The archazolids are complex polyketides isolated from the myxobacterium Archangium gephyra and are potent inhibitors of vacuolar type ATPases. Herein, we report the first total synthesis of archazolid A, which establishes unequivocally the relative and absolute configuration of this macrolide antibiotic. Key features of our synthesis include an aldol condensation for construction of the delicate (Z,Z,E)-triene-system, an E-selective Heck reaction on a highly elaborate substrate, and a HWE macrocyclization to close the 24-membered macrolactone.

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Aqueous aza Diels−Alder reactions of chiral aldehydes, prepared from carbohydrates, with benzylamine hydrochloride and cyclopentadiene, were promoted by lanthanide triflates. The exo/endo selectivities and diastereoselectivities of the reactions were elucidated by NMR, CD spectroscopy, and X-ray crystallography. The nitrogen-containing heterocyclic products were further transformed to azasugars, which are potential inhibitors against glycoprocessing enzymes.

The large and steadily growing demand for medicines combined with their inherent resource-intensive manufacturing necessitates a relentless push for their sustainable production. Pharmaceutical companies are constantly seeking to perform reliable life cycle assessments of their medicinal products and assess the true value of their sustainable development achievements; however, they find themselves impeded by the lack of a universal metric system that allows for objective quantification of the underlying core denominators. Guided by the unambivalent purpose of the United Nations Sustainable Development Goal 12, which aims at substantially reducing production waste by 2030, and driven by a vision to catalyze greener active pharmaceutical ingredient (API) manufacturing around the globe, the authors set out to overcome current obstacles by defining an improved model for the metric named innovation green aspiration level, iGAL 2.0. We propose yield and convergence as new key sustainability indicators and include a new formula for convergence with potential applicability in computer assisted synthesis planning (CASP) algorithms. The improved statistical model of iGAL 2.0 represents a valuable extension to the common API process waste metrics, process mass intensity (PMI) and complete E factor (cEF), by putting those measures into perspective: iGAL 2.0 enables determination of relative process greenness (RPG) to identify potentially underperforming and environmentally concerning processes early and thereby deliver environmental value. At the same time, iGAL 2.0 generates economic value since reduced waste correlates to lower API production costs. The metric is complemented by its scorecard companion to highlight the impact of innovation on reductions of API manufacturing waste, enabling scientists to readily communicate the value of their work to their peers, managers, and the general public. We believe that iGAL 2.0 can readily be adopted by pharmaceutical firms around the globe and thereby empower and inspire their scientists to make meaningful and significant contributions to global sustainability.

Nobiletin (NOB) is a naturally occurring compound, commonly found in citrus peel, that shows hepatoprotective and lipid-reducing effects. However, the lipid biomarkers and the potential improvement mechanisms have not been adequately explored. Therefore, we investigated the ameliorative effect and the molecular mechanism of NOB on NAFLD induced by a high-fat diet in mice. The results showed that supplementation with NOB over 12 weeks markedly improved glucose tolerance, serum lipid profiles, inflammatory factors, hepatic steatosis, and oxidative stress. These beneficial effects were mainly related to reduced levels of potential lipid biomarkers including free fatty acids, diacylglycerols, triacylglycerols, and cholesteryl esters according to hepatic lipidomic analysis. Twenty lipids, including DGs and phosphatidylcholines, were identified as potential lipid biomarkers. Furthermore, RT-qPCR and Western blot analysis indicated that NOB inhibited the expression of lipogenesis-related factors such as SREBP-1c, SCD-1, and FAS, and upregulated the expression of lipid oxidation (PPARα) and cholesterol conversion (LXRα, CYP7A1, and CYP27A1) genes as well as antioxidation-related factors (Nucl-Nrf2, NQO1, HO-1, and GCLC), indicating that NOB intake may reduce lipid biosynthesis and increase lipid consumption to improve hepatic steatosis and oxidative stress. This study is beneficial for understanding the ameliorative effects of NOB on NAFLD.

Chemical investigation of the fungal strain Gymnoascus reessii za-130, which was previously isolated from the rhizosphere of tomato plants infected by the root-knot nematode Meloidogyne incognita, led to the isolation and identification of a new indoloditerpenoid metabolite designated gymnoascole acetate. Its structure was established by spectroscopic methods including 1D- and 2D-NMR and MS analyses. Gymnoascole acetate demonstrated strong adverse effects on M. incognita second-stage juvenