Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway.

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as ß-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

Semisynthesis and antitumor activity of endertiin B and related triterpenoids from Ganoderma lucidum.

Ganoderma lucidum, a fungus used in traditional Chinese medicine, is known for its medicinal value attributed to its active components called Ganoderma triterpenoids (GTs). However, the limited isolation rate of these GTs has hindered their potential as promising drug candidates. Therefore, it is imperative to achieve large-scale preparation of GTs. In this study, four GTs were effectively synthesised from lanosterol. The antitumor activity of these GTs was evaluated in vivo. Endertiin B exhibited potent inhibitory activity against breast cancer cells (9.85 ± 0.91 µM and 12.12 ± 0.95 µM). Further investigations demonstrated that endertiin B significantly upregulated p21 and p27 and downregulated cyclinD1 expression, arresting the cell cycle at the G0/G1 phase and inducing apoptosis by decreasing BCL-2 and increasing BAX and BAK levels. Additionally, endertiin B was found to reduce the expression of proteins associated with the PI3K-AKT signaling pathway. To summarize, endertiin B effectively inhibited cell proliferation by blocking the cell cycle and inducing apoptosis through the PI3K-AKT pathway.

Total Synthesis of Pallamolides A-E.

We have achieved the first total synthesis of pallamolides A-E. Of these compounds, pallamolides B-E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael addition reactions to construct the bicyclo[2.2.2]octane core with the simultaneous generation of two quaternary carbon centers, a one-pot SmI2-mediated intramolecular ketyl-enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid-mediated deprotection/oxa-Michael addition/ß-hydroxy elimination cascade sequence to assemble the tetracyclic pallamolide skeleton. Kinetic resolution of ketone 14 through Corey-Bakshi-Shibata reduction enabled the asymmetric synthesis of pallamolides A-E.

Bioinspired Total Synthesis of Bipolarolides A and B.

We have achieved the first total synthesis of bipolarolides A and B, which possess an intriguing and complex 5/6/6/6/5 caged pentacyclic skeleton with seven contiguous stereocenters. The synthesis features a lithium-halogen exchange/intermolecular nucleophilic addition to link two enantioenriched fragments, two ring-closing metathesis reactions to assemble the five- and eight-membered rings, and a bioinspired Prins reaction/ether formation cascade cyclization to construct the 5/6/6/6/5 caged skeleton.

Total Synthesis of (+)-Aberrarone.

The structurally intriguing diterpene (+)-aberrarone has been assembled in only 12 steps from the commercially available (S,S)-carveol without protecting group manipulations. This concise synthesis features a Cu-catalyzed asymmetric hydroboration to generate the chiral methyl group, a Ni-catalyzed reductive coupling to link two fragments, and a Mn-mediated radical cascade cyclization to construct the triquinane system.

Design, syntheses and biological evaluation of natural product aiphanol derivatives and analogues: Discovery of potent anticancer agents.

The natural product aiphanol (1) is one of the substances with anticancer biological activity isolated from traditional Chinese medicines (TCM) Smilax glabra Roxb. (Tufuling). Our recent research found that aiphanol could suppress angiogenesis and tumor growth by dual-blocking VEGF/VEGFRs and COX2 signal pathway. In this study, four series of 40 aiphanol derivatives and analogues were designed, synthesized and evaluated for their anticancer activity. Among them, the analogues 10j and 14c exhibited the most potent inhibition and broad-spectrum antiproliferative activity toward nine tumor cell lines. The IC50 values of the analogues 10j and 14c range from 0.81 to 10 µmol/L which up to 80-fold vs. parent compound aiphanol. The structure-activity relationship (SAR) studies indicated that the substrate at 7-position of benzo 1,4-dioxane is very crucial for anticancer activity. Molecular docking indicated that the compound 14c (ent-14c) tightly binds to VEGFR2 and COX2, respectively. Therefore, compounds 10j and 14c could be promising candidates for the development of anticancer agents in the future.

Aiphanol, a multi-targeting stilbenolignan, potently suppresses mouse lymphangiogenesis and lymphatic metastasis.

