Discovery of a botanical compound as a broad-spectrum inhibitor against gut microbial ß-glucuronidases from the Tibetan medicine Rhodiola crenulata.

Gut microbial ß-glucuronidases (gmß-GUS) played crucial roles in regulating a variety of endogenous substances and xenobiotics on the circulating level, thus had been recognized as key modulators of drug toxicity and human diseases. Inhibition or inactivation of gmß-GUS enzymes has become a promising therapeutic strategy to alleviate drug-induced intestinal toxicity. Herein, the Rhodiola crenulata extract (RCE) was found with potent and broad-spectrum inhibition on multiple gmß-GUS enzymes. Subsequently, the anti-gmß-GUS activities of the major constituents in RCE were tested and the results showed that 1,2,3,4,6-penta-O-galloyl-ß-d-glucopyranose (PGG) acted as a strong and broad-spectrum inhibitor on multiple gmß-GUS (including EcGUS, CpGUS, SaGUS, and EeGUS). Inhibition kinetic assays demonstrated that PGG effectively inhibited four gmß-GUS in a non-competitive manner, with the Ki values ranging from 0.12 µM to 1.29 µM. Docking simulations showed that PGG could tightly bound to the non-catalytic sites of various gmß-GUS, mainly via hydrogen bonding and aromatic interactions. It was also found that PGG could strongly inhibit the total gmß-GUS activity in mice feces, with the IC50 value of 1.24 µM. Collectively, our findings revealed that RCE and its constituent PGG could strongly inhibit multiple gmß-GUS enzymes, suggesting that RCE and PGG could be used for alleviating gmß-GUS associated enterotoxicity.

Expanded Azahelicenes with Large Dissymmetry Factors.

Expanded azahelicenes, as heteroanalogues of helically chiral helicenes, hold significant potential for chiroptical materials. Nevertheless, their investigation and research have remained largely unexplored. Herein, we present the facile synthesis of a series of expanded azahelicenes NHn (n=1-5) consisting of 11, 19, 27, 35, and 43 fused rings, mainly by Suzuki coupling followed by Bi(OTf)3-mediated cyclization of vinyl ethers. The structures of NH2, NH3 and NH4 were confirmed through X-ray crystallography analysis, and their (P)- and (M)- enantiomers were also isolated with chiral high performance liquid chromatography. The enantiomers exhibit large absorption (abs) and luminescence (lum) dissymmetry factors, with |gabs|max=0.044; |glum|max=0.003 for NH2, |gabs|max=0.048; |glum|=0.014 for NH3, and |gabs|max=0.043; |glum|max=0.021 for NH4, which are superior to their respective all-carbon analogues.

Unveiling Möbius/Hückel Topology and Aromaticity in A Core-Expanded [10]Annulene at Different Oxidation States.

The exploration of annulene's conformation, electronic properties and aromaticity has generated enduring interest over the years, yet it continues to present formidable challenges for annulenes with more than ten carbon atoms. In this study, we present the synthesis of a stable [10]cyclo-para-phenylmethine derivative (1), which bears a resemblance to [10]annulene. 1 can be readily oxidized into its respective cations, wherein electrons are effectively delocalized along the backbone, resulting in different conformations and aromaticity. Both 1 and its tetracation (14+ ⋅ 4SbF6 - ) exhibit a nearly planar conformation with a rectangular shape, akin to the E,Z,E,Z,Z-[10]annulene. In contrast, the radical cation (1⋅+ ⋅ SbCl6 - ) possesses a doubly twisted Hückel topology. Furthermore, the dication (12+ ⋅ 2SbCl6 - ) displays conformational flexibility in solution and crystalizes with the simultaneous presence of Möbius-twisted (1a2+ ⋅ 2SbCl6 - ) and Hückel-planar (1b2+ ⋅ 2SbCl6 - ) isomers in its unit cell. Detailed experimental measurements and theoretical calculations reveal that: (1) 1 demonstrates localized aromaticity with an alternating benzenoid/quinoid structure; (2) 1a2+ ⋅ 2SbCl6 - and 1b2+ ⋅ 2SbCl6 - with 48π electrons are weakly Möbius aromatic and Hückel antiaromatic, respectively; (3) 14+ ⋅ 4SbF6 - exhibits Hückel aromaticity (46π) and open-shell diradical character.

[2,2]Paracyclophane Bridged, Thiophene Based Macrocycles: Synthesis and Electronic Properties in Different Redox States.

