Polycyclic Compounds Research Articles

Liquidambaric lactone is a potent inhibitor of TRAF2 for cancer therapy

BackgroundTumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an oncogenic regulator of Wnt/β-catenin signaling in colon cancer. Previously we have reported a pentacyclic triterpenoid compound liquidambaric acid (LDA) inhibiting Wnt/β-catenin signaling via targeting TRAF2, however, LDA inhibition of cancer cells was observed only at high doses. It is important to identify small molecules targeting TRAF2 in colon cancer with higher potency . MethodsMicroscale thermophoresis (MST) assay was used to screen a panel of pentacyclic triterpenoids. Cellular thermal shift assay (CETSA) was used to confirm target engagment in living cells. Drug affinity responsive target stability (DARTS) coupled with mass spectrometry (MS) was used to identify the potential targets of candidate TRAF2 binder. Wnt signaling inhibition was evaluated by 7TGC reporter assay, TOPFlash assay, reverse transcription and real-time quantitative PCR, as well as zebrafish eyeless assay. Cancer inhibition was assessed by cell viability assay, colony formation assay and xenograft studies. CRISPR/Cas9 knockout HCT116 cells was used to assess the requirement of TRAF2 for liquidambaric lactone (LDL) inhibition of cancer. ResultsA LDA analogue LDL selectively targeted TRAF2 with higher binding affinity. Both LDL and LDA targeted the TRAF-C domain of TRAF2 with slightly different binding sites. Of note, LDL showed much stronger inhibition of colon cancer cells than LDA in colony formation assay. LDL inhibition of cancer was also comfirmed in xenograft mice. Depletion of TRAF2 totally blocked LDL inhibition of Wnt signaling, TNF signaling and growth of cancer cells. ConclusionsA natural product LDL is a potent inhibitor of TRAF2 for cancer therapy, and TRAF2 is required for LDL inhibition of cancer.

Domino protocol for the synthesis of diversely functionalized derivatives of a novel fused pentacyclic antioxidant/anticancer fluorescent scaffold: Pyrazolo[5'',1'':2',3']pyrimido[4',5':5,6][1,4]thiazino[2,3-b]quinoxaline

Rising to the challenge of formidable multi-step reaction needed for the synthesis of polycyclic compounds, an efficient one-pot two-step procedure for the synthesis of densely functionalized novel pyrazolo[5″,1'':2′,3']pyrimido[4′,5':5,6] [1,4]thiazino[2,3-b]quinoxalines from synthetically accessible starting materials 6-bromo-7-chloro-3-cyano-2-(ethylthio)-5-methylpyrazolo[1,5-a]pyrimidine, 3-aminoquinoxaline-2-thiol and some readily accessible alkyl halides was established. The domino reaction pathway involves cyclocondensation/N-alkylation sequence in K2CO3/N,N-dimethyl formamide under heating condition. DPPH free radical scavenging activity of all synthesized pyrazolo[5″,1'':2′,3']pyrimido[4′,5':5,6][1,4]thiazino[2,3-b]quinoxalines was evaluated to determine their antioxidant potentials. IC50 values were recorded in the range of 29–71 μM. N-benzyl substituted derivative represented the most effective antioxidant activity as well as antiproliferative activity against MCF-7 cells. Moreover, fluorescence in solution for these compounds exhibited strong red emission in the visible region (λflu. = 536–558 nm) with good to excellent quantum yields (61–95%). Due to their interesting fluorescence properties, these novel pentacyclic fluorophores can be used as fluorescent markers and probes for studies in biochemistry and pharmacology.

Synthesis and Characterization of a Rhenanaphthalene Isomer.