The high incidence of lymphatic metastasis is closely related to poor prognosis and mortality in cancers. Potent inhibitors to prevent pathological lymphangiogenesis and lymphatic spread are urgently needed. The VEGF-C-VEGFR3 pathway plays a vital role in driving lymphangiogenesis and lymph node metastasis. In addition, COX2 in tumor cells and tumor-associated macrophages (TAMs) facilitates lymphangiogenesis. We recently reported that aiphanol, a natural stilbenolignan, attenuates tumor angiogenesis by repressing VEGFR2 and COX2. In this study, we evaluated the antilymphangiogenic and antimetastatic potency of aiphanol using in vitro, ex vivo and in vivo systems. We first demonstrated that aiphanol directly bound to VEGFR3 and blocked its kinase activity with an half-maximal inhibitory concentration (IC50) value of 0.29 µM in an in vitro ADP-GloTM kinase assay. Furthermore, we showed that aiphanol (7.5-30 µM) dose-dependently counteracted VEGF-C-induced proliferation, migration and tubular formation of lymphatic endothelial cells (LECs), which was further verified in vivo. VEGFR3 knockdown markedly mitigated the inhibitory potency of aiphanol on lymphangiogenesis. In 4T1-luc breast tumor-bearing mice, oral administration of aiphanol (5 and 30 mg· kg-1 ·d-1) dose-dependently decreased lymphatic metastasis and prolonged survival time, which was associated with impaired lymphangiogenesis, angiogenesis and, interestingly, macrophage infiltration. In addition, we found that aiphanol decreased the COX2-dependent secretion of PGE2 and VEGF-C from tumor cells and macrophages. These results demonstrate that aiphanol is an appealing agent for preventing lymphangiogenesis and lymphatic dissemination by synergistically targeting VEGFR3 and inhibiting the COX2-PGE2-VEGF-C signaling axis.

Total Synthesis of (-)-Principinol C.

We have achieved the first total synthesis of (-)-principinol C, which possesses an intriguing and complex 5/7/6/5 tetracyclic skeleton with eight contiguous stereocenters. The 5/7/6/5 tetracyclic skeleton of principinol C was assembled using an intramolecular Pauson-Khand reaction as the key step. This synthetic route represents the first application of the intramolecular Pauson-Khand reaction of enyne to construct the 7,5-bicyclic ring system in natural product synthesis.

High slope-efficiency quantum-dot lasers grown on planar exact silicon (001) with asymmetric waveguide structures.

We report electrically pumped continuous-wave (CW) InAs/GaAs quantum dot lasers directly grown on planar exact silicon (001) with asymmetric waveguide structures. Surface hydrogen-annealing for the GaAs/ Si (001) templates and low-temperature growth for GaInP upper cladding layers were combined in the growth of the laser structure to achieve a high slope efficiency. For the broad-stripe edge-emitting lasers with 2-mm cavity length and 20-µm stripe width made from the above laser structure, a threshold current density of 203.5 A/cm2 and a single-facet slope efficiency of 0.158 W/A are achieved at ∼1.31 µm band under CW conditions. The extrapolated mean-time-to-failure reaches up to 21000 hours at room temperature, which is deduced from the data measured from C-mount packaged devices. Importantly, these results can provide a practical strategy to realize 1.3 µm wavelength band distributed feedback lasers directly on planar exact Si (001) templates with thin buffer layers.

Divergent Total Synthesis of Four Kopsane Alkaloids: N-Carbomethoxy-10,22-dioxokopsane, Epikopsanol-10-lactam, 10,22-Dioxokopsane, and N-Methylkopsanone.

We have achieved the divergent total synthesis of four kopsane alkaloids which share a complex heptacyclic caged ring system. Key transformations include an asymmetric Diels-Alder reaction to assemble the central bicyclo[2.2.2]octane moiety and the quaternary stereocenter at C20, a SmI2 -mediated cascade reduction/aldol reaction to construct the five-membered ring and the quaternary stereocenter at C7, and a late-stage cascade reductive amination/cyclization to establish the highly strained caged ring system.

Bioinspired Total Synthesis of (+)-Euphorikanin A.

We have achieved a bioinspired total synthesis of (+)-euphorikanin A, which possesses an intriguing and complex 5/6/7/3-fused tetracyclic skeleton bearing a bridged [3.2.1]-γ-lactone moiety. Key transformations include stereoselective alkylation and aldol condensation to install the main stereocenters, an intramolecular nucleophile-catalyzed aldol lactonization of carboxylic acid-ketone to assemble the five-membered ring, a McMurry coupling to construct the seven-membered ring, and a biomimetic benzilic acid type rearrangement to form the bridged [3.2.1]-γ-lactone moiety.

Divergent Strategy in Natural Product Total Synthesis.

The divergent total syntheses of complex natural products from a common intermediate have attracted enormous attention in the chemical community in the past few years because it can improve the efficiency of chemical synthesis. A number of powerful and unified strategies have been developed by emulating the natural biosynthesis or through innovative transformations. This review focuses on the total synthesis of natural products by applying divergent strategies and the literature covering from 2013 to June 2017. On the basis of where the diversity comes from, the examples are grouped into three parts and discussed in detail. In each group, the examples that synthesize natural products belonging to the same subfamily are put together to contrast with one another.

Total Synthesis of (-)-Glaucocalyxin†A.

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)3 -mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (-)-glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels-Alder reaction to assemble the A/B ring system.

Synthetic approaches to natural products containing 2,3-dihydrobenzofuran skeleton.

Covering: 2000 to 2018 Natural products containing the 2,3-dihydrobenzofuran (2,3-DHB) skeleton have been the focus of a substantial number of synthetic studies since 2000. Herein, we review the total syntheses of decursivine, serotobenine, lithospermic acid, linderol A, bisabosqual A, pterocarpans, conocarpan, heliannuols, and some resveratrol oligomers, with emphasis on the synthetic strategies employed.

Eight-Step Total Synthesis of Phalarine by Bioinspired Oxidative Coupling of Indole and Phenol.

We report for the first time that the benzofuro[3,2-b]indoline framework could be obtained by PIDA-mediated direct oxidative coupling of 2,3-disubstituted-indoles with phenols. Application of this chemistry allows for an eight-step total synthesis of phalarine from commercially available tryptamine.

A Ten-Step Total Synthesis of Speradine†C.

The first total synthesis of speradine C has been achieved in only ten steps from a commercially available 4-bromoindole. Salient features of the work are the formation of four rings through three cyclizations, namely a bioinspired [3+2] annulation to form the C/D rings, an NCS-mediated oxidation to construct the E ring, and a Ru-catalyzed ketohydroxylation to assemble the F ring. This work highlights how strategic ring constructions can streamline the synthesis of polycyclic compounds.

Enantioselective Total Syntheses of Pallambins†A-D.

The first enantioselective total syntheses of (-)-pallambins A-D have been achieved in 15 or 16 steps from a known chiral cyclohexenone. Salient features of the syntheses include a palladium-catalyzed oxidative cyclization to assemble the [3.2.1]bicyclic moiety, an Eschenmoser-Claisen rearrangement/lactone formation sequence to construct the C ring, an intramolecular Wittig reaction to form the D ring, and individual transformations of pallambins C and D to generate pallambins A and B. The described synthesis avoids protecting-group manipulations through the design of highly chemo- and stereoselective transformations. During the course of this work, a palladium-catalyzed method for the dehydrobromination of α-bromoketones was developed, and the scope of this transformation was also investigated.

Ergot alkaloids: synthetic approaches to lysergic acid and clavine alkaloids.

Covering: 2000 to 2017Ergot alkaloids are among the most important pharmaceuticals and natural toxins. Significant progress has been achieved in recent years on the research of ergot alkaloids. In this review, we re-introduced the history of ergot alkaloids. Meanwhile, we summarized all the natural products and semi-synthetic derivatives of ergot alkaloids. We also briefly described the biosynthesis and semi-synthesis of ergot alkaloid drugs from raw materials obtained by fermentation. Moreover, we reviewed the advances that have been made in the total synthesis of ergot alkaloids since 2000.

Formal Synthesis of (+)-Kopsihainanine A and Synthetic Study toward (+)-Limaspermidine.

The formal synthesis of (+)-kopsihainanine A has been achieved via stereoselective reduction of tetracyclic iminium ion intermediates (24). However, attempts to synthesize (+)-limaspermidine by reduction of the same tetracyclic iminium ion intermediates have failed. The synthesis features a Suzuki cross-coupling reaction, a cyclization reaction mediated by trifluoromethanesulfonic anhydride, and stereoselective reduction of an iminium ion.

Protecting-Group-Free Enantioselective Synthesis of (-)-Pallavicinin and (+)-Neopallavicinin.

The first enantioselective synthesis of (-)-pallavicinin and (+)-neopallavicinin has been achieved in 15 steps. The described synthesis avoids protecting-group manipulations by synthesis designs predicated on highly chemo- and stereoselective transformations. Highlights of the synthesis include a palladium-catalyzed enantioselective decarboxylative allylation to form the chiral all-carbon quaternary stereocenter, a palladium-catalyzed oxidative cyclization to assemble the [3.2.1]-bicyclic moiety, and an unprecedented LiBHEt3-induced fragmentation/protonation of an α-hydroxy epoxide to form the α-furan ketone with the desired configuration.