The study of through-space electronic coupling in π-conjugated systems remains an underexplored area. In this work, we present the facile synthesis of two isomeric macrocycles (1 and 2) bridged by [2,2]paracyclophane (pCp) and based on thiophene. The structures of these macrocycles have been confirmed through X-ray crystallographic analysis. Our investigation centers on their electronic properties across various redox states, with a specific focus on potential through-space electronic coupling and global aromaticity. Experimental measurements, including UV-vis-NIR electronic absorption, NMR, ESR spectra, and X-ray diffraction, combined with theoretical calculations, reveal that both the neutral compounds and their tetracations exhibit a closed-shell ground state. However, their dications manifest as diradical dications with a subtle magnetic exchange interaction. Consequently, the through-space electronic coupling facilitated by the pCp unit in their respective ground states appears to be weak.

Evolution of SARS-CoV-2 Spikes shapes their binding affinities to animal ACE2 orthologs.

IMPORTANCE: Spike-receptor interaction is a critical determinant for the host range of coronaviruses. In this study, we investigated the SARS-CoV-2 WHU01 strain and five WHO-designated SARS-CoV-2 variants of concern (VOCs), including Alpha, Beta, Gamma, Delta, and the early Omicron variant, for their Spike interactions with ACE2 proteins of 18 animal species. First, the receptor-binding domains (RBDs) of Alpha, Beta, Gamma, and Omicron were found to display progressive gain of affinity to mouse ACE2. More interestingly, these RBDs were also found with progressive loss of affinities to multiple ACE2 orthologs. The Omicron RBD showed decreased or complete loss of affinity to eight tested animal ACE2 orthologs, including that of some livestock animals (horse, donkey, and pig), pet animals (dog and cat), and wild animals (pangolin, American pika, and Rhinolophus sinicus bat). These findings shed light on potential host range shift of SARS-CoV-2 VOCs, especially that of the Omicron variant.

Bis-peri-dinaphtho-rylenes: Facile Synthesis via Radical-Mediated Coupling Reactions and their Distinctive Electronic Structures.

Polycyclic aromatic hydrocarbons (PAHs) with a one-dimensional (1D), ribbon-like structure have the potential to serve as both model compounds for corresponding graphene nanoribbons (GNRs) and as materials for optoelectronics applications. However, synthesizing molecules of this type with extended π-conjugation presents a significant challenge. In this study, we present a straightforward synthetic method for a series of bis-peri-dinaphtho-rylene molecules, wherein the peri-positions of perylene, quaterrylene, and hexarylene are fused with naphtho-units. These molecules were efficiently synthesized primarily through intramolecular or intermolecular radical coupling of in situ generated organic radical species. Their structures were confirmed using X-ray crystallographic analysis, which also revealed a slightly bent geometry due to the incorporation of a cyclopentadiene ring at the bay regions of the rylene backbones. Bond lengh analysis and theoretical calculations indicate that their electronic structures resemble pyrenacenes more than quinoidal rylenes. That is, the aromatic sextets are predominantly localized along the long axis of the skeletones. As the chain length increases, these molecules exhibit enhanced electronic absorption with a bathochromic shift, and multiple amphoteric redox waves. This study introduces a novel synthetic approach for generating 1D extended PAHs and GNRs, along with their structure-dependent electronic properties.

Uncovering the anti-obesity constituents in Ginkgo biloba extract and deciphering their synergistic effects.

Obesity has been recognized as a key risk factor for multiple metabolic disorders, including diabetes, cardiovascular diseases and many types of cancer. Herbal medicines have been frequently used for preventing and treating obesity in many countries, but in most cases, the key anti-obesity constituents in herbs and their anti-obesity mechanisms are poorly understood. This study demonstrated a case study for uncovering the anti-obesity constituents in an anti-obesity herbal medicine (Ginkgo biloba extract) and deciphering their synergistic effects via targeting human pancreatic lipase (hPL). Following screening the anti-hPL effects of eighty herbal medicines, Ginkgo biloba extract (GBE50) was found with the most potent anti-hPL activity. Global chemical profiling of herbal constituents coupling with hPL inhibition assay revealed that the bioflavonoids and several flavonoids in GBE50 were key anti-hPL constituents. Among all tested thirty-eight constituents, sciadopitysin, bilobetin, quercetin, isoginkgetin, and ginkgetin showed potent anti-hPL effects (IC50 values <2.5 µM). Inhibition kinetic analyses suggested that sciadopitysin, bilobetin, quercetin, isoginkgetin, and ginkgetin acted as non-competitive inhibitors of hPL, with the Ki values were <2 µM. Docking simulations revealed that four bioflavonoids (sciadopitysin, bilobetin, isoginkgetin, and ginkgetin) could tightly bind on hPL at cavity 2, which it is different from the binding cavity of quercetin on hPL. Further investigations demonstrated that the combinations of quercetin and one bioflavonoid-type hPL inhibitor (sciadopitysin or bilobetin) showed synergistic anti-hPL effects, suggesting that the multi-components in GBE50 may generate more potent anti-hPL effect. Collectively, our findings uncovered the anti-obesity constituents in GBE50, and explored their anti-hPL mechanisms as well as synergistic effects at molecular levels, which will be very helpful for further understanding the anti-obesity mechanisms of Ginkgo biloba.

