Bicyclic System Research Articles

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.

Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles and Macrocycles

The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review.

A Spatial-Temporal Aggregated Graph Neural Network for Docked Bike-Sharing Demand Forecasting

Predicting the number of rented and returned bikes at each station is crucial for operators to proactively manage shared bike relocation. Although existing research has proposed spatial-temporal prediction models that significantly advance traffic prediction, these models often neglect the unique characteristics of shared bike systems (BSS). Spatially, the entire bike-sharing system (BSS) experiences peak activity during morning and evening rush hours, whereas, during other periods, activity is localized to local stations, with some recording no rides, highlighting the need to distinguish between global and local spatial information across different times. Temporally, the historical riding records for each station exhibit non-stationary patterns, necessitating the analysis of both global trends and local fluctuations. Existing Graph Neural Network (GNN) approaches to predicting shared bike demand primarily capture static spatial-temporal data and fail to account for the dynamic nature of bike flows. Moreover, these studies focus on global spatial-temporal information without considering local nuances, making it challenging to capture spatiotemporal dynamics in fluctuating BSS. To address these challenges, we introduce the Spatial-Temporal Aggregated Graph Neural Network (STAGNN). Our model first constructs a dynamic adjacent matrix to describe the evolving connections between stations, followed by local and global information layers to capture spatial-temporal information from large-scale shared bike networks accurately. Our methodology has been validated through experiments on four real-world datasets, comparing it against benchmark models to demonstrate superior prediction accuracy. Additionally, we conduct extended experiments on four datasets during the morning and evening rush hours, and the results also affirm the efficacy of the STAGNN in enhancing prediction performance.

Data mining of PubChem bioassay records reveals diverse OXPHOS inhibitory chemotypes as potential therapeutic agents against ovarian cancer

Focused screening on target-prioritized compound sets can be an efficient alternative to high throughput screening (HTS). For most biomolecular targets, compound prioritization models depend on prior screening data or a target structure. For phenotypic or multi-protein pathway targets, it may not be clear which public assay records provide relevant data. The question also arises as to whether data collected from disparate assays might be usefully consolidated. Here, we report on the development and application of a data mining pipeline to examine these issues. To illustrate, we focus on identifying inhibitors of oxidative phosphorylation, a druggable metabolic process in epithelial ovarian tumors. The pipeline compiled 8415 available OXPHOS-related bioassays in the PubChem data repository involving 312,093 unique compound records. Application of PubChem assay activity annotations, PAINS (Pan Assay Interference Compounds), and Lipinski-like bioavailability filters yields 1852 putative OXPHOS-active compounds that fall into 464 clusters. These chemotypes are diverse but have relatively high hydrophobicity and molecular weight but lower complexity and drug-likeness. These chemotypes show a high abundance of bicyclic ring systems and oxygen containing functional groups including ketones, allylic oxides (alpha/beta unsaturated carbonyls), hydroxyl groups, and ethers. In contrast, amide and primary amine functional groups have a notably lower than random prevalence. UMAP representation of the chemical space shows strong divergence in the regions occupied by OXPHOS-inactive and -active compounds. Of the six compounds selected for biological testing, 4 showed statistically significant inhibition of electron transport in bioenergetics assays. Two of these four compounds, lacidipine and esbiothrin, increased in intracellular oxygen radicals (a major hallmark of most OXPHOS inhibitors) and decreased the viability of two ovarian cancer cell lines, ID8 and OVCAR5. Finally, data from the pipeline were used to train random forest and support vector classifiers that effectively prioritized OXPHOS inhibitory compounds within a held-out test set (ROCAUC 0.962 and 0.927, respectively) and on another set containing 44 documented OXPHOS inhibitors outside of the training set (ROCAUC 0.900 and 0.823). This prototype pipeline is extensible and could be adapted for focus screening on other phenotypic targets for which sufficient public data are available.Scientific contributionHere, we describe and apply an assay data mining pipeline to compile, process, filter, and mine public bioassay data. We believe the procedure may be more broadly applied to guide compound selection in early-stage hit finding on novel multi-protein mechanistic or phenotypic targets. To demonstrate the utility of our approach, we apply a data mining strategy on a large set of public assay data to find drug-like molecules that inhibit oxidative phosphorylation (OXPHOS) as candidates for ovarian cancer therapies.Graphical

Maydisens, Sesterterpenoids with Anti-MDR Activity from Bipolaris maydis.

