Stereoselective total synthesis of (3Z)- and (3E)-elatenynes.

We describe here the highly stereoselective total synthesis of the Laurencia C15 acetogenins (3Z)- and (3E)-elatenynes having a 7,12-dibromo-6,9-cis-10,13-cis adjacent bis-tetrahydrofuran (THF) core. The present synthesis features a highly stereoselective, protecting group-dependent, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 7-hydroxy-6,7-cis-6,9-cis-THF intermediate 10, deployment of the sequential ate complex (n-BuLi/DIBAL-H) reduction/Keck allylation/cross metathesis (CM) protocol for the stereoselective introduction of the C(10)-C(15) unit, a sequential Sharpless asymmetric dihydroxylation (SAD)/intramolecular Williamson etherification for the construction of the 10,13-cis-THF ring, and a modified Nakata chloromethanesulfonate-mediated SN2 displacement for the 7,12-dibromo functionality. Furthermore, our strategy based on chelate-controlled IAEA methodology would provide access to any member of the C15 adjacent bis-THF acetogenin class.

Total Synthesis and Structure Confirmation of (-)-Asimitrin, a C37 Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core.

The total synthesis and structure confirmation of the potent cytotoxic agent (-)-asimitrin (1), a C37 annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17-erythro-16,19-trans-THF 6, our direct ketone synthesis/l-Selectride reduction protocol for stereoselective introduction of the C(21)-C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23-trans-THF ring.

Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin (1) exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Here, we provide the 7-prenylated chrysin derivatives, chrysin 5-benzyl-7-prenylether compound 10 and chrysin 5,7-diprenylether compound 11, with the improved pharmacological profile compared with chrysin (1). Nuclear receptor binding and ligand-induced coactivator recruitment assays revealed that compounds 10 and 11 functioned as peroxisome proliferator-activated receptor (PPAR)γ partial agonists. These findings were supported by molecular docking simulation, followed by experimental validation. Notably, compound 11 showed PPARγ binding affinity as potent as that of the PPARγ agonists pioglitazone and telmisartan. This study presents a novel PPARγ partial agonist pharmacophore and suggests that prenylated chrysin derivatives have therapeutic potential in various human diseases associated with hypoadiponectinemia.

Macakurzin C Derivatives as a Novel Pharmacophore for Pan-Peroxisome Proliferator-Activated Receptor Modulator.

The natural flavonoid macakurzin C (1) exhibited adiponectin biosynthesis-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells and its molecular mechanism was directly associated with a pan-peroxisome proliferator-activated receptor (PPAR) modulator affecting all three PPAR subtypes α, γ, and δ. In this study, increases in adiponectin biosynthesis-inducing activity by macakurzin C derivatives (2-7) were studied. The most potent adiponectin biosynthesis-inducing compound 6, macakurzin C 3,5-dimethylether, was elucidated as a dual PPARα/γ modulator. Compound 6 may exhibit the most potent activity because of the antagonistic relationship between PPARδ and PPARγ. Docking studies revealed that the O-methylation of macakurzin C to generate compound 6 significantly disrupted PPARδ binding. Compound 6 has therapeutic potential in hypoadiponectinemia-related metabolic diseases.

Highly Stereodivergent Construction of a C2-Symmetric cis,cis- and trans,trans-2,6-Dioxabicyclo[3.3.0]octane Framework by Double Intramolecular Amide Enolate Alkylation: Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene.

The highly stereoselective construction of C2-symmetric cis,cis- and trans,trans-2,6-dioxabicyclo[3.3.0]octane (fused bis-tetrahydrofuran) skeletons 4a and 4b has been accomplished via a novel stereodivergent double intramolecular amide enolate alkylation of common cyclization substrate 5 through the judicious choice of "chelate" versus crown ether-promoted "nonchelate" control. Application of this methodology has provided access to substrate-controlled concise total syntheses of (+)-laurenidificin (3) and (+)-aplysiallene (ent-2), which possess cis/cis- and trans/trans-fused bis-tetrahydrofuran cores, respectively.

Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist.

