Bicyclic System Research Articles

Pogocablanols A–G, a new class of sesquiterpenoids with an unprecedented bicyclic sesquiterpenoid skeleton from Pogostemon cablin (patchouli) and their activities

Pogocablanols A–G (1–7), seven new compounds with an unprecedented sesquiterpenoid skeleton, were isolated from the aerial parts of Pogostemon cablin. This novel type of sesquiterpenoids, named pogocablane-type sesquiterpenoids, possesses a bicyclic nonisoprenoid system, including a five-membered carbocycle with a methyl group, a six-membered carbocycle with two methyl groups, and a methylene connecting the two carbocycles. Particularly, three isomers have an interesting 1-oxaspiro[4,4]nonane moiety. Their structures and absolute configurations were determined using extensive spectroscopic evidence, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Pogocablanols A–D (1–4) exhibited a concentration-dependent inhibitory effect on rat jejunum smooth muscle contraction induced by acetylcholine, with Emax values varying from 48.87 ± 4.01% to 69.02 ± 7.54%. Preliminary structure–activity relationship analysis suggested that the oxaspirocycle and the pyran ring in pogocablanols are important structural features for the relaxing effects on jejunum smooth muscle. This study offered crucial support for more investigation and development of P. cablin by showing that these pogocablane-type sesquiterpenoids had the potential to be applied in pharmaceutical and functional food formulations.

Monoterpenoids from the root bark of Acanthopanax gracilistylus and their inhibitory effects on neutrophil elastase, 5-lipoxygenase, andcyclooxygenase-2 in vitro

Twenty-four monoterpenoids, including three previously undescribed compounds (1–3), were isolated from the root bark of Acanthopanax gracilistylus W. W. Smith (Acanthopanacis Cortex). Their structures were unambiguously established based on spectroscopic analysis (HR-ESIMS, IR, 1D, and 2D NMR), and the absolute configurations of 1–3 were elucidated by comparing their experimental and calculated electronic circular dichroism spectra. In addition, the structure of 8 was confirmed by single-crystal X-ray diffraction. The inhibitory activities of 1–24 against neutrophil elastase, 5-lipoxygenase, and cyclooxygenase-2 (COX-2) were studied in vitro for the first time, and the results showed that compound 24 possessed a significant inhibitory effect on COX-2 with an IC50 value of 1.53 ± 0.10 μΜ. This research first reported the presence of monoterpenoids in Acanthopanacis Cortex, including one monoterpenoid 2 with an unusual 4/5 bicyclic lactone system, and compounds 4 and 5 have never been reported in nature.

How do walking environments along the connecting path affect the disparity in public bicycle usage among multiple docking stations around tube stations?

The integration of public bicycles with tube systems has the potential to enhance urban transportation sustainability and efficiency. However, the utilization of public bicycles can significantly differ among various docking stations, even when they fall within the coverage area of the same tube station. Understanding the factors that attract or discourage individuals from using public bicycles in different locations is essential for informed decision-making regarding infrastructure and policy enhancements. This study examines the disparity in public bicycle usage, with a specific focus on the micro-level walking environments along connecting paths between docking stations and tube stations. Transaction data collected from London public bicycle and tube systems are utilized, alongside micro-level walking environment and macro-level built environment and socio-economic factors. A generalized additive mixed model is employed to capture nonlinear effects and spatial autocorrelations in docking station usage.The results reveal significant effects of walking environments along connecting paths on docking station usage. Specifically, positive associations are observed between bicycle station usage and footpaths quality, presence of pedestrian crossing, and points of interests (e.g., green space) along the connecting path, as well as tube ridership, cycle facilities, and land-use mixture. Conversely, negative relationships are observed with walking distance, physical barriers, road crossed, and bus stops. Moreover, proximity to transit, distance to the city center, and deprivation level demonstrate threshold effects on bicycle station usage. This study provides several practical implications for improving the multi-mode transportation system and the planning of docking stations around tube station, aiming to create cycling-friendly and transit-oriented environments.

Reactions of Tetra(o-tolyl)diborane(4) with Organic Azides: Formation of Fluorescent Boron-Fused Hexazenes.

The reaction of tetra(o-tolyl)diborane(4) with organic azides afforded three different compounds, diborylamines, diboryltriazenes, and B2 -hexazenes having a bicyclic B2 N6 ring system. The reaction with aryl azides gave diborylamines, while the reaction with 1 equiv. of alkyl azides furnished diboryltriazenes. In the case of the reaction with an excess amount of primary alkyl azide, a new heterocyclic B2 -hexazenes were obtained. The formation of the B2 N6 structure could be explained by one general reaction mechanism via the diboryltriazene intermediate according to the control experiments and DFT calculations. The B2 -hexazenes exhibited a strong fluorescence with a remarkably high fluorescent quantum yield of up to 96 %.