Fourteen previously undescribed sesterterpenoids (1-14) were isolated from Bipolaris maydis. Their structures with absolute configurations were elucidated by NMR, HRESIMS, DP4+ calculations, ECD calculations, single-crystal X-ray diffraction analyses, and the modified Mosher's method. Compounds 1-5 possess an uncommon 5/11 bicyclic ring system identified from B. maydis for the first time. Compounds 6-14 have a 5/8/5 tricyclic ring system, and these compounds both possess carbonyl groups in ring A. Compound 10 showed significant reversal of paclitaxel resistance in cancer cells.

Two-Step Synthesis of Enantiomerically Pure Morphans from (R)-Carvone.

Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8-13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki=58 nM and 20 nM).

Visualization of explainable artificial intelligence for GeoAI

Shapley additive explanations are a widely used technique for explaining machine learning models. They can be applied to basically any type of model and provide both global and local explanations. While there are different plots available to visualize Shapley values, there is a lack of suitable visualization for geospatial use cases, resulting in the loss of the geospatial context in traditional plots. This study presents a concept for visualizing Shapley values in geospatial use cases and demonstrate its feasibility through an exemplary use case—predicting bike activity in a rental bike system. The visualizations show that visualizing Shapley values on geographic maps can provide valuable insights that are not visible in traditional plots for Shapley additive explanations. Geovisualizations are recommended for explaining machine learning models in geospatial applications or for extracting knowledge about real-world applications. Suitable visualizations for the considered use case are a proportional symbol map and a mapping of computed Voronoi values to the street network.

Cobalt-Catalyzed (3 + 2) Cycloaddition of Cyclopropene-Tethered Alkynes: Versatile Access to Bicyclic Cyclopentadienyl Systems and Their CpM Complexes.

Low-valent cobalt complexes can promote intramolecular (3 + 2) cycloadditions of alkyne-tethered cyclopropenes to provide bicyclic systems containing highly substituted cyclopentadienyl moieties with electronically diverse functional groups. The adducts can be easily transformed into new types of CpRh(III) and CpIr(III) complexes, which show catalytic activity in several relevant transformations. Preliminary computational (DFT) and experimental studies provide relevant information on the mechanistic peculiarities of the cobalt-catalyzed process and allow us to rationalize its advantages over the homologous rhodium-promoted reaction.

Developing deep learning models for predicting urban bike-sharing usage patterns

Urban traffic systems are facing significant challenges due to the ever-growing number of vehicles on the road, leading to increased congestion and suboptimal traffic flow. Traditional research focusing on individual traffic flows is often insufficient to meet the complex demands of modern urban transportation. While studying integrated shared single-vehicle flows offers a potential solution to mitigate these issues, the unique characteristics of shared bikes present substantial obstacles to accurate traffic flow research. These obstacles include the high liquidity, sparsity, and variability of shared bikes, the vagueness of travel characteristics, the lack of correlation between travel groups, and the unpredictability of travel patterns. The study endeavors to confront the challenges above by proposing an innovative model that correlates multiuser interactions and elucidates behavioral dynamics. This model utilizes a deep clustering method to analyze the evolution of superlarge-scale shared bike systems in Beijing. It uncovers the complex mechanisms governing user behavior and employs a neural network algorithm to predict shared bike users’ travel patterns effectively. By focusing on the theoretical and algorithmic aspects of behavioral dynamics for large-scale shared single-vehicle flows, this study offers a unique contribution to the field, with significant implications for multi-traffic flow management and urban planning in scenarios with extensive multi-traffic flows.

Stereoselective Synthesis of Fused Bicyclic Systems via a Palladium-Catalyzed Domino Reaction

Stereoselective Synthesis of Fused Bicyclic Systems via a Palladium-Catalyzed Domino Reaction

Exploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy

With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.

Tagpyrrollins A and B and Tagpyrrollidone A: Three Pyrrole Steroid Analogues with AKR1B1-Targeting Inhibitory Activity from the Sponges Stylissa massa and Pseudospongosorites suberitoides.

