Structure Revision of Type B Polycyclic Polyprenylated Acylphloroglucinols Fused to a Partly Reduced Furan Ring.

Four previous papers reported the isolation and structural determination of 10 polycyclic polyprenylated acylphloroglucinols (PPAPs), uraliones F, G, K, and O, attenuatumiones E and F, and scabrumiones A-D, from Hypericum species. Their structures were identified as type B PPAPs that featured not only the characteristic acyl group at C-3 of the bicyclo[3.3.1]nonane core but also a partly reduced furan ring fused to the C-1-C-2-O-2 atoms of the core. However, the 1D and 2D NMR data of these compounds were more consistent with type A PPAPs that featured not only the acyl group at C-1 but also a partially reduced furan ring fused to the C-3-C-2-O-2 atoms of the core. Now we revise these 10 previously proposed structures to the corresponding type A PPAPs via NMR analysis. Additionally, we propose a rule that uses NMR data to determine whether a particular PPAP that is fused to a partly reduced furan ring at C-3-C-2-O-2 or C-1-C-2-O-2 is type A or type B, respectively. We also propose a rule to assign the relative configurations of corresponding type A PPAPs at C-18 and revise the configurations of sampsonione N, hypericumoxides A-C, and hyperscabin G.

Programming hydrogel adhesion with engineered polymer network topology.

Hydrogel adhesion that can be easily modulated in magnitude, space, and time is desirable in many emerging applications ranging from tissue engineering and soft robotics to wearable devices. In synthetic materials, these complex adhesion behaviors are often achieved individually with mechanisms and apparatus that are difficult to integrate. Here, we report a universal strategy to embody multifaceted adhesion programmability in synthetic hydrogels. By designing the surface network topology of a hydrogel, supramolecular linkages that result in contrasting adhesion behaviors are formed on the hydrogel interface. The incorporation of different topological linkages leads to dynamically tunable adhesion with high-resolution spatial programmability without alteration of bulk mechanics and chemistry. Further, the association of linkages enables stable and tunable adhesion kinetics that can be tailored to suit different applications. We rationalize the physics of polymer chain slippage, rupture, and diffusion at play in the emergence of the programmable behaviors. With the understanding, we design and fabricate various soft devices such as smart wound patches, fluidic channels, drug-eluting devices, and reconfigurable soft robotics. Our study presents a simple and robust platform in which adhesion controllability in multiple aspects can be easily integrated into a single design of a hydrogel network.

Metamaterial adhesives for programmable adhesion through reverse crack propagation.

Adhesives are typically either strong and permanent or reversible with limited strength. However, current strategies to create strong yet reversible adhesives needed for wearable devices, robotics and material disassembly lack independent control of strength and release, require complex fabrication or only work in specific conditions. Here we report metamaterial adhesives that simultaneously achieve strong and releasable adhesion with spatially selectable adhesion strength through programmed cut architectures. Nonlinear cuts uniquely suppress crack propagation by forcing cracks to propagate backwards for 60× enhancement in adhesion, while allowing crack growth in the opposite direction for easy release and reusability. This mechanism functions in numerous adhesives on diverse substrates in wet and dry conditions and enables highly tunable adhesion with independently programmable adhesion strength in two directions simultaneously at any location. We create these multifunctional materials in a maskless, digital fabrication framework to rapidly customize adhesive characteristics with deterministic control for next-generation adhesives.

Total synthesis and structural reassignment of garcinielliptone FC, a polycyclic polyprenylated acylphloroglucinol with diverse bioactivity.

Garcinielliptone FC (GFC) was assigned to be a type A polycyclic polyprenylated acylphloroglucinol (PPAP) and was found to exhibit diverse biological activities. Now we revise the structure of GFC to xanthochymol, a type B PPAP, via NMR and total synthesis methods. The total syntheses of (±)-xanthochymol and (±)-cycloxanthochymol were accomplished in 12 and 13 steps, respectively.

Creasing in microscale, soft static friction.