Human Carboxylesterase 1A Plays a Predominant Role in Hydrolysis of the Anti-Dyslipidemia Agent Fenofibrate in Humans.

Fenofibrate, a marketed peroxisome proliferator-activated receptor-α (PPARα) agonist, has been widely used for treating severe hypertriglyceridemia and mixed dyslipidemia. As a canonical prodrug, fenofibrate can be rapidly hydrolyzed to release the active metabolite (fenofibric acid) in vivo, but the crucial enzyme(s) responsible for fenofibrate hydrolysis and the related hydrolytic kinetics have not been well-investigated. This study aimed to assign the key organs and crucial enzymes involved in fenofibrate hydrolysis in humans, as well as reveal the impact of fenofibrate hydrolysis on its non-PPAR-mediated biologic activities. Our results demonstrated that fenofibrate could be rapidly hydrolyzed in the preparations from both human liver and lung to release fenofibric acid. Reaction phenotyping assays coupling with chemical inhibition assays showed that human carboxylesterase 1A (hCES1A) played a predominant role in fenofibrate hydrolysis in human liver and lung, while human carboxylesterase 2A (hCES2A) and human monoacylglycerol esterase (hMAGL) contributed to a very lesser extent. Kinetic analyses showed that fenofibrate could be rapidly hydrolyzed by hCES1A in human liver preparations, while the inherent clearance of hCES1A-catalyzed fenofibrate hydrolysis is much higher (>200-fold) than than that of hCES2A or hMAGL. Biologic assays demonstrated that both fenofibrate and fenofibric acid showed very closed Nrf2 agonist effects, but fenofibrate hydrolysis strongly weakens its inhibitory effects against both hCES2A and hNtoum. Collectively, our findings reveal that the liver is the major organ and hCES1A is the predominant enzyme-catalyzing fenofibrate hydrolysis in humans, while fenofibrate hydrolysis significantly reduces inhibitory effects of fenofibrate against serine hydrolases. SIGNIFICANCE STATEMENT: Fenofibrate can be completely converted to fenofibric acid in humans and subsequently exert its pharmacological effects, but the hydrolytic pathways of fenofibrate in humans have not been well-investigated. This study reported that the liver was the predominant organ and human carboxylesterase 1A was the crucial enzyme involved in fenofibrate hydrolysis in humans.

Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase.

Obesity is a growing global health problem and is associated with increased prevalence of many metabolic disorders, including diabetes, hypertension and cardiovascular disease. Pancreatic lipase (PL) has been validated as a key target for developing anti-obesity agents, owing to its crucial role in lipid digestion and absorption. In the past few decades, porcine PL (pPL) is always used as the enzyme source for screening PL inhibitors, which generate numerous pPL inhibitors but the potent inhibitors against human PL (hPL) are rarely reported. Herein, a series of salicylanilide derivatives were designed and synthesized, while their anti-hPL effects were assayed by a fluorescence-based biochemical approach. To investigate the structure-activity relationships of salicylanilide derivatives as hPL inhibitors in detail, structural modifications on three rings (A, B and C) of the salicylanilide skeleton were performed. Among all tested compounds, 2t and 2u were found possessing the most potent anti-PL activity, showing IC50 values of 1.86 µM and 1.63 µM, respectively. Inhibition kinetic analyses suggested that both 2t and 2u could effectively inhibit hPL in a non-competitive manner, with the ki value of 1.67 µM and 1.70 µM, respectively. Fluorescence quenching assays suggested that two inhibitors could quench the fluorescence of hPL via a static quenching procedure. Molecular docking simulations suggested that 2t and 2u could tightly bind on an allosteric site of hPL. Collectively, the structure-activity relationships of salicylanilide derivatives as hPL inhibitors were carefully investigated, while two newly identified reversible hPL inhibitors (2t and 2u) could be used as promising lead compounds to develop novel anti-obesity drugs.

