrangement to complete the skeleton construction and an Eosin Y photoinduced Barton-McCombie deoxygenation to realize the challenging oxidation state adjustment of the sterically hindered C11 position.

Bioinspired synthesis of cucurbalsaminones B and C

Cucurbalsaminones B (1) and C (2) are two abeo‐cucurbitane triterpenoids with a unique 5/6/3/6/5‐fused ring system and exhibited potent multidrug resistance (MDR)‐reversing activity. Herein, we report the first synthesis of these two natural products, both of them were accomplished in 14 steps from commercially available inexpensive resource compound lanosterol. Key features of this synthesis include a biomimetic tandem Wagner‐Meerwein type lanostane‐to‐cucurbitane rearrangement followed by a bioinspired photochemical oxa‐di‐π‐methane (ODPM) rearrangement to complete the skeleton construction and an Eosin Y photoinduced Barton‐McCombie deoxygenation to realize the challenging oxidation state adjustment of the sterically hindered C11 position.

Synthesis of New Tetracyclic Ring Systems: Bridged Derivatives of Hydroxy‐, Sulfanyl‐ and Amino‐Substituted Dibenzo[c,f][1,2]Thiazepine S,S‐Dioxides

AbstractIn continuation of our commitment to the synthesis of new ring systems based on the 6,11‐dihydrodibenzo[c,f][1,2]thiazepine 5,5‐dioxide core of the antidepressant drug tianeptine, we have incorporated two‐ and/or three‐carbon bridges between the nitrogen atom of the sulfonamide moiety and the N‐, O‐ or S‐substituent at position 11 of the tricycle. The synthesis of 5 new ring systems is described and demonstrated with several target compounds.

Herpetosin A, a nor-cucurbitane triterpenoid with a 5/6/6/5 ring system from Herpetospermum pedunculosum.

Two previously undescribed triterpenoids, herpetosin A (1) and herpetosin B (2), together with two known compounds, cucurbitacin B (3) and dihydrocucurbitacin E (4), were isolated from the seeds of Herpetospermum pedunculosum. Their structures were elucidated by analysis of the NMR, HR-ESI-MS, X-ray data and quantum chemical calculation. Compound 1 featured an unprecedented nor-cucurbitane triterpenoid skeleton with a 5/6/6/5 ring system. Among all the isolates, compound 4 exhibited anti-proliferative effect with IC50 values of 4.5 ± 0.1 μM against A549 cells, 8.2 ± 0.5 μM against MDA-MB-231 cells, and 2.4 ± 0.3 μM against HepG2 cells, respectively.

Quinoline- and pyrimidine-based allosteric modulators of the sarco/endoplasmic reticulum calcium ATPase.

Small-molecule allosteric activators of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA) hold promise as novel experimental tools to manipulate intracellular calcium concentrations and as therapeutic agents to treat medical conditions associated with elevated cytosolic calcium levels. Here, we synthesized and characterized 20 analogs of the known allosteric SERCA activator CDN1163 and tested their ability to stimulate SERCA activity. The structures of the compounds varied in the alkyl group of the parent scaffold's ether moiety as well as in the composition of the nitrogenous aromatic ring system. The most active compounds exhibited potencies in the sub-micromolar range while increasing enzyme activity by more than 25%. The observed structure-activity relationships indicated that bulky alkyl groups in the ether moiety along with a quinoline ring methyl substituent were beneficial for activity. Replacement of the quinoline by a pyrimidine ring system reduced activity. To conceive a potential mechanism of action, we generated a molecular model of the transition state of SERCA when undergoing the rate-limiting step of its catalytic cycle. Subsequent blind docking with CDN1163 identified a high-affinity binding site close to the enzyme's ATP binding pocket, suggesting that the activators may accelerate SERCA's catalytic cycle by aiding in ATP binding and positioning.