Benzimidazole: A Promising target for the development of novel drug molecules against breast cancer

Breast cancer is considered as one of the deadliest diseases dominantly in developed and developing countries. Continuous research is required in order to design and develop better therapeutic agents for cancer treatment with more selectivity, efficacy and reduced toxicity. Fused heterocyclic ring system has been identified as a privileged structure by several researchers that can be used as a template for drug discovery and development in Medicinal Chemistry. Wide range of drugs with therapeutic potential contain hetero-aromatic bicyclic ring system as pharmacophore. According to various research outputs in the literature substituted benzimidazoles have wide range of pharmacological profiles with multi-targeting ability, making them an important basic nucleus for the design and development of novel therapeutic agents for the treatment of complex cancers including breast cancer, skin cancer, and blood cancer. In the presented article we have discussed research outputs by many scientists in the last few years that support the candidature of benzimidazole scaffold for the development of novel therapeutic agents against breast cancer along with their mechanism of action. This review also focuses on little introductory idea about benzimidazole nucleus and types of breast cancer.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems.

An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH2) and Pd(II) complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99% ee) and diastereoselectivity (up to >20:1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as ∆6-protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH2 catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N-H of the enamine motif and the C=O of the directing group MQ, and the counterion of the Pd(II) complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems

AbstractAn asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD‐NH2) and PdII complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ6‐protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD‐NH2 catalyst and the branched chain of the substrate, hydrogen‐bonding interactions between the N−H of the enamine motif and the C=O of the directing group MQ, and the counterion of the PdII complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.

Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N6, C2 and 5′-Modified (N)-methanocarba-adenosine derivatives

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B serotonin receptors as antagonists, predominantly containing branched N6-alkyl groups. N6-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT2Rs, while only N6-dicyclohexyl-methyl derivative 35 showed weak 5-HT2AR affinity (Ki 3.6 μM). The highest 5-HT2BR affinities were Ki 11–23 nM (N6-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5′-deoxy-5′-methylthio 15 and N6-((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and Ki 73 nM at 5-HT2CR for 36. Direct comparison of adenine ribosides and their corresponding rigid (N)-methanocarba derivatives (cf. 51 and MRS8099 45) indicated a multifold affinity enhancement with the bicyclic ring system. Compounds 43, 45 and 48 were functional 5-HT2BR (KB 2–3 nM) and 5-HT2CR (KB 79–328 nM) antagonists in a Gq-mediated calcium flux assay, with 5-HT2BR functional selectivity ranging from 45- (48) to 113-fold (43). Substantial adenosine receptor (AR) affinity (Ki, A1AR < Ki, A3AR < Ki, A2AAR) was still present in this series, suggestive of dual acting compounds: 5-HT2B antagonist and A1AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT2BR binding selectivity (32-fold vs. 5-HT2CR, 4-fold vs. A1AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.

Synthesis of 4,6-disubstituted bicyclo[3.3.1]nona-3,6-dien-2-ones

Bicyclo[3.3.1]nonane system is an important structural motif observed in a diverse natural products. Here, we report a concise synthetic route exploiting aldol condensation reactions for construction bicyclo[3.3.1]nonane ring system. Our strategy employes cyclohex-2-enones bearing another carbonyl group in side chain as key structural unit. The reaction showed good results for substrates bearing electron-donating groups in aromatic substituents. Overall, the described synthesis of bicyclo[3.3.1]nona-3,6-dien-2-ones required 2 steps and only 2 building blocks (such as Mannich base and acetoacetic ester) to access desired bicyclic system.

Sulfamidate-Based Stereoselective Total Synthesis of (+)-Preussin Using Gold(I)-Catalyzed Intramolecular Dehydrative Amination: Dead End and Detour.

A sulfamidate-based stereoselective total synthesis of (+)-preussin has been developed. The key step involves a gold(I)-catalyzed intramolecular dehydrative amination of sulfamate esters tethered to allylic alcohols, which allows for the construction of the cyclic sulfamidate with high stereoselectivity. Further manipulation to highly constrained bicyclic sulfamidate and the following ring-opening process afford 3-hydroxypyrrolidine motif stereoselectively. The energy of the constrained bicyclic ring system is relieved by the subsequent ring-opening process, which leads to a stereoselective formation of the 3-hydroxypyrrolidine motif under mild reaction conditions. The success of this approach not only provides a new method for the total synthesis of enantiomerically pure (+)-preussin but also highlights the synthetic utility of sulfamidates in constructing valuable natural product architectures.