Circumpentacene with Open-Shell Singlet Diradical Character.

Circumacenes (CAs) are a distinctive type of benzenoid polycyclic aromatic hydrocarbons where an acene unit is completely enclosed by a layer of outer fused benzene rings. Despite their unique structures, the synthesis of CAs is challenging, and until recently, the largest CA molecule synthesized was circumanthracene. In this study, we report the successful synthesis of an extended circumpentacene derivative 1, which represents the largest CA molecule synthesized to date. Its structure was confirmed by X-ray crystallographic analysis and its electronic properties were systematically investigated by both experiments and theoretical calculations. It shows a unique open-shell diradical character due to the existence of extended zigzag edges, with a moderate diradical character index (y0 =39.7 %) and a small singlet-triplet energy gap (ΔES-T =-4.47 kcal/mol). It exhibits a dominant local aromatic character with π-electrons delocalized in the individual aromatic sextet rings. It has a small HOMO-LUMO energy gap and displays amphoteric redox behavior. The electronic structures of its dication and dianion can be considered as doubly charged structures in which two coronene units are fused with a central aromatic benzene ring. This study provides a new route toward stable multizigzag-edged graphene-like molecules with open-shell di/polyradical character.

Laparoscopic versus open surgical management in elderly patients with rectal cancer aged 70 and older.

Background: This retrospective study aimed to compare the short- and long-term surgical outcomes of laparoscopic surgery versus open surgery in elderly patients with rectal cancer. Patients and Methods: Elderly patients (≥70 years old) with rectal cancer who received radical surgery were retrospectively analysed. Patients were matched (1:1 ratio) using propensity score matching (PSM), with age, sex, body mass index, American Society of Anesthesiologists score and tumour-node-metastasis staging included as covariates. Baseline characteristics, post-operative complications, short- and long-term surgical outcomes and overall survival (OS) were compared between the two matched groups. Results: Sixty-one pairs were selected after PSM. Patients with laparoscopic surgery had a longer duration of operation time, lower estimated blood loss, shorter duration of post-operative analgesics administered, time to first flatus, time to first oral diet and post-operative hospitalisation stay than those observed in patients with open surgery (All P < 0.05). The incidence of post-operative complications in the open surgery group was numerically higher than that occurred in the laparoscopic surgery group (30.6% vs. 17.7%). Median OS was 67.0 months (95% confidence interval [CI], 62.2-71.8) in the laparoscopic surgery group and 65.0 months (95% CI, 59.9-70.1) in the open surgery group, however, Kaplan-Meier curves indicated that no significant differences in OS (Log-rank test, P = 0.535) were noted between the two matched groups. Conclusions: Compared with the open surgery, laparoscopic surgery had the advantages of less trauma and faster recovery, and provided similar long-term prognostic outcome in elderly patients with rectal cancer.

Fused Indacene Dimers.

Polycyclic hydrocarbons consisting of two or more directly fused antiaromatic subunits are rare due to their high reactivity. However, it is important to understand how the interactions between the antiaromatic subunits influence the electronic properties of the fused structure. Herein, we present the synthesis of two fused indacene dimer isomers: s-indaceno[2,1-a]-s-indacene (s-ID) and as-indaceno[3,2-b]-as-indacene (as-ID), containing two fused antiaromatic s-indacene or as-indacene units, respectively. Their structures were confirmed by X-ray crystallographic analysis. 1 H NMR/ESR measurements and DFT calculations revealed that both s-ID and as-ID have an open-shell singlet ground state. However, while localized antiaromaticity was observed in s-ID, as-ID showed weak global aromaticity. Moreover, as-ID exhibited a larger diradical character and a smaller singlet-triplet gap than s-ID. All the differences can be attributed to their distinct quinoidal substructures.

Fused Triangulene Dimers: Facile Synthesis by Intramolecular Radical-Radical Coupling and Application for Near-Infrared Lasers.