Utilizing colloidal probe, lateral force microscopy and simultaneous confocal microscopy, combined with finite element analysis, we investigate how a microparticle starts moving laterally on a soft, adhesive surface. We find that the surface can form a self-contacting crease at the leading front, which results from a buildup of compressive stress. Experimentally, creases are observed on substrates that exhibit either high or low adhesion when measured in the normal direction, motivating the use of simulations to consider the role of adhesion energy and interfacial strength. Our simulations illustrate that the interfacial strength plays a dominating role in the nucleation of a crease. After the crease forms, it progresses through the contact zone in a Schallamach wave-like fashion. Interestingly, our results suggest that this Schallamach wave-like motion is facilitated by free slip at the adhesive, self-contacting interface within the crease.

Prenylated acylphloroglucinols from the fruits of Garcinia xanthochymus.

Our continuous study of the dry fruits of Garcinia xanthochymus led to the isolation and structural characterization of four new prenylated acylphloroglucinols, xanthochymusones J-M (1-4), together with the known polycyclic polyprenylated acylphloroglucinols, garciniagifolone A (5) and garcinialiptone A (6). Their structures were elucidated by interpretation of NMR and MS spectroscopic data. Compound 1 bearing a similar core to that of hulupinic acid should be derived via oxidization and ring contraction of prenylated acylphloroglucinol. The inhibitory activities of all the compounds against three human hepatocellular carcinoma cell lines Huh-7, Hep 3B, and Hep G2 were evaluated, and compounds 4 and 5/6 exhibited moderate cytotoxic activities against Hep G2 cells with IC50 values10.4 and 8.8 µM.

Polycyclic Polyprenylated Acylphloroglucinols Bearing a Lavandulyl-Derived Substituent from Garcinia xanthochymus Fruits.

Many type B polycyclic polyprenylated acylphloroglucinols (PPAPs) bear a lavandulyl-derived substituent, and the configurational assignment of this side chain can be difficult and sometimes leads to erroneous conclusions. In this study, 21 PPAPs, including the new xanthochymusones A-I (1-9), have been isolated from the fruits of Garcinia xanthochymus and structurally characterized. The relative configuration of the C-30 stereocenter was assigned by a combination of chemical transformations, 1H-1H coupling constants, conformational analysis, and NOE experiments. The configurational assignment of compound 7 indicates that the relative configuration at C-30 of PPAPs is not always the same. The absolute configurations of the new compounds were assigned by ECD and X-ray diffraction data, as well as by biosynthetic considerations. Analysis of NMR data enabled the configurational revision of garcicowins C and D. All the isolated PPAPs were tested for antiproliferative activity against three human hepatocellular carcinoma cell lines, including Huh-7, Hep 3B, and HepG2. Compounds 5 and 6, 7-epi-isogarcinol (16), and coccinone C (17) exhibited moderate antiproliferative activity. Compounds 6 and 16 induced apoptosis and inhibited cell migration in Huh-7 cells, probably through downregulating the STAT3 signaling pathway. This study provides effective methods for configurational assignments of type B PPAPs.

Anticarin-ß shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis.

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10% of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-ß that can specifically bind to and inhibit CCT4. Anticarin-ß shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-ß potently impedes CCT4-mediated STAT3 maturation. Anticarin-ß displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.

Tuberindine A, a Truffle Alkaloid with an Unprecedented Skeleton Exhibiting Anti-hyperuricemic Bioactivity.

Tuberindines A and B (1 and 2), truffle alkaloids with intriguing structures, were isolated from Tuber indicum and detected in other truffle species. They appear to arise biosynthetically from amino acid and isosaccharinic units. Compound 1 upregulated the expression of organic anion transporters OAT1 and ABCG2 and significantly exhibited antihyperuricemic bioactivity in vitro and in vivo, which might support the value of truffles as a dietary supplement.

C19 Benzylisoquinoline Alkaloid with Unprecedented Architecture from Hypecoum erectum.