Pyrrole alkaloids (PAs) are a diverse class of natural products with complex carbon frameworks and broad bioactivities that are usually derived from marine sponges. Stylissa massa and Pseudospongosorites suberitoides are two independent sponges collected from the South China Sea in 2013 and 2018, respectively. We discovered PAs are common constituents in both two sponges; more specifically, S. massa produces pyrrole-imidazole alkaloids, and P. suberitoides contains pyrrolidone alkaloids. In this study, three pyrrole steroid metabolites were obtained. Compounds 1 and 2 are a pair of epimers sharing a new 5/7/5/6/6 pentacyclic structural configuration, and compound 3 has a new rigid 5/6/6 tricyclic structure. Interestingly, their scaffolds all possess a 6/6 bicyclic system on the featured classic pyrrole/pyrrolidone skeletons, so-dubbed tagpyrrollins A and B (1 and 2, respectively) and tagpyrrollidone A (3). From a biosynthetic viewpoint, 4,5-dihydroxypent-2-enal probably plays a crucial role in constructing these pyrrole steroid analogues. Based on our previous study on the inhibitory activity of spongiacidin targeting AKR1B1, a drug target for the treatment of chronic diabetic complications, in this study we found that tagpyrrolin A (1) also exhibits an inhibitory effect against AKR1B1.

Spontaneous Formation of Strained Anti-Bredt Bridgehead Alkenes upon Computational GeometryOptimization of Bicyclic β-Halo Carbanions

Bridgehead alkenes are polycyclic molecules bearing at least one C=C bond that includes a bridgehead carbon atom. For small bicyclic systems, these bonds are highly strained due to geometric constraints placed on the sp2 hybridized carbon atoms. These small, strained molecules have been termed “anti-Bredt” alkenes. β-halo carbanions have served as convenient precursors to bridgehead alkenes in experimental studies. We observed that upon attempted computational geometric optimizations (ωB97X-D/aug-cc-pVDZ) of the precursors, spontaneous elimination of the halide occurs along with formation of the anti-Bredt alkene in many cases. Such computational eliminations were shown to faithfully mimic experimentally obtained results. Computational elimination was not observed for [1.1.1] or [2.1.1] frameworks, in agreement with predictions that these bridgehead alkenes are too strained to be formed. However, computational elimination from the [2.2.1] framework was observed to form 1-norbornene, a compound suggested in experimental work to be a reactive intermediate. Similarly, [3.1.1] frameworks and higher led to eliminations upon computational geometric optimization, in agreement with experimental findings. Natural bond order (NBO) calculations of the starting geometries proved to be excellent predictors as to whether elimination would take place. Those precursor compounds exhibiting delocalization energies in the order of 10 kcal/mol between the lone-pair electrons of the carbon atom and σ*C-Br were generally found to undergo elimination. Thus, computational optimization of β-halo substituted bicyclic precursor anions can be used to predict whether strained anti-Bredt alkenes are likely to be formed, thereby saving valuable time and costs in the experimental lab.

Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner-Meerwein rearrangement.

Herein, we report the first environmentally friendly systematic fluoroalkoxylation reactions in bicyclic systems. New oxyfluorination products were obtained with excellent yields (up to 98%) via Wagner-Meerwein rearrangement using benzonorbornadiene and the chiral natural compound (+)-camphene as bicyclic alkenes, selectfluor as an electrophilic fluorine source, and water and various alcohols as nucleophile sources. The structure of bicyclic oxy- and alkoxyfluorine compounds was determined by NMR and QTOF-MS analyses.

Undescribed polyketides from endophytes associated with the critically endangered conifer Abies beshanzuensis

Four undescribed polyketides, beshanzones A (1) and B (2) as well as beshanhexanols A (3) and B (4), along with three known ones (5–7) were isolated from the rice fermentation of two endophytic fungi associated with the critically endangered Chinese endemic conifer Abies beshanzuensis. γ-Butyrolactone derivatives 1, 2, and 5 were isolated from Phomopsis sp. BSZ-AZ-2, an interesting strain that drawn our attention this time. The cyclohexanol derivatives 3, 4, 6, and 7 were obtained during a follow-up investigation on Penicillium commune BSZ-P-4-1. The chemical structures including absolute configurations of compounds 1–4 were determined by spectroscopic methods, Mo2(OAc)4 induced electronic circular dichroism (IECD), GIAO NMR calculations and DP4+ probability analyses. In particular, compound 2 contains a novel 5/5 bicyclic ring system, which might be biogenetically derived from the known compound 5 through hydrolysis followed by an Aldol reaction. All isolates were evaluated for their antimicrobial activities against a small panel of bacterial and fungal pathogens. Compounds 6 and 7 showed moderate inhibitory activities against Candida albicans, with MIC values of 16 and 32 μg/mL, respectively.