Dust ring and gap formation by gas flow induced by low-mass planets embedded in protoplanetary disks. II. Time-dependent model

The observed dust rings and gaps in protoplanetary disks could be imprints of forming planets. Even low-mass planets in the 1--10 Earth-mass regime, which have not yet carved deep gas gaps, can generate such dust rings and gaps by driving a radially-outward gas flow, as shown in previous work. However, understanding the creation and evolution of these dust structures is challenging due to dust drift and diffusion, requiring an approach beyond previous steady state models. Here we investigate the time evolution of the dust surface density influenced by the planet-induced gas flow based on post-processing three-dimensional hydrodynamical simulations. We find that planets larger than a dimensionless thermal mass of $m=0.05$ corresponding to $0.3$ Earth mass at 1 au or 1.7 Earth masses at 10 au generate dust rings and gaps provided that solids have small Stokes numbers St and that the disk midplane is weakly turbulent ($ diff As dust particles pile up outside the orbit of the planet, the interior gap expands with time when the advective flux dominates over diffusion. Dust gap depths range from a factor of a few to several orders of magnitude, depending on planet mass and the level of midplane particle diffusion. We constructed a semi-analytic model describing the width of the dust ring and gap, and then compared it with the observational data. We find that up to 65<!PCT!> of the observed wide-orbit gaps could be explained as resulting from the presence of a low-mass planet, assuming diff and St However, it is more challenging to explain the observed wide rings, which in our model would require the presence of a population of small particles ($ Further work is needed to explore the role of pebble fragmentation, planet migration, and the effect of multiple planets.

Cytotoxic monoterpenoid indole alkaloids from Tabernaemontana bovina.

Chemical investigation of the native medicinal plant Tabernaemontana bovina led to the isolation of five previously unreported monoterpenoid indole alkaloids tabernovinaines A-E (1-5) together with twenty-seven known analogs (6-32), including a bisindole alkaloid 1 with the (E)-4-aminobut-3-en-2-one fragment, as well as a unique cage skeleton 2 containing 6/5/8/6/6 ring system. The chemical structures of these unreported compounds were elucidated using mass spectrometry, NMR spectroscopy, circular dichroism, density functional theory calculations, and derivatizations. The activity evaluation shows that the bisindole alkaloid 1 revealed a potential cytotoxic effect by inducing HepG2 cell apoptosis and damaging clonal sphere expansion.

Synthesis and Biological Activity of Tetracyclic Dispiro Core Derivatives of Natural Products Dispirocochlearoids A-C.

Natural products dispirocochlearoids A-C, which are meroterpenoids derived from Ganoderma fungi, feature a 6/6/5/6/6/6 ring system and exhibit selective COX-2 inhibitory activity. Herein, the concise total synthesis of the tetracyclic core structure of dispirocochlearoids A-C was achieved through an aldol reaction/cyclization/deprotection/cyclization cascade sequence. A series of simplified tetracyclic analogues was successfully constructed and their anti-inflammatory activity was further explored, with several tetracyclic analogues (such as compound 8ab) exhibiting strong inhibitory activity against IL-1β expression in lipopolysaccharide-stimulated bone marrow-derived macrophage cells (IC50 = 2.8 μM).

New nor-ent-halimane and nor-clerodane diterpenes from Callicarpa integerrima with anti-MRSA activity

Two new nor-ent-halimane diterpenes and three previously unreported nor-clerodane diterpenes, designated callicaintides A−E (1−5), were isolated from Callicarpa integerrima. Compounds 1 and 2 feature a distinctive 5/6-membered ring system, while compounds 3−5 are characterized by progressively truncated carbon skeletons, containing 18, 17, and 16 carbons, respectively. In addition, four known compounds 6−9 were also identified. Their structures were elucidated using advanced spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), ultraviolet (UV), infrared radiation (IR), optical rotatory dispersion (ORD), DP4+ analysis and electronic circular dichroism (ECD), supported by quantum chemical calculations. Compounds 1−9 were evaluated for their anti-MRSA activity. Among them, compound 6 demonstrated significant anti-MRSA activity, with a minimum inhibitory concentration (MIC) of 16 μg·mL−1.

Recent Progress in Synthetic Chemistry and Biological Activities of Pyrimido[ 4,5-b] Quinoline Derivatives (Part III)

Abstract: Amongst heterocyclic compounds, quinoline and pyrimidine are advantaged scaffolds that appear as significant assembly motifs for the development of new drug entities. Moreover, quinolinepyrimidine- inspired hybrids have a number of biological characteristics that are known. In addition, many pyrimido[4,5-b]quinoline ring systems (PyQs4,5-b), specifically concerning medicinal chemistry, have been reported over the past decade. The synthesis of (PyQs4,5-b) using barbituric acid, thiobarbituric acid, pyrimidine, and their derivatives is presented in this review. The preparation of PyQs4,5-b was clarified through the following chemical reactions: Friedländer, Vilsmeier-Haack formylation, Hantzsch-like reaction, and one-pot three-component reaction.