Hyperectumine (1), the first C19 benzylisoquinoline alkaloid with a complicated ring system, was isolated from Hypecoum erectum and structurally characterized. Its biosynthetic origin should involve a hybrid pattern of C8 + C8 + C1 + C2, from which a C17 benzylisoquinoline alkaloid might be further attacked by a malonamic acid and undergo decarboxylation and cyclization to produce 1. Compound (-)-1 exhibited moderate anti-inflammatory activity via suppression of LPS-activated inflammatory mediators in RAW 264.7 macrophage cells.

Structural Revision of Hyperibrin B and Hyperscabrones H and I by Biosynthetic Considerations, NMR Analysis, and Chemical Synthesis.

Previously, Gao et al. reported the isolation and structural determination of three natural products, hyperibrin B (HB), hyperscabrone H (HH), and hyperscabrone I (HI), from Hypericum scabrum. HB and HH had different NMR spectroscopic data, but they were assigned identical structures. Furthermore, these compounds should be derived from bicyclic polyprenylated acylphloroglucinols (BPAPs) via degradation, but the assigned structural features of the prenyl and prenylmethyl groups being cis and meta-substituted on the cyclohexanone core were not consistent with their biosynthetic origin. In this note, we revise the structures of HB, HH, and HI via NMR and MS spectroscopic analyses and biosynthetic considerations. We also complete a total synthesis of the revised structure of HB as well as its analogue, hyperibrin A, to further confirm the revision. The revised structures of HB, HH, and HI have not been reported.

Stimulation Modulates Adhesion and Mechanics of Hydrogel Adhesives.

The ability to modulate the adhesion of soft materials on-demand is desired for broad applications ranging from tissue repair to soft robotics. Research effort has been focused on the chemistry and architecture of interfaces, leaving the mechanics of soft adhesives overlooked. Stimuli-responsive mechanisms of smart hydrogels could be leveraged for achieving stimuli-responsive hydrogel adhesives that respond mechanically to external stimuli. Such stimuli-responsive hydrogel adhesives involve complex chemomechanical coupling and interfacial fracture phenomena, calling for mechanistic understanding to enable rational design. Here, we combine experimental, computational, and analytical approaches to study a thermo-responsive hydrogel adhesive. Experimentally, we show that the adhesion and mechanical properties of a stimuli-responsive hydrogel adhesive are both enhanced by the application of a stimulus. Our analysis further reveals that the enhanced adhesion stems from the increased fracture energy of the bulk hydrogel and the insignificant residual stress on the adhesive-tissue interface. This study presents a framework for designing stimuli-responsive hydrogel adhesives based on the modulation of bulk properties and sheds light on the development of smart adhesives with tunable mechanics.

Antioxidant and Cytoprotective Effects of New Diarylheptanoids from Rhynchanthus beesianus.

Rhynchanthus beesianus (Zingiberaceae) has been an important food spice and vegetable in southern China. Fifteen phenolic compounds (1-15) including three new diarylheptanoids, rhynchanines A-C (1-3) and one new phenylpropanoid, 4-O-methylstroside B (9), were isolated from R. beesianus rhizomes. The structures of new compounds were elucidated by comprehensive analyses through NMR, HRMS technique, acid hydrolysis, and Mosher's reaction. Among them, compound 5 is the first isolated natural product and its NMR data are reported. Most of the isolated compounds, especially 3-6 and 8, showed significant antioxidant activities on DPPH, ABTS+ radical scavenging, and FRAP assays. Furthermore, the antioxidant phenolic compounds were evaluated for their cytoprotective capacity against H2O2-induced oxidative stress in HepG-2 cells. Compounds 3 and 5 could significantly inhibit reactive oxygen species production, and compounds 3, 5, and 6 could remarkably prevent the cell apoptosis. Then, the R. beesianus rhizome, which contained phenolic compounds, might serve as a functional food for potential application on preventing oxidative stress-connected diseases.

An integrated study on the pyrolysis mecanism of peanut shell based on the kinetic analysis and solid/gas characterization.