A Truly Model City or Just a Fairy Tale?

Nowadays, all kinds of climate disasters, such as global warming and the melting of glaciers, are happening all over the world. Human beings also gradually realized the importance of protecting our only earth and took some measures. Green cities were proposed in the course of the "Green Movement" to protect the global environment. The green city refers to urban construction that emphasizes not only ecological balance and nature protection but also human health and cultural development. Curitiba, Brazil, as one of the representatives of green cities, has not only made innovations in the city's public transport system, BRT but also combined the urban park green space with water control, which not only managed the flood disaster but also provided leisure and entertainment space for citizens. At the same time, they also advocate the EcoCitizen program, which encourages citizens to exchange garbage for food and solves the problem of garbage sorting and recycling and also deals with most of the excess food. At the end of the article, we also searched some pieces of literature and video interviews with Curitiba residents to discuss whether these measures are effective as advertised by the government, as well as the existing problems of green space fairness and the bicycle system. And take Curitiba as a case to summarize and analyze.

A Point Processes approach to bicycle sharing systems’ design and management

Public bicycle systems have attracted a great deal of attention in recent years. The success of this service heavily depends on the topology of the city and on the locations of bike stations in relation to potential demand. In fact, it is primarily important that users find bike stations in convenient locations, sufficiently close both to the origins of their trips and to their destinations, and that each rental station guarantees the availability both of enough bicycles and of enough empty docking slots.This paper proposes a point processes approach to the study of bike-sharing systems, allowing us to quantify and control parameters having a key role in decisions both of strategic and operational type.Differently from previous studies, the point processes approach catches both the interdependence among the stations and the links between spatial and time aspects of the problem.The application of point processes, in particular spatial mixed Poisson processes, to this field requires the statement and proof of an invariance property of such processes under stochastic dependent transformations, that may be of interest also from a theoretical point of view.

Convenient Approach to 10‐ and 11‐Membered Azalactams

AbstractA convenient method for the synthesis of 10‐ and 11‐membered azalactams via reductive cleavage of bicyclic systems featuring an amidine fragment was studied. It was found that the ring‐expansion reaction of bicyclic dihydropyrimidones depends on the ring size of saturated fragment, substituents in the pyrimidone core and reaction conditions. A new efficient method for the synthesis of medium ring azalactams by reductive cleavage of quaternary salts of annulated dihydropyrimidones was proposed as well. The obtained medium ring azalactams with a secondary amine function were used in the synthesis of bicyclic heteroaromatic systems.

Conformationally restrained coumarin hemicyanines: Improved quantum yields and potential applications in bioimaging and photodynamic therapy

In this work, by installing a bicyclic ring system into the skeleton of traditional coumarin-hemicyanines (CHCs), a new class of conformationally restrained coumarin-hemicyanines (RCHCs) were constructed, which showed dramatically improved fluorescence quantum yields (close to near-unity in CH2Cl2), while retaining the large Stokes shifts of CHCs. The feature was also reflected in living cell imaging, where the representative RCHCs, i.e. RCHC1 and RCHC2, showed significantly improved intracellular fluorescence brightness relative to control dye CHC1, along with excellent lysosome and mitochondria targetability. Based on RCHC1 platform, a carboxy-functionalized derivative, i.e., RCHC1-COOH, was developed, and its potential in fluorescently discriminating between cancer and normal cells was demonstrated in terms of its specific accumulation in lipid rafts localized in plasma membrane and enriched in cancer cells. Based on RCHC2 platform, a photosensitizer (PS) RCHC2-I was exploited for photodynamic therapy (PDT) of tumor, which exhibited markedly enhanced singlet oxygen generating ability due to its strong propensity to form aggregates. In vitro and in vivo PDT assays proved that RCHC2-I could cause extensive cancer cell death and tumor ablation upon light irradiation.

Using a Data Mining Method to Explore Strategies for Improving the Social Interaction Environment Quality of Urban Neighborhood Open Spaces

With the intensification of population aging and the increasing awareness of public health protection in the post-epidemic era, the renewal of the old urban community neighborhood space is facing many new challenges and problems. Neighborhood Public Open Space (POS) is the main place for people to carry out various social activities in community life. The quality of the social interaction environment that a neighborhood POS can provide can have a vital impact on people’s well-being, as well as their physical and mental health. Therefore, the purpose of this research is to identify and clarify the key physical environmental design attributes/features of the old urban community neighborhood POS, and to explore the relationship between them from the perspective of creating a high-quality social environment. Through the investigation of relevant cases in Shenzhen and Guangzhou, China, the classification performance of each case on the key physical and environmental elements is used as the conditional attribute, and the quality of the social interaction environment in the current situation of each case is used as the decision making attribute to conduct a data mining analysis. Using rough set theory, this study screened out four important elements: greenbelt form planning (C1); ped and bike system (C2); space organization and zoning planning (C6); Public facilities (C8). Moreover, this study also presents a set of hierarchical decision rules to describe the classification status of the matching physical environmental design elements when the social interaction environment reaches a high quality in the neighborhood POS. This study provides local policy makers with key current situation assessment and diagnostic tools in urban-built environmental renewal projects. The results of this study can help designers draw up the renovation design plans of neighborhood POS on the basis of efficiently obtaining the practical experience of relevant cases, and then create a high-quality social interaction environment.

Three-Step Modular Synthesis of N-Substituted Bicyclic Systems

Key words isoquinolinones - palladium catalysis - ring closure - alkylation - mechanistic studies

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series.

Terpene compounds probably represent the most diversified class of secondary metabolites. Some classes of terpenes, mainly diterpenes (C20) and sesterterpenes (C25) and to a lesser extent sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki-Hiyama-Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson-Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis.

Exploring the Impact of First Mile/Last Mile Solutions on Traffic Congestion and Air Quality in Urban Areas

Ride-hailing and bike-sharing have gained popularity as first-mile/last-mile solutions in urban areas, as these services can improve the efficiency and sustainability of urban transport systems. However, they can also affect traffic congestion and air quality. This paper examines the impact of different first-mile/last-mile solutions for ride-hailing and shared bikes on traffic congestion and air quality in urban areas. Shared bikes are considered an effective solution to reduce vehicle mileage and improve air quality. Several studies have found that shared bike systems have great potential to reduce traffic congestion and emissions. The paper also uses population density and land models to demonstrate the effectiveness of the proposal, illustrating the availability of alternative modes such as public transport or walking and cycling infrastructure.

Simultaneous Formation of Isomeric and Polycyclic Proton Sponges Derived from 1,8‐Diaminonaphthalenes and Xylylene Dibromides

AbstractThe interaction of 1,8‐diaminonaphthalene with o‐xylylene dibromide leads to two topologically relevant isomeric products, 1,8‐di(isoindolin‐2‐yl)naphthalene (reported previously), and its structural isomer with the bridgehead nitrogens in a bicyclic system (reported for the first time). This is the first case of isolating two heterocyclic analogs of 1,8‐bis(dimethylamino)naphthalene (proton sponge or DMAN) in one reaction. Both isomers are formed in parallel reactions and are not interconverted upon acid treatment. The first representative of heterocyclic “amide proton sponges”, which is still able to participate in intramolecular protonation due to the amide nitrogen atom, was synthesized by direct oxidation of the corresponding isoindoline derivative. Using p‐xylylene dibromide as a bridging bielectrophile, a macroheterocyclization was effectively realized to construct the first paracyclophane extended by two DMAN subunits. Mostly driven by the proximity effect, the molecular structure, unusual protonation trends and reactivity of peri‐diaminonaphthalenes N‐linked with o‐ and p‐xylylene fragments are also discussed.

Rh(I) Complexes with Hemilabile Thioether-Functionalized NHC Ligands as Catalysts for [2 + 2 + 2] Cycloaddition of 1,5-Bisallenes and Alkynes.

The [2 + 2 + 2] cycloaddition of 1,5-bisallenes and alkynes under the catalysis of Rh(I) with hemilabile thioether-functionalized N-heterocyclic carbene ligands is described. This protocol effectively provides an entry to different trans-5,6-fused bicyclic systems with two exocyclic double bonds in the cyclohexene ring. The process is totally chemoselective with the two internal double bonds of the 1,5-bisallenes being involved in the cycloaddition. The complete mechanism of this transformation as well as the preference for the trans-fusion over the cis-fusion has been rationalized by density functional theory calculations. The reaction follows a typical [2 + 2 + 2] cycloaddition mechanism. The oxidative addition takes place between the alkyne and one of the allenes and it is when the second allene is inserted into the rhodacyclopentene that the trans-fusion is generated. Remarkably, the hemilabile character of the sulfur atom in the N-heterocyclic carbene ligand modulates the electron density in key intermediates, facilitating the overall transformation.