This is the first report to elucidate the biosynthetic pathway of benzyl derivatives and production of vanillin from I. resinosum.A new traceless directing group, 2-(hydroxymethyl)pyridine, has been reported for the Cp*-free cobalt-catalyzed C-H activation/annulation reaction to synthesize isoquinolinones. The reaction exhibits good functional group tolerance, affording products in good to excellent isolated yields under mild conditions. Notably, the directing group can be removed directly in situ along the catalytic process.Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/β-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.The presence of a carbonyl group in a molecule usually leads to the identification of a π-hole on the molecular electrostatic potential (MESP) of the species. How does this electrophilic site influence the formation of microhydrated complexes? To address this point, a panel of R2CO solutes with various MESPs was selected, and we identified the structures and properties of several complexes containing one, two, three and six water molecules. The following solutes were considered in the present study H2CO, F2CO, Cl2CO,(NC)2CO and H2C═CO. Geometry optimizations and frequency calculations were carried out at the LC-ωPBE/6-311++G(d,p) level, with the GD3BJ empirical correction for dispersion. For a number of n water molecules around the R2CO solute, the structure and the features of the most stable (H2O)n(R2CO) complexes are highly dependent on the MESP of the isolated R2CO solute. The formation of pi-hole bondings appears to play a decisive role in the initiation of a three-dimensional organization of water molecules around the solute.Dithiolopyrrolones are microbial natural products containing a disulfide or thiosulfonate bridge embedded in a unique bicyclic structure. By interfering with zinc ion homeostasis in living cells, they show strong antibacterial activity against a variety of bacterial pathogens, as well as potent cytotoxicity against human cancer cells. In the current study, two new dithiolopyrrolones, pyrroloformamide C (3) and pyrroloformamide D (4), were isolated from Streptomyces sp. CB02980, together with the known pyrroloformamides 1 and 2. The biosynthetic gene cluster for pyrroloformamides was identified from Streptomyces sp. CB02980, which shared high sequence similarity with those of dithiolopyrrolones, including holomycin and thiolutin. Gene replacement of pyfE, which encodes a nonribosomal peptide synthetase (NRPS), abolished the production of 1-4. check details Overexpression of pyfN, a type II thioesterase gene, increased the production of 1 and 2. Genome neighborhood network analysis of the characterized and orphan gene clusters of dithiolopyrrolones revealed a unified mechanism for their biosynthesis, involving an iterative-acting NRPS and a set of conserved tailoring enzymes for the bicyclic core formation.The solvation and solubilization of selected anesthetic active pharmaceutical ingredients (bupivacaine, prilocaine, and procaine) in arginine-based deep eutectic solvents are studied using a theoretical approach considering quantum chemistry and classical molecular dynamics. The intermolecular forces between the anesthetics and the solvent are characterized, with particular attention to hydrogen bonding, in terms of strength, topological properties, interaction mechanism, structuring, and dynamic properties of solvation shells. The reported results show the nanoscopic properties that confirm these solvents as suitable materials for anesthetics drug delivery in the liquid phase.Sigillins are highly chlorinated natural products from the springtail Ceratophysella sigillata (Collembola) that are used to deter arthropod predators. We report here the isolation and structure elucidation of sigillin F, a hydrogenated benzopyranone compound bearing two trichloromethyl groups, and the synthesis of trideoxysigillin (8), a non-natural compound representing the basic scaffold of the sigillins. Sigillins A and F showed insecticidal activity toward various insects, similar to the commercial insecticide imidacloprid, whereas 8 was inactive. The highest mortality was observed for the aphids Megoura viciae and Myzus persicae, but other insect species were also susceptible. Sigillins act as noncompetitive antagonists of the GABA receptor. This mode of action is identical to that of known insecticides with high chlorine content such as dieldrin or endosulfan. The high content of sigillins in C. sigillata, more than 4 mM in concentration, indicates self-resistance. Strikingly, the Collembola and humans have both arrived at the same target with related types of compounds to combat insects.Medicinal chemistry plays a fundamental and underlying role in chemical biology, pharmacology, and medicine to discover safe and efficacious drugs. Small molecule medicinal chemistry relies on iterative learning cycles composed of compound design, synthesis, testing, and data analysis to provide new chemical probes and lead compounds for novel and druggable targets. Using traditional approaches, the time from hypothesis to obtaining the results can be protracted, thus limiting the number of compounds that can be advanced into clinical studies. This challenge can be tackled with the recourse of enabling technologies that are showing great potential in improving the drug discovery process. In this Perspective, we highlight recent developments toward innovative medicinal chemistry strategies based on continuous flow systems coupled with automation and bioassays. After a discussion of the aims and concepts, we describe equipment and representative examples of automated flow systems and end-to-end prototypes realized to expedite medicinal chemistry discovery cycles.