An in-depth understanding of peanut shell pyrolysis reaction is essential for its efficient utilization. Detailed analysis of thermodynamics, kinetics, and reaction products can provide valuable information about pyrolysis reaction. In this work, pyrolytic reaction mechanism was elucidated with the analysis of thermogravimetric-mass spectrometry and the structural characterization of the derived biochar. The thermodynamic and kinetic parameters of three sub-stages were matched well in different model-free methods. The positive ΔH and ΔG values indicated that the pyrolysis reactions for three stages were endothermic and nonspontaneous. The reaction mechanism predicted by integral master-plots were F3 (f(α) = (1-α)3), F1 (f(α) = (1-α), and F3 (f(α) = (1-α)3) for the three sub-stages, respectively. The negative ΔS in the third stage was related to the reduced releasing of low-molecular weight gases and ordered graphite-like carbon structure. This study provides a prospective approach to understand the pyrolysis mechanism of biomass.

Diverse isoquinolines with anti-inflammatory and analgesic bioactivities from Hypecoum erectum.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypecoum erectum has been used extensively in folk medicine to treat inflammation, fever, and pain. However, few investigations have been carried out on the biological activities related to its traditional use. The chemical constituents of this plant along with their anti-inflammatory and analgesic effects have yet to be revealed. AIM OF THE STUDY: This study aimed to support the traditional use of H. erectum by first assessing its anti-inflammatory and analgesic effects and then investigating its chemical constituents to identify any anti-inflammatory and/or analgesic compounds. MATERIAL AND METHODS: The in vivo anti-inflammatory and analgesic activities of the MeOH extract (ME), total alkaloid (AL), and non-alkaloid (Non-AL) fractions of H. erectum at doses of 200, 100, and 50 mg/kg and four major constituents (20, 21, 22, and 27) at doses of 100 and 50 mg/kg delivered via intragastrical administration were evaluated using carrageenan-induced paw edema and acetic acid-stimulated writhing animal models. A phytochemical study of the bioactive (AL) fraction was conducted using various chromatographic techniques, and the structures of the obtained isoquinolines were identified by multiple spectroscopic analyses and quantum chemical computations. Moreover, the anti-inflammatory activities of all the isolates were assessed in vitro based on the suppression of lipopolysaccharide-activated inflammatory mediators (COX-2, IL-1ß, and TNF-α) in RAW 264.7 macrophage cells. RESULTS: At the dose of 200 mg/kg, the three fractions (ME, AL, and Non-AL) of H. erectum ameliorated the paw edema by carrageenan-stimulated and reduced the number of writhing by acetic acid-induced in mice compared to the model group, with the AL fraction showing the most potent effects. Subsequent phytochemical investigation of the AL fraction led to the isolation of six new isoquinoline alkaloids (1-6) as well as 23 known analogues (7-29). However, compared to common isoquinolines, compounds 1-4 possess an additional nitrogen atom, while compound 5 has two additional nitrogen atoms. These additional atoms enrich the diversity of natural isoquinoline alkaloids. Further pharmacological evaluation in vivo revealed that the four major constituents (20, 21, 22, and 27) significantly relieved paw edema at 100 mg/kg, while protopine (20) and oxyhydrastinin (27) remarkably decreased the number of writhing at 100 mg/kg. In addition, most of the isolates displayed anti-inflammatory effects, as indicated by the inhibition of inflammatory mediators (COX-2, IL-1ß, and/or TNF-α) in vitro at a treatment concentration of 5 µg/mL. trans-benzindenoazepines (13), protopine (20), and 1,3,6,6-tetramethyl-5,6,7,8-tetrahyboisoquiolin-8-one (25) showed comparable anti-inflammatory activity to dexamethasone by inhibiting the secretion of IL-1ß. CONCLUSIONS: This investigation validated the traditional use of H. erectum by assessing its anti-inflammatory and analgesic effects. Phytochemical investigation revealed the diversity and novelty of the natural isoquinoline alkaloids in H. erectum. Four major isoquinolines were identified as the bioactive constituents of H. erectum. The findings provide scientific justification to support the traditional application of H. erectum for treating inflammatory and pain disorders.

