Spirodalesol, an NLRP3 Inflammasome Activation Inhibitor

Autoimmune and inflammatory diseases are associated with inappropriate activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, but suitable inhibitors against such improper activations remain scarce. Here, spirodalesol (<b>1</b>) from Daldinia eschscholzii was structurally characterized and is biosynthetically proposed as an NLRP3 inflammasome activation inhibitor with an unprecedented carbon skeleton

Protecting Group-Free Total Synthesis of (−)-Lannotinidine B

The first total synthesis of (−)-lannotinidine B, a unique tetracyclic constitutent of <i>Lycopodium annotinum</i>, has been accomplished in 10 steps with 23% overall yield. The completed short and efficient synthesis is characterized with three highly chemo- and/or stereoselective reductive-amination steps to furnish the desired <i>trans</i>-fused 6/6 bicycle and the aza seven-membered ring system, and a direct intramolecular acyloin condensation to deliver the cyclopentanone moiety, as well as successful application of a protecting group-free strategy and an optimal redox order

Protecting Group-Free Total Synthesis of (−)-Lannotinidine B

The first total synthesis of (−)-lannotinidine B, a unique tetracyclic constitutent of <i>Lycopodium annotinum</i>, has been accomplished in 10 steps with 23% overall yield. The completed short and efficient synthesis is characterized with three highly chemo- and/or stereoselective reductive-amination steps to furnish the desired <i>trans</i>-fused 6/6 bicycle and the aza seven-membered ring system, and a direct intramolecular acyloin condensation to deliver the cyclopentanone moiety, as well as successful application of a protecting group-free strategy and an optimal redox order

Gene-Directed Generation of Unprecedented Bioactive Compounds

Bioactive compounds with previously undescribed frameworks are highly desired for the discovery and development of new drugs and agrochemicals, but very few attempts have been reported to generate such molecules in biological contexts. Here, we present a gene-directed generation of architecturally unprecedented polyketide–indole hybrids (PIHs), which was conceptualized and materialized by employing polyketide synthases expressed in a heterologous vector, with simultaneous exposure to exogenous chemicals. To make an exemplification to this generally applicable approach, the ChrA and ChrB genes of Daldinia eschscholzii IFB-TL01 were integrated into the Aspergillus oryzae (AO) cell, and the resultant ChrA/ChrB-AO transformant was cultured in the indole-3-carbinol (I3C)-supplemented medium, leading to the production of seven skeletally undescribed PIHs named aochrabines A–G. Among them, aochrabines A–C exhibited a broad spectrum in inhibiting the growth of Gram-positive bacteria, whereas aochrabines B, C, and G showed moderate antitumor activities. Unexpectedly, the construction of such aochrabine molecules was achieved by the regioselective Michael addition of 3-methyleneindolium (3MI, generated from I3C in the AO culture) to different polyketide precursors with the yields (much) higher than those in the D. eschscholzii culture where comparable. Chemically, the benzyl-methine carbons in the precursor molecules were found to be made more vulnerable to the 3MI attack by the hydrogen-bonding between the ortho-hydroxyl and meta-carbonyl groups. Collectively, this is the first report of the ortho- and meta-substituent co-driven regioselective Michael addition of electrophilic methylene compounds to heterologous PKS production platform to in situ multiply the chemodiversity of microbial cultures, thus showing great potential in producing valuable compounds with new chemical space

Curindolizine, an Anti-Inflammatory Agent Assembled via Michael Addition of Pyrrole Alkaloids Inside Fungal Cells

<i>Curvularia</i> sp. IFB-Z10, a white croaker-associated fungus, generates a skeletally unprecedented indolizine alkaloid named curindolizine (<b>1</b>), which displays an anti-inflammatory action in lipopolyssacharide (LPS)-induced RAW 264.7 macrophages with an IC₅₀ value of 5.31 ± 0.21 μM. The enzymatic transformation test demonstrated that the unique curindolizine architecture was most likely produced by the regiospecific in-cell Michael addition reaction between pyrrole alkaloids, curvulamine, and 3,5-dimethylindolizin-8­(5<i>H</i>)-one

Acaulins A and B, Trimeric Macrodiolides from <i>Acaulium</i> sp. H‑JQSF

Acaulin A (<b>1</b>) and its macrolactone ring-opened congener acaulin B (<b>2</b>) were characterized from the culture of <i>Acaulium</i> sp. H-JQSF (an isopod-associated fungus) as architecturally undescribed trimeric macrodiolides, with the former being antiosteoporotic at 0.4 μM in the prednisolone-induced osteoporotic zebrafish. Identification of acaudiolic acid (<b>3</b>) as the monomeric macrodiolide precursor facilitated the proposal of the acaulin biosynthetic pathway

Acaulide, an Osteogenic Macrodiolide from <i>Acaulium</i> sp. H‑JQSF, an Isopod-Associated Fungus

Acaulide (<b>1</b>), a macrodiolide with an unprecedented framework, was characterized along with its shunt productsacaulones A (<b>2</b>) and B (<b>3</b>)from the culture of <i>Acaulium</i> sp. H-JQSF associated with the isopod <i>Armadillidium vulgare</i>. The spiro-linked 14-, 14-, and 6-membered cycles of <b>1</b> arise likely from iterative intermolecular Michael addition reactions. Biological evaluation in the prednisolone-induced osteoporotic zebrafish demonstrated that <b>1</b> is antiosteoporotic at 0.4 and 2.0 μM

Citrofulvicin, an Antiosteoporotic Polyketide from <i>Penicillium velutinum</i>

Citrofulvicin (<b>1</b>), along with its early shunt product fulvionol (<b>2</b>), was characterized as a skeletally unprecedented antiosteoporotic agent from a human sputum-derived fungus <i>Penicillium velutinum.</i> The unique citrofulvicin framework is likely formed by a nonenzymatic intermolecular Diels–Alder cycloaddition between heptaketide-based intermediates. Citrofulvicin and fulvionol were demonstrated to be osteogenic at 0.1 μM in the prednisolone-induced osteoporotic zebrafish

An Epigenetic Compound Library Screen Identifies BET Inhibitors That Promote HSV-1 and -2 Replication by Bridging P-TEFb to Viral Gene Promoters through BRD4

<div><p>The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection. BRD4 regulates HSV replication through complex formation involving CDK9 and RNAP II; whereas, JQ1 promotes HSV-1 infection by allocating the complex to HSV gene promoters. Therefore, suppression of BRD4 expression or inhibition of CDK9 activity impeded HSV infection. Our data support a model that JQ1 enhances HSV infection by switching BRD4 to transcription regulation of viral gene expression from chromatin targeting since transient expression of BRD4 BD1 or BD1/2 domain had similar effect to that by JQ1 treatment. In addition to the identification that BRD4 is a modulator for JQ1 action on HSV infection, this study demonstrates BRD4 has an essential role in HSV infection.</p></div