Large graphene-like molecules with four zigzag edges are ideal gain medium materials for organic near-infrared (NIR) lasers. However, synthesizing them becomes increasingly challenging as the molecular size increases. In this study, we introduce a new intramolecular radical-radical coupling approach and successfully synthesize two fused triangulene dimers (1 a/1 b) efficiently. X-ray crystallographic analysis of 1 a indicates that there is no intermolecular π-π stacking in the solid state. When the more soluble derivative 1 b is dispersed in polystyrene thin films, amplified spontaneous emission in the NIR region is observed. Using 1 b as the active gain material, we fabricate solution-processed distributed feedback lasers that exhibit a narrow emission linewidth at around 790 nm. The laser devices also exhibit low thresholds with high photostability. Our study provides a new synthetic strategy for extended nanographenes, which have diverse applications in electronics and photonics.

Aromaticity in Fully π-Conjugated Multicyclic Macrocycles.

The research on aromaticity has mainly focused on monocyclic [n]annulene-like systems or polycyclic aromatic hydrocarbons. For fully π-conjugated multicyclic macrocycles (MMCs), the electronic coupling between the individual constitutional macrocycles would lead to unique electronic structures and aromaticity. The studies on MMCs, however, are quite limited, presumably due to the great challenges to design and synthesize a fully π-conjugated MMC molecule. Herein, we report the facile synthesis of two MMCs (2TMC and 3TMC) in which two and three thiophene-based macrocycles are fused together by employing both intramolecular and intermolecular Yamamoto coupling reactions of a properly designed precursor (7). The monocyclic macrocycle (1TMC) was also synthesized as a model compound. The geometry, aromaticity, and electronic properties of these macrocycles at different oxidation states were investigated by X-ray crystallographic analysis, NMR, and theoretical calculations, which disclosed how the constitutional macrocycles interplay with each other and lead to unique aromatic/antiaromatic character. This study provides new insights into the complex aromaticity in MMC systems.

A rationally engineered specific near-infrared fluorogenic substrate of human pancreatic lipase for functional imaging and inhibitor screening.

Obesity, now widespread all over the world, is frequently associated with several chronic diseases. Human pancreatic lipase (hPL) is a crucial digestive enzyme responsible for the digestion of dietary lipids in humans, and the inhibition of hPL is effective in reducing triglyceride intake and thus preventing and treating obesity. In this work, a practical sequential screening strategy was developed to construct a highly selective near-infrared fluorogenic substrate 7-STCFC for hPL. Under physiological conditions, 7-STCFC can be rapidly hydrolyzed by hPL to form 7-HTCFC, which triggers 254-fold NIR signal enhancement at 670 nm. 7-STCFC was successfully applied for the sensing and imaging of endogenous PL in living systems (including living cells, tissues and organs) with low cytotoxicity and high imaging resolution. Moreover, a high-throughput screening platform was established using 7-STCFC, and the inhibitory effects of 94 kinds of herbs toward hPL were evaluated. Among them, Pu-erh tea stood out with outstanding hPL inhibitory effects, and the inhibitory ingredients and involved inhibitory mechanism were further revealed, which strongly facilitates the discovery of novel anti-obesity agents targeting hPL. Collectively, these findings suggested that our strategy was practical to develop an isoform-specific fluorogenic substrate for a target enzyme, and 7-STCFC was a powerful tool for monitoring PL activity in complex biological systems with value for exploring physiological functions and rapid screening of inhibitors.

A Fused [5]Helicene Dimer with a Figure-Eight Topology: Synthesis, Chiral Resolution, and Electronic Properties.

Chiral shape-persistent molecular nanocarbons are promising chiroptical materials; their synthesis, however, remains a big challenge. Herein, we report the facile synthesis and chiral resolution of a double-stranded figure-eight carbon nanobelt 1 in which two [5]helicene units are fused together. Two synthetic routes were developed, and, in particular, a strategy involving Suzuki coupling-mediated macrocyclization followed by Bi(OTf)3 -catalyzed cyclization of vinyl ether turned out to be the most efficient. The structure of 1 was confirmed by X-ray crystallographic analysis. The isolated (P,P)- and (M,M)- enantiomers show persistent chiroptical properties with relatively large dissymmetric factors (|gabs |=5.4×10-3 and |glum |=1.0×10-2 ), which can be explained by the effective electron delocalization along the fully conjugated belt and the unique D2 symmetry. 1 exhibits local aromatic character with a dominant structure containing eight Clar's aromatic sextet rings.

Circumcoronenes.