The upregulation of adiponectin production has been suggested as a novel strategy for the treatment of metabolic diseases. Galangin, a natural flavonoid, exhibited adiponectin synthesis-promoting activity during adipogenesis in human bone marrow mesenchymal stem cells. In target identification, galangin bound both peroxisome proliferator-activated receptor (PPAR) γ and estrogen receptor (ER) ß. Novel galangin derivatives were synthesized to improve adiponectin synthesis-promoting compounds by increasing the PPARγ activity of galangin and reducing its ERß activity, because PPARγ functions can be inhibited by ERß. Three galangin 3-benzyl-5-methylether derivatives significantly promoted adiponectin production by 2.88-, 4.47-, and 2.76-fold, respectively, compared to the effect of galangin. The most potent compound, galangin 3-benzyl-5,7-dimethylether, selectively bound to PPARγ (Ki, 1.7 µM), whereas it did not bind to ERß. Galangin 3-benzyl-5,7-dimethylether was identified as a PPARγ partial agonist in docking and pharmacological competition studies, suggesting that it may have diverse therapeutic potential in a variety of metabolic diseases.

Asymmetric Total Synthesis and Determination of the Absolute Configuration of (+)-Srilankenyne via Sequence-Sensitive Halogenations Guided by Conformational Analysis.

This first asymmetric total synthesis of (+)-srilankenyne (1), a halogenated C15 tetrahydropyran acetogenin isolated from Aplysia oculifera, features a sequence-sensitive process guided by conformational analysis to solve the challenging problem of introducing halogens. A competing semipinacol rearrangement during the installation of C(12)-bromide was suppressed by our A1,3 strain-controlled bromination protocol with support from X-ray crystallographic and computational studies. The C(10)-chloride was then placed by the Nakata chloromesylate-mediated chlorination.

Automated Classification of Online Sources for Infectious Disease Occurrences Using Machine-Learning-Based Natural Language Processing Approaches.

Collecting valid information from electronic sources to detect the potential outbreak of infectious disease is time-consuming and labor-intensive. The automated identification of relevant information using machine learning is necessary to respond to a potential disease outbreak. A total of 2864 documents were collected from various websites and subsequently manually categorized and labeled by two reviewers. Accurate labels for the training and test data were provided based on a reviewer consensus. Two machine learning algorithms-ConvNet and bidirectional long short-term memory (BiLSTM)-and two classification methods-DocClass and SenClass-were used for classifying the documents. The precision, recall, F1, accuracy, and area under the curve were measured to evaluate the performance of each model. ConvNet yielded higher average, min, and max accuracies (87.6%, 85.2%, and 91.1%, respectively) than BiLSTM with DocClass, while BiLSTM performed better than ConvNet with SenClass with average, min, and max accuracies of 92.8%, 92.6%, and 93.3%, respectively. The performance of BiLSTM with SenClass yielded an overall accuracy of 92.9% in classifying infectious disease occurrences. Machine learning had a compatible performance with a human expert given a particular text extraction system. This study suggests that analyzing information from the website using machine learning can achieve significant accuracies in the presence of abundant articles/documents.

Total Synthesis and Biological Evaluation of Sericetin for Protection against Cisplatin-Induced Acute Kidney Injury.

A concise synthesis of sericetin (1) was performed in four steps from readily available 3- O-benzylgalangin (4), featuring electrocyclization to produce the tricyclic core and a sequential aromatic Claisen/Cope rearrangement to incorporate the 8-prenyl group of 1. In addition, the therapeutic potential of sericetin (1), isosericetin (2), and three prenylated tetracyclic synthetic intermediates (11, 12, and 14) against cisplatin-induced nephrotoxicity using renal tubular cells were evaluated. Compound 14 showed therapeutic potential against cisplatin-induced kidney damage.

Stereoselective Substrate-Controlled Asymmetric Syntheses of both 2,5-cis- and 2,5-trans-Tetrahydrofuranoid Oxylipids: Stereodivergent Intramolecular Amide Enolate Alkylation.

The concise, highly stereoselective, substrate-controlled asymmetric total syntheses of both 2,5-cis- and 2,5-trans-tetrahydrofuranoid nematocidal oxylipids from the Australian brown algae Notheia anomala have been accomplished in a stereodivergent fashion. The highly stereoselective intramolecular amide enolate alkylation strategy provides access to both stereoisomers of the 3-hydroxy-2,5-disubstituted tetrahydrofuran core of these marine natural products through chelate and nonchelate control, which is driven by the C3-hydroxy protecting group. This approach offers an optional and highly stereoelective access to any of the eight possible stereoisomers of the 2,5-disubstituted-3-oxygenated tetrahydrofuran skeleton, an important structural feature which is present in many biologically active natural products.

Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.

Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3C(pro)) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 µM, but exhibited mild cellular cytotoxicity at 50 µM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.