Components and Persistent Free Radicals in the Volatiles during Pyrolysis of Lignocellulose Biomass.

Persistent free radicals (PFRs) may cause negative impacts to human health and the environment because of the induced reactive oxygen species. We expect that PFRs could be generated in the condensable volatiles formed during lignocellulose biomass pyrolysis. Elucidating the structural origin and the formation mechanism of PFRs is important for an in-depth understanding of air pollutants from the pyrolysis or combustion of lignocellulose biomass. This work selected rice straw and pine sawdust to represent agricultural and forest biomass residues. The pyrolysis mechanism, volatile components, and PFR generation were discussed based on the analysis of thermogravimetry-Fourier transform infrared spectroscopy-mass spectrometry (MS), pyrolysis-gas chromatography/MS, and electron spin resonance (ESR). Levoglucosan, furans, and 2-methoxyphenols were the main pyrolytic compounds for cellulose (CL), hemicellulose (HC), and lignin (LG), respectively. Obvious ESR signals were detected in the condensable volatiles of LG, while no ESR signals were detected for those of CL and HC. Higher ESR signals were detected in lignocellulose with a higher content of LG. Therefore, LG was the main structural basis to generate PFRs in lignocellulose condensable volatiles, mostly attributed to the methoxyphenol components. This study provides useful information regarding the generation mechanisms of and the structures related to PFRs, which is essential to understand the risks of lignocellulose pyrolytic volatiles.

"Kidney Tea" and Its Bioactive Secondary Metabolites for Treatment of Gout.

Clerodendranthus spicatus, popularly known as "kidney tea" in China, is consumed traditionally as a functional food for treatment of renal inflammation, dysuria, and gout. We evaluated the effects of C. spicatus on gout by assessing activities of antihyperuricemia, anti-gouty arthritis, and analgesia in vivo, and the results indicated that the ethyl acetate fraction shows potential activities. Subsequent phytochemical investigation of this fraction led to the isolation of 32 compounds, consisting of 20 diterpenoids (including the new orthosiphonones E and F), 2 triterpenoids, 6 flavonoids, 2 lignanoids, and 2 phenolic acid derivatives. Pharmacological investigation of the pure compounds in the cellular model of hyperuricemia indicated that 12 compounds could promote the excretion of uric acid at 10 µg/mL, and compounds 3, 4, 5, and 21 had better effects than that of benzbromarone, a famous uricosuric drug. Furthermore, compounds 4, 6, 7, 9, 14, 15, 23, 26, and 31 showed significant anti-gouty arthritis activity in monosodium urate (MSU)-induced joint swelling at the dose of 50 mg/kg, while compounds 4, 5, 7, 9, and 26 exhibited significant inhibition of pain induced by acetic acid. Our findings provided scientific justification to support the traditional application of "kidney tea" for treating gout and suggested its good application prospects in the future.