Cyclic Ruthenium(II)-Halocarbon Complexes Derived from Ru(II)-Induced Cyclization of Homopropargylic Halopyridines: Mechanism, Bonding and Reactivity.

The activation of various homopropargylic pyridines by cis-[RuII/OsII(dppm)2Cl2] (dppm = 1,1-bis(diphenylphosphino)methane) has previously been shown to generate a diverse array of metallacycles and metalated heterocyclic complexes. However, a minor structural modification of introducing a halide onto the pyridyl group of the alkyne substrate resulted in the formation of unprecedented Ru(II)/Os(II)-haloquinolizine complexes. These complexes display (1) κ2(X,C)-haloquinolizine chelates arising from the cycloisomerization of HC≡CC(OH)(CH2(6-X-2-py))(Ph) on [RuII/OsII(dppm)2]2+ moieties via a vinylidene pathway, (2) five-membered Ru/Os-X-C-N-C rings (X = F, Cl, Br) ortho- and peri-fused to quinolizinium skeletons, and (3) uncommon M-X-R bonding interactions that are atypical in coordination complexes. Despite being divalent and integrated into a five-membered Ru-X-C-N-C ring system, the X atoms in the Ru(II) complexes are susceptible to substitution by O in the presence of -OH, resulting in the formation of quinolizinium-fused ruthenaoxazole complexes. Overall, this work highlights the importance of considering metal-halocarbon bonding interactions in catalytic or coordination designs.

Ligand-controlled regiodivergent aminocarbonylation of cyclobutanols toward 1,1- and 1,2-substituted cyclobutanecarboxamides

Four-membered carbocycles are among the most sought-after backbones which are commonly found in biologically active molecules. However, difficulties on their producing are existing due to its highly strained ring system. On the other hand, cyclobutanols can be straightforwardly prepared and can serves as precursors for synthesizing cyclobutane derivatives. Here we report an example of regioselective aminocarbonylation of cyclobutanols in which the cyclobutane core remained intact. The method exhibits good functional group compatibility, as well as high regio- and stereoselectivity, offering new pathways for synthesizing several pharmaceuticals. Furthermore, this strategy enables the rapid installation of cyclobutane as a conformational restricted skeleton, greatly facilitating direct access to valuable drug molecules that require conformational restriction.

The missing rings around Solar System moons

Context. Rings are complex structures that surround various bodies within the Solar System, such as giant planets and certain minor bodies. While some formation mechanisms could also potentially promote their existence around (regular or irregular) satellites, none of these bodies currently bear these structures. Aims. We aim to understand the underlying mechanisms that govern the potential formation, stability, and/or decay of hypothetical circumsatellital rings (CSRs) orbiting the largest moons in the Solar System. This extends to the exploration of short-term morphological features within these rings, providing insights into the ring survival timescales and the interactions that drive their evolution. Methods. To conduct this study, we used numerical N-body simulations under the perturbing influence of the host planet and other moon companions. Results. We found that, as suspected, moons with a lower Roche-to-Hill radius can preserve their rings over extended periods. Moreover, the gravitational environment in which these rings are immersed influences the morphological evolution of the system (e.g. ring size), inducing gaps through the excitation of eccentricity and inclination of constituent particles. Specifically, our results show that the rings of Iapetus and Rhea experience minimal variations in their orbital parameters, enhancing their long-term stability. This agrees with the hypothesis that some of the features of Iapetus and Rhea were produced by ancient ring systems, for example, the huge ridge in the Iapetus equator as a result of a decaying ring. Conclusions. From a dynamical perspective, we found that there are no mechanisms that preclude the existence of CSRs, and we attribute their current absence to non-gravitational phenomena. Effects such as stellar radiation, magnetic fields, and the influence of magnetospheric plasma can significantly impact the dynamics of constituent particles and trigger their decay. This highlights the importance of future studies of these effects.