Exploration of organometallic metallacycles has led to the development of various polycyclic compouds with fascinating structures, which could be used as functional materials. In this work, a new rhenanaphthalene isomer was isolated from the reaction of ReH5(PMe2Ph)3 with o-ethynylphenyl alkyne in the presence of excess HCl. Its structure was then identified using the single-crystal X-ray diffraction and NMR spectroscopy. DFT studies suggest that its formation involves two protonation reactions and two migration reactions. This new rhenanaphthalene isomer enriches the family of metallacycles.

The Design, Synthesis and Application of Nitrogen Heteropolycyclic Compounds with UV Resistance Properties.

Exposure to ultraviolet (UV) light is known to cause skin aging, skin damage, cancer, and eye diseases, as well as polymer material aging. Therefore, significant attention has been devoted to the research and development of UV absorbers. Considering the robust hydrogen bonding and conjugated structure present in nitrogen-containing polycyclic compounds, these compounds have been selected as potential candidates for exploring ultraviolet absorption properties. After structural optimization and the simulation of ultraviolet absorption spectra, four tris-[1,2,4]-triazolo-[1,3,5]-triazine (TTTs) derivatives, namely TTTB, TTTD, TTTJ, and TTTL, were selected as the preferred compounds and synthesized. The structure of the compound was determined using various analytical techniques, including FTIR, 1HNMR, 13CNMR, HRMS, and XRD. Subsequently, composite films of polyvinyl chloride (PVC) and TTTs were produced using a simple solvent casting technique. The PVC films were subjected to UV age testing by exposing them to an ultraviolet aging chamber. The age-resistant performance of the fabricated films was evaluated using an ultraviolet spectrophotometer and Fourier infrared spectrum instrument. The findings suggest that TTTs exhibit a noteworthy capacity for absorbing ultraviolet radiation. The TTTL compound exhibits a superior UV absorption performance compared to commercially available UV absorbers such as UV-0 and UV-327 in the market.

Radical Cascade Cyclization of Alkene‐Tethered Compounds: Versatile Approach towards Ring‐Fused Polycyclic Structures

AbstractRing‐fused polycyclic structures widely exist in a myriad of natural products and pharmaceutical molecules. Consequently, the construction of such structures from readily available substrates becomes an important researching topic in organic synthesis. Triggered by the addition of radicals to the (activated or unactivated) double bonds in alkenes, the subsequent intramolecular addition/cyclization leads to polycyclic compounds. Following this procedure, a variety of functionalized ring‐fused structures were formed. Great achievements have been witnessed recently. Those works provided efficient, atom economy, and operational simple approaches toward versatile functionalized polycyclic structures from readily available alkene‐based substrates. Here, we summarized the recent achievements on the formation of ring‐fused polycyclic structures via the radical‐triggered cascade reactions of alkenes. Construction of polycyclic structures with no less than 3 fused rings developed during the last decade were included in this Review, corresponding mechanisms were also discussed.

Ursolic Acid against Prostate and Urogenital Cancers: A Review of In Vitro and In Vivo Studies.

Prostate cancer is the second most diagnosed form of cancer in men worldwide and accounted for roughly 1.3 million cases and 359,000 deaths globally in 2018, despite all the available treatment strategies including surgery, radiotherapy, and chemotherapy. Finding novel approaches to prevent and treat prostate and other urogenital cancers effectively is of major importance. Chemicals derived from plants, such as docetaxel and paclitaxel, have been used in cancer treatment, and in recent years, research interest has focused on finding other plant-derived chemicals that can be used in the fight against cancer. Ursolic acid, found in high concentrations in cranberries, is a pentacyclic triterpenoid compound demonstrated to have anti-inflammatory, antioxidant, and anticancer properties. In the present review, we summarize the research studies examining the effects of ursolic acid and its derivatives against prostate and other urogenital cancers. Collectively, the existing data indicate that ursolic acid inhibits human prostate, renal, bladder, and testicular cancer cell proliferation and induces apoptosis. A limited number of studies have shown significant reduction in tumor volume in animals xenografted with human prostate cancer cells and treated with ursolic acid. More animal studies and human clinical studies are required to examine the potential of ursolic acid to inhibit prostate and other urogenital cancers in vivo.

Effect of Sub- and Supercritical Water on the Transformation of High-Molecular-Mass Components of High-Carbon Rocks from Unconventional Formations (A Review)

State-of-the-art in the field of recovering high-molecular-mass hydrocarbon components of bituminous and shale rocks by intrastratum transformation into readily recoverable forms using sub- and supercritical water is analyzed. The phase composition of water and its properties in the critical state and the transformations of a number of substances in subcritical (SBW) and supercritical (SCW) water are discussed. The substances under consideration include model polycyclic and heteroatomic compounds containing nitrogen, sulfur, and oxygen, metal porphyrin complexes, asphaltenes, oil sands, and heavy oils and organic matter (OM) of kerogen-containing shale rocks. The preventing effect of hydrogen donors and catalysts for hydrogenation and oxidative cracking on the coking in the course of transformation of heavy hydrocarbons in SCW is compared. The catalytic effect of the mineral matrix of rocks in the course of generation of oil fractions from them is analyzed in detail. The published data concerning the possibility of using SBW and SCW for the transformation of high-molecular-mass components of high-carbon dense rocks from unconventional formations demonstrate high potential of hydrothermal and supercritical fluid technologies

Polycyclic High-Density Cage Compounds via Cross Metathesis

AbstractThe synthesis of various highly functionalized caged systems suitable as high energy density materials, which were assembled by utilization of an olefin cross-metathesis strategy, is reported. E-Selectivity was observed during the cross-metathesis by using Grubbs second generation catalyst (G-II) and N-tolyl Grubbs catalyst in most of the cross-metathesis products. The stereochemistry of the olefin formed during the cross-metathesis has been determined unambiguously by a single-crystal X-ray diffraction study.

Suppression of SIRT1/FXR signaling pathway contributes to oleanolic acid-induced liver injury

Oleanolic acid (OA) is a pentacyclic triterpenoid compound used clinically for acute and chronic hepatitis. However, high dose or long-term use of OA causes hepatotoxicity, which limits its clinical application. Hepatic Sirtuin (SIRT1) participates in the regulation of FXR signaling and maintains hepatic metabolic homeostasis. This study was designed to determine whether SIRT1/FXR signaling pathway contributes to the hepatotoxicity caused by OA. C57BL/6J mice were administered with OA for 4 consecutive days to induce hepatotoxicity. The results showed that OA suppressed the expression of FXR and its downstream targets CYP7A1, CYP8B1, BSEP and MRP2 at both mRNA and protein levels, breaking the homeostasis of bile acid leading to hepatotoxicity. However, treatment with FXR agonist GW4064 noticeably attenuated hepatotoxicity caused by OA. Furthermore, it was found that OA inhibited protein expression of SIRT1. Activation of SIRT1 by its agonist SRT1720 significantly improved OA-induced hepatotoxicity. Meanwhile, SRT1720 significantly reduced the inhibition of protein expression of FXR and FXR-downstream proteins. These results suggested that OA may cause hepatotoxicity through SIRT1 dependent suppression of FXR signaling pathway. In vitro experiments confirmed that OA suppressed protein expressions of FXR and its targets through inhibition of SIRT1. It was further revealed that silencing of HNF1α with siRNA significantly weakened regulatory effects of SIRT1 on the expression of FXR as well as its target genes. In conclusion, our study reveals that SIRT1/FXR pathway is crucial in OA-induced hepatotoxicity. Activation of SIRT1/HNF1α/FXR axis may represent a novel therapeutic target for ameliorating OA and other herb-induced hepatotoxicity.