Anti-inflammatory and analgesic activities of Neolamarckia cadamba and its bioactive monoterpenoid indole alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Neolamarckia cadamba has been used traditionally to treat inflammation, fever, and pruritus in the Dai ethnopharmacy in Yunnan province, P.R. China. However, according to literature survey, the action basis of anti-inflammatory and analgesic activities of this plant were rarely reported, which accounts for the original intentions of this investigation. AIM OF THE STUDY: The study aimed to investigate the anti-inflammatory and analgesic action of methanolic extract (ME), ethyl acetate (EA), and aqueous (AQS) fractions of N. cadamba and further explore the accurate compounds responsible for the activities of EA fraction. MATERIALS AND METHODS: The in vivo anti-inflammatory and analgesic activities of ME, EA, and AQS fractions at the doses of 200 and 400 mg/kg and two major constituents (compounds 5 and 7) at 50 and 100 mg/kg via intragastrically administrated, respectively, were evaluated by carrageenan-induced paw edema and acetic acid-stimulated writhing animal models. Aspirin (ASP) was used as the positive control at the dose of 200 mg/kg. The monoterpenoid indole alkaloids (MIAs) in EA fraction were phytochemically studied utilizing chromatographic techniques, and their structures and absolute configurations were established on the basis of multiple spectroscopic analyses and quantum computational chemistry method. Moreover, the in vitro anti-inflammatory activities of all the isolates were assessed by suppressing releases of LPS-activated inflammatory mediators (TNF-α, IL-1ß, and COX-2) in RAW 264.7 macrophage cells at a concentration of 10 µg/mL. Dexamethasone (DXM) was used as the positive control. RESULTS: Three fractions (ME, EA, and AQS) significantly ameliorated the paw edema caused by carrageenan and reduced the number of writhing induced by acetic acid in comparison to the control group at the doses of 200 and/or 400 mg/kg (in vivo). Subsequent phytochemical investigation of EA fraction led to the structural characterization of four new monoterpenoid indole alkaloids, neocadambines A-D (1-4), as well as eight known analogues (5-12). Neocadambine A possesses a novel 14-nor-MIA skeleton that could be derived from the corynantheine-type MIAs via oxidative cleavage of C3-C14 bond and subsequently degradation of C14. Moreover, the structure of a bioactive known MIA, cadambine acid (6), was reassigned by analysis of its NMR spectroscopic data. Further biological assays revealed that the major constituent 3ß-dihydrocadambine (7) significantly relieved the paw edema and decreased the number of writhing at 100 mg/kg in vivo. In addition, most of the isolates displayed remarkable in vitro anti-inflammatory effects by inhibiting the secretion of aforementioned inflammatory mediators (COX-2, IL-1ß, and TNF-α) at a concentration of 10 µg/mL, and compounds 4, 7, and 9 showed better anti-inflammatory effects than that of positive control, dexamethasone. CONCLUSIONS: This study further validated the anti-inflammatory and analgesic activities of N. cadamba, and revealed that monoterpenoid indole alkaloids could partly contribute to the efficacy of this ethnodrug. The major constituent 3ß-dihydrocadambine (7) showed significant anti-inflammatory activities both in vitro and in vivo, which suggested that it could be a promising anti-inflammatory lead compound. Our findings provided scientific justification to support the traditional application of N. cadamba for treating inflammatory and nociceptive disorders.

Structural Revision of Garcinielliptin Oxide and Garcinielliptone E.

Previously, Lin et al. reported the isolation and structural determination of two triterpenoids, garcinielliptin oxide (GO) and garcinielliptone E (GE). Their unusual structural features, which remained unparalleled in subsequent decades despite the intervening discovery of hundreds of other polycyclic polyprenylated acylphloroglucinols (PPAPs), caused us to question the originally assigned structures, so GO was reisolated from Garcinia subelliptica, and its NMR spectra were reacquired. In this Note, we revise the structures of GO and the related GE via NMR analysis, biosynthetic considerations, and chemical conversion. Garcinielliptone T, a new PPAP, was also isolated and characterized. GO exhibited weak inhibitory activity against acetylcholinesterase with an IC50 value of 20.7 µM.

Cytotoxic androstane derivatives from Sarcococca ruscifolia.

Sarcorusones A-D (1-4), four new androstane (C19-steroid) derivatives were characterized from Sarcococca ruscifolia along with five known compounds. Their structures were elucidated on the basis of extensive MS and NMR spectroscopic analysis. All the new structures share common 14-hydroxyl and 17-ketone functional groups, and compounds 2-4 feature a seneciamide group connecting to C-3 position. The inhibitory activities of all the isolates against melanoma cell B16F10 and lung cancer cell H1299 were evaluated, and compounds 2, 3, 5, and 6 exhibited moderate cytotoxic activities against B16F10 and H1299 cell lines with IC50 values 2.7-8.0 µM.