Circumcoronene, a hexagonal graphene fragment with six zigzag edges, has been the focus of theoretical studies for many years, but its synthesis in solution has remained a challenge. In this study, we present a facile method for synthesizing three derivatives of circumcoronene using Brønsted/Lewis acid-mediated cyclization of vinyl ether or alkyne. Their structures were confirmed through X-ray crystallographic analysis. Bond length analysis, NMR measurement, and theoretical calculations showed that circumcoronene mostly follows Clar's bonding model and exhibits dominant local aromaticity. Its absorption and emission spectra are similar to those of the smaller hexagonal coronene due to its six-fold symmetry.

Facile Synthesis and Chiral Resolution of Expanded Helicenes with up to 35 cata-Fused Benzene Rings.

Expanded helicenes are expected to show enhanced chiroptical properties as compared to the classical helicenes but the synthesis is very challenging. Herein, we report the facile synthesis of a series of expanded helicenes Hn (n=1-4) containing 11, 19, 27 and 35 cata-fused benzene rings through Suzuki coupling-based oligomerization followed by Bi(OTf)3 -mediated regioselective cyclization of vinyl ethers. Their structures were determined by X-ray crystallographic analysis. Enantiopure H2, H3, and H4 can be isolated by chiral HPLC and they all exhibit strong chiroptical responses with high absorption dissymmetry factor (|gabs |) values (0.020 for H2, 0.021 for H3, and 0.021-0.024 for H4).

Small intestinal angiosarcoma on clinical presentation, diagnosis, management and prognosis: A case report and review of the literature.

BACKGROUND: Angiosarcoma is a highly malignant soft-tissue sarcoma derived from vascular endothelial cells that mainly occurs in the skin and subcutaneous tissues. Small-intestinal angiosarcomas are rare, and the prognosis is poor. CASE SUMMARY: We reported a case of primary multifocal ileal angiosarcoma and analyze previously reported cases to improve our understanding of small intestinal angiosarcoma. Small intestinal angiosarcoma is more common in elderly and male patients. Gastrointestinal bleeding, anemia, abdominal pain, weakness, and weight loss were the common symptoms. CD31, CD34, factor VIII-related antigen, ETS-related gene, friend leukemia integration 1, and von Willebrand factor are valuable immunohistochemical markers for the diagnosis of small-intestinal angiosarcoma. Small-intestinal angiosarcoma most commonly occurs in the jejunum, followed by the ileum and duodenum. Radiation and toxicant exposure are risk factors for angiosarcoma. After a definite diagnosis, the mean and median survival time was 8 mo and 3 mo, respectively. Kaplan-Meier survival analysis showed that age, infiltration depth, chemotherapy, and the number of small intestinal segments invaded by tumor lesions were prognostic factors for small intestinal angiosarcoma. Multivariate Cox regression analysis showed that chemotherapy and surgery significantly improved patient prognosis. CONCLUSION: Angiosarcoma should be considered for unexplained melena and abdominal pain, especially in older men and patients with a history of radiation exposure. Prompt treatment, including surgery and adjuvant chemotherapy, is essential to prolonging patient survival.

Aromaticity in Fully π-Conjugated Open-Cage Molecules.

Although aromaticity in 2D π-conjugated monocyclic and polycyclic molecules has been intensively studied, aromaticity in 3D fully π-conjugated molecular cages remains largely unexplored mainly due to the synthetic challenges. Herein, we report the facile synthesis of a π-conjugated molecular cage (1) containing four dimethylmethylene-bridged triphenylamine (DTPA) units via platinum-mediated assembly of four molecules of a pinacol borate trisubstituted DTPA derivative, followed by reductive elimination. 1 has an open-cage structure, consisting of two isomeric trimers in trans- and cis-configurations, and an additional macrocycle across four DTPA units. Accordingly, the trans- (2) and cis- (3) macrocyclic trimers were also synthesized for comparison. 1-3 can be facilely oxidized into their respective cations in which electrons are effectively delocalized at two or three dimensions. The detailed experimental measurements and theoretical calculations reveal that (1) the neutral cage 1 shows localized aromaticity in individual benzene rings; (2) the dication 12+·2SbF6- displays bicyclic (anti)aromaticity with one macrocycle being aromatic (38π) and another macrocycle being antiaromatic (28π); on the other hand, the dications of the model compounds 2 and 3 are globally antiaromatic and nonaromatic, respectively; (3) the tetracation 14+·4SbF6- exhibits dominant 2D Hückel antiaromaticity in one of the macrocycles (36π). In addition, 12+·2SbF6-, 14+·4SbF6-, and 22+·2SbF6- possess open-shell singlet ground state with significant diradical character, while 32+·2SbF6- adopts a triplet ground state to release strain.