Attaching Metal-Containing Moieties to β-Lactam Antibiotics: The Case of Penicillin and Cephalosporin.

Procedures for the preparation of transition metal complexes having intact bicyclic cepham or penam systems as ligands have been developed. Starting from readily available 4-azido-2-azetidinones, a synthetic approach has been tuned using a copper-catalyzed azide-alkyne cycloaddition between 3-azido-2-azetinones and alkynes, followed by methylation and transmetalation to Au(I) and Ir(III) complexes from the mesoionic carbene Ag(I) complexes. This methodology was applied to 6-azido penam and 7-azido cepham derivatives to build 6-(1,2,3-triazolyl)penam and 7-(1,2,3-triazolyl)cepham proligands, which upon methylation and metalation with Au(I) and Ir(III) complexes yielded products derived from the coordination of the metal to the penam C6 and cepham C7 positions, preserving intact the bicyclic structure of the penicillin and cephalosporin scaffolds. The crystal structure of complex 28b, which has an Ir atom directly bonded to the intact penicillin bicycle, was determined by X-ray diffraction. This is the first structural report of a penicillin-transition-metal complex having the bicyclic system of these antibiotics intact. The selectivity of the coordination processes was interpreted using DFT calculations.

Synthesis of sulfonylamides containing an isoxazole moiety

The authors obtained a number of new sulfonylamides with isoxazole moiety by sulfonyl chlorination of bicyclic systems containing isoxazole heterocycle and interaction of the obtained sulfonyl chlorides with amino compounds. The authors also obtained isoxazole derivatives containing a sulfogroup in the isoxazole ring by sulfonyl chlorination of 3-aryl-5-N-acylaminoisoxazoles.

TRASUTA: The Effect of the Structural Rigidity of a Mesocyclic AAZTA-like Chelating Agent on the Thermodynamic, Kinetic, and Structural Properties of Some Divalent Metal and Ga3+ Complexes.

Mesocyclic chelating agents such as AAZTA and its derivatives have been recently reported to overcome the relatively low thermodynamic stability of metal complexes of acyclic chelating agents and the slow complexation kinetics of macrocyclic chelating agents. This work reports the preparation of a spirobicyclic hexadentate AAZTA-like chelating agent (TRASUTA) and the investigation of the thermodynamic, kinetic, and structural properties of the corresponding chelates with the PET-relevant Ga3+ and selected metal ions. A combination of analytical techniques allowed identification of a coordination isomerization process, involving the coordinating side arms and the inversion of a nitrogen atom and leading to lower thermodynamic and kinetic inertness with respect to mononuclear mesocyclic analogues. The bicyclic system of TRASUTA retains significant dynamics despite the conformational constraint imposed by the spiro-fusion, resulting in a lower stability of the corresponding metal chelates.

Shared Bike Usage Analysis

This essay delves into the realm of data analytics to examine patterns and trends in shared bike usage. Leveraging large-scale datasets from shared bike platforms, the analysis encompasses factors influencing usage, including geographical patterns, temporal variations, and user demographics. The essay employs advanced data analytics techniques, such as machine learning algorithms, to uncover hidden insights and predict future usage trends. By scrutinizing the data, the essay aims to contribute valuable insights for optimizing shared bike systems, enhancing urban mobility, and informing sustainable transportation policies.

Optimizing shared bike systems for economic gain: Integrating land use and retail

This study explores the optimization of shared-bike station locations, emphasizing the cycling role in low-carbon mobility and local economic revitalization. A unique aspect of this research is the incorporation of the retail activity index in determining station locations, land-use mix, transit proximity, and population and employment densities. A novel weighting method, combining the multi-criteria decision method “Criteria Importance Through Inter-criteria Correlation (CRITIC)” with Ensemble-based predictive algorithms (Random Forest, XGBoost, Gradient Boosting), was developed to evaluate these factors. Using a geographic information system-based spatial model, this study conducted a suitability analysis by applying these weights to assess and propose bike station sites. The findings from the Seoul case indicate a balanced land-use mix, a low number of transactions linked to cyclists, and a significant gap in multimodal transport integration. The weighting results revealed a high priority for transit proximity and retail activity in station placement. Suitability scores across districts revealed significant variability, suggesting the need for greater integration of cycling policies into urban planning. High-scoring districts, such as Gangnam-gu and Seocho-gu, offer insights for improvements in less suitable areas. This study advocates expanded cycling planning, focusing on enhancing access to public transit and retail areas.