Stable, aromatic, and electrophilic azepinium ions: Design using quantum chemical methods.

Cyclic nitrenium ions containing five-membered and six-membered rings are available, however, the seven-membered cyclic nitrenium ions (azepinium ions) are rare. The chemistry of these species is related to their stability originating from the aromaticity due to 6π electrons. Very few theoretical and experimental studies have been conducted on the azepinium ions. Related clozapine and olanzapine cations (diazepinium ions) were observed during drug metabolism studies. In this work, quantum chemical analysis has been carried out to estimate the stability, aromaticity, and electrophilicity of several derivatives of azepinium ions. A few of the designed azepinium ions carry ΔES-T values in the range of 50 kcal/mol favoring singlet state; π donating groups at the 2nd position increase the singlet-triplet energy differences. Most of the substituents reduce the NICS(1) values compared to the parent system. Ring fusion with heterocyclic five-membered rings generally increases the aromaticity and the stability of the azepinium ion ring systems. The electrophilicity parameters estimated in terms of HIA, FIA, and ω values indicate that it is possible to fine-tune the chemical properties of azepinium ions with appropriate modulation.

Total Synthesis Analysis of Pseuboyenes D

In this work, we propose a total synthesis route for the antifungal agent Pseuboyenes D, a compound derived from Pseudallescheria boydii CS-793. Pseuboyenes D exhibits antifungal activity comparable to Amphotericin B while offering the advantage of a simpler structure, making it a promising candidate for clinical applications. The system became the focus of this analysis due to its regioselectivity, and after exploration, a [2+2] photocycloaddition and ring expansion strategy was adopted to construct the key bridged ring system. The route employs readily available substrates and mild reaction conditions, making it scalable and suitable for large-scale production. Computational analysis of the regioselectivity of the photocycloaddition revealed that the bridged adduct was thermodynamically favored over the fused system. The synthetic route was further diversified by incorporating functional group modifications using TMS derivatives, enhancing the potential for pharmacological applications. Overall, this work establishes an efficient and scalable synthetic pathway for Pseuboyenes D, paving the way for future applications in antifungal drug development.

Experimental and Theoretical Characterization of 4π‐Electron Möbius Aromatic System of a 1,2‐Digermacyclobutadiene†

AbstractWe present the visualization of the experimental valence electron‐density distribution (EDD) in the isolated 1,2‐digermacyclobutadiene ring system, revealing the unique 4π electron‐delocalization on the four‐membered Ge2C2 ring. A remarkably high Möbius 4π‐electron aromatic character in the Ge2C2 ring can be suggested from theoretical calculations, in sharp contrast to the significant antiaromaticity of the all‐carbon cyclobutadiene ring.

High-throughput prediction of oral acute toxicity in Rat and Mouse of over 100,000 polychlorinated persistent organic pollutants (PC-POPs) by interpretable data fusion-driven machine learning global models

This study utilized available oral acute toxicity data in Rat and Mouse for polychlorinated persistent organic pollutants (PC-POPs) to construct data fusion-driven machine learning (ML) global models. Based on atom-centered fragments (ACFs), the collected high-throughput data overcame the applicability limitations, enabling accurate toxicity prediction for a wide range of PC-POPs series compounds using only single models. The data variances in the Rat training and test sets were 1.52 and 1.34, respectively, while for the Mouse, the values were 1.48 and 1.36, respectively. Genetic algorithm (GA) was used to build multiple linear regression (MLR) models and pre-screen descriptors, addressing the “black-box” problem prevalent in ML and enhancing model interpretability. The best ML models for Rat and Mouse achieved approximately 90 % prediction reliability for over 100,000 true untested compounds. Ultimately, a warning list of highly toxic compounds for eight categories of polychlorinated atom-centered fragments (PCACFs) was generated based on the prediction results. The analysis of descriptors revealed that dioxin analogs generally exhibited higher toxicity, because the heteroatoms and ring systems increased structural complexity and formed larger conjugated systems, contributing to greater oral acute toxicity. The present study provides valuable insights for guiding the subsequent in vivo tests, environmental risk assessment and the improvement of global governance system of pollutants.