Lithium-Mediated Mechanochemical Cyclodehydrogenation

Cyclodehydrogenation is an essential synthetic method for the preparation of polycyclic aromatic hydrocarbons, polycyclic heteroaromatic compounds, and nanographenes. Among the many examples, anionic cyclodehydrogenation using potassium(0) has attracted synthetic chemists because of its irreplaceable reactivity and utility in obtaining rylene structures from binaphthyl derivatives. However, existing methods are difficult to use in terms of practicality, pyrophoricity, and lack of scalability and applicability. Herein, we report the development of a lithium(0)-mediated mechanochemical anionic cyclodehydrogenation reaction for the first time. This reaction could be easily performed using a conventional and easy-to-handle lithium(0) wire at room temperature, even under air, and the reaction of 1,1'-binaphthyl is complete within 30 min to afford perylene in 94% yield. Using this novel and user-friendly protocol, we investigated substrate scope, reaction mechanism, and gram-scale synthesis. As a result, remarkable applicability and practicality over previous methods, as well as limitations, were comprehensively studied by computational studies and nuclear magnetic resonance analysis. Furthermore, we demonstrated two-, three-, and five-fold cyclodehydrogenations for the synthesis of novel nanographenes. In particular, quinterrylene ([5]rylene or pentarylene), the longest nonsubstituted molecular rylene, was synthesized for the first time.

Comparative assessment of liquid product from hydrothermal treatment of lignosulfonate in batch and nozzle reactors for aromatic compounds recovery

Lignosulfonate is one of the main by-products of the pulping process, with enormous potential for application as an alternative source of aromatic and bioactive compounds, especially in a closed-loop Circular Economy Concept. The lignin-derived bioactive compounds have attracted enormous interest in the scientific community due to their positive effects on human health. In the present paper, hydrothermal treatment technologies of the 10 wt% and 20 wt% lignosulfonate solutions i.e., slow HTL in batch reactor and fast HTL in continuous-flow (CF) reactor, are compared, and discussed, to assess their potential for obtaining bioactive and aromatic compounds. The hydrothermal liquefaction (HTL) in the two reactors was carried out at 275 °C at a pressure of 21.4 MPa, a 1:3 feed-to-water ratio. GC-MS and LC-MS-QTOF analyses were used to determine the chemical composition of the liquid products. According to the chromatogram integrated peak areas (PA), the fast HTL of the lignosulfonate produced the most isoeugenol (35.8–49.2%), eugenol (10.4–16.9%), and homovanillyl alcohol (13.8–18.4%). Slow HTL product, on the other hand, was rich in guiacol (62%) and apocynin (19.7%). LC-MS analysis of the product showed a similar composition to the liquid product in terms of heaviest compounds. Observed m/z values in the chromatograms indicated a presence of the compounds with masses between 121.159 and 934.021 u, possible configurations of the polycyclic phenolic compounds are presented.

Regiodivergent catalytic asymmetric dearomative cycloaddition of bicyclic heteroaromatics.

The catalytic dearomative cycloaddition of bicyclic heteroaromatics including benzofurans and indoles provides rapid access to functionalized heterocyclic molecules. Because of the inherent stereoelectronic differences, the furan or pyrrole nucleus is more prone to dearomative cycloaddition than the benzene ring. Here, we realized a geometry-based differentiation approach for achieving C6-C7 and C7-C7a regioselectivity. The rotationally restricted σ bond at C7 position respectively placed the C6-C7 and C7-C7a sites of benzofurans or indoles in an optimal spatial orientation toward the axially chiral heterodiene, thus affording two enantioenriched polycyclic compounds from a single racemic heterobiaryl atropisomers. Calculation results of density functional theory interpreted the mechanism of this parallel kinetic resolution. The bioactivity of the dearomatized products was evaluated in cancer cell lines with certain compounds exhibiting interesting biological activities.

Potential Role of Oleanolic and Ursolic Acids from Food and Plant Materials as Natural Ingredients for the Cosmetic Industry: A Review

Cosmeceuticals have emerged as health and beauty aid products that integrate active ingredients from natural sources. Phytochemicals have prevailed in this market as an effective alternative toward different skin conditions. This is mainly due to the increasing demand for natural products that overcome the side effects of conventional treatments. Alopecia, acne, and skin aging are prevalent skin-related conditions worldwide. These conditions are characterized by high levels of inflammatory biomarkers and oxidative stress conditions. Oleanolic and ursolic acids are two biologically active pentacyclic triterpenoid isomeric compounds. They have shown strong potential for the prevention and treatment of diverse skin-related conditions through their effective antioxidant and anti-inflammatory capacity. This review presents the latest available information on the biological potential of oleanolic and ursolic acids, highlighting their cosmeceutical potential. In the pursuit of a better understanding of their potential as natural ingredients of dermatological relevance, graphical analysis is provided to propose the molecular mechanisms involved in the effects of each skin-related condition.

Rediscovery of Tetronomycin as a Broad-Spectrum and Potent Antibiotic against Drug-Resistant Gram-Positive Bacteria.

Tetronomycin (1), first isolated from a cultured broth of Streptomyces sp. by Juslen et al. in 1974, is a polycyclic polyether compound. However, the biological activity of 1 has not been thoroughly examined. In this study, we found that 1 exhibits more potent antibacterial activity than two well-known antibacterial drugs (vancomycin and linezolid) and is effective against several drug-resistant clinical isolates including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. Furthermore, we reassigned the 13C NMR spectra of 1 and performed a preliminary structure-activity relationship study of 1 to synthesize a chemical probe for target identification, which implied different targets based on its ionophore activity.

Investigation on selective separation of oxygen-containing compounds in lignite and sub-bitumite

To realize the high value-added utilization of low-rank coal and elucidate the selectivity of solvent structure and oxygen-containing compounds in low-rank coal, Zhaotong (ZT) lignite and Naomaohu (NMH) sub-bitumite were subjected to thermal dissolution in three types of oxygen-containing solvents with different properties, namely ethanol (ET), tetrahydrofuran (THF) and ethyl acetate (EA). The soluble portions (SPs) obtained were separated by column chromatography into three types of fractions: hydrocarbon (HY), non-hydrocarbon (NHY) and asphaltene (ASP). The results indicated that the yields of SPs in all three solvents for each coal was ET > THF > EA, and the ratios of column chromatographic fractions of SPs of the two coals were significantly different, with lower asphaltene content in the SPs of NMH. The thermal dissolution process of the three solvents significantly reduced the oxygen content of low-rank coal, and the deoxygenation capacity was in the order of ET > THF > EA. More medium or low polarity compounds could be obtained from NMH than from ZT through thermal dissolution process. ET showed excellent selectivity for the generation of both phenols and esters, where the phenols were mainly alkylphenols. THF could release highly condensed polycyclic compounds from coal thus more naphthalenols containing substituent groups were detected in phenols. And it was more selective to COO bonds in NMH than ZT from the results of XPS. More esters were detected in the SPs of NMH compared with ZT. EA had a strong selectivity for CO in low-rank coals, and the thermal dissolution process released a large number of esters, which could be divided into alkanoates and aromatic acid esters. This study can provide a theoretical basis for extracting high value-added chemicals from low-rank coal under mild conditions.

Visible-Light-Induced 1,7-Enyne Dicyclization: Synthesis of Ester-Substituted Benzo[j]phenanthridines.

A novel alkoxycarbonyl-radical-triggered cascade cyclization of 1,7-enynes, with alkyloxalyl chlorides as the ester units, for the synthesis of benzo[j]phenanthridines is described. The reaction conditions exhibit excellent compatibility with a broad range of alkoxycarbonyl radical sources and realize the installation of an ester group in the polycyclic compound. This radical cascade cyclization reaction features excellent functional group tolerance, mild reaction conditions, and good to excellent yields.

Sea Ice Melting Drives Substantial Change in Dissolved Organic Matter in Surface Water off Prydz Bay, East Antarctic

AbstractPolar ecosystems are vulnerable to climate warming and are characterized by a rapid decline in sea ice. In this study, we collected surface water samples from the Southern Ocean off Prydz Bay during and after sea ice melting season (SIM). After removing the particles using 0.7‐μm pore size filters, we measured the concentration of dissolved organic carbon (DOC) and the composition of dissolved organic matter (DOM) by using the total organic carbon analyzer, optical spectrometry, and high‐resolution mass spectrometry. The mean DOC concentration during the SIM is 1.3‐fold higher than that during the post‐SIM, whereas the a350 value, an indicator of chromophoric DOM, showed the opposite trend by a factor of 2.8. Five components, including three humic‐like and two protein‐like substances were identified by fluorescence excitation emission matrices‐parallel factor analysis, in which protein‐like biolabile components were enriched during the SIM and humic‐like refractory components were enriched during the post‐SIM. The DOM in the water samples from the SIM had higher proportions of polycyclic aromatics, polyphenols, and compounds within molecular lability boundary, whereas the DOM from the post‐SIM had a higher proportion of highly unsaturated compounds. Statistical analysis revealed significant correlations between DOM and sea‐ice melting/associated environmental factors (e.g., water temperature, salinity, and microbial activity). These collective results suggest that sea ice melting is an important factor driving a transition from more labile to more refractory DOM in the surface water off Prydz Bay, which may have a profound impact on the marine ecosystem and carbon cycle in the polar ocean.

C-O Coupling/[4+2] Cycloaddition Tandem Reactions via Oxidative Dearomatization of BINOLs: Access to Bridged Polycyclic Compounds.

Intramolecular C-H activation/C-O coupling, dearomatization, and [4+2] cycloaddition of BINOL units have been well developed in a one-pot approach with maleimide derivatives as the dienophiles. This tandem catalytic system generates a variety of functionalized bridged polycyclic products in a step-economical manner, which greatly enriches the modification methods and strategies for the BINOL skeletons.

(2R,6′R,E)-3′-(1-Aminoethylidene)-7-chloro-4,6-dimethoxy-6′-methyl-3H-spiro[benzofuran-2,1′-cyclohexane]-2′,3,4′-trione

A novel synthesis approach for griseofulvin derivatives was developed. The presented method is based on a two-stage process that includes preliminary acetylation of griseofulvic acid followed by condensation with ammonium acetate. The advantages of this protocol include readily available starting materials and a simple target product isolation procedure. The structure of the synthesized polycyclic compound was approved by 1H, 13C-NMR spectroscopy, high-resolution mass spectrometry with electrospray ionization (ESI-HRMS), and X-ray diffraction.

Kinetic Model and Mechanism of Heterogeneous Hydrogenation of Strained Polycyclic Compounds Derived from 5-Vinyl-2-norbornene

The main pathways of liquid-phase hydrogenation of 5-ethenylbicyclo[2.2.1]hept-2-ene (5-vinyl-2-norbornene, VNE) in the presence of PK-25 palladium catalyst (Pd/γ-Al2O3, 0.25% Pd) were studied. All the reaction products were identified, and the material balance was examined. The effect of the prevalent adsorption of the norbornene double bond on the Pd active site (AS) was confirmed. The parallel-consecutive scheme of the process mechanism, based on the set of experimental and theoretical data, was suggested. It involves the successive substrate hydrogenation and significant role of the isomerization of the vinyl group into the ethylidene group in intermediates on AS in a hydrogen atmosphere. The reaction is zero-order in a wide interval of initial VNE concentrations. An adequate kinetic model of the process, based on the Langmuir–Hinshelwood approach and the concept of multiple adsorption of substrates on one AS, was developed. Five steps, including two parallel steps, significantly contribute to the reaction rate. Their rate constants and the adsorption constants of AS complexes with unsaturated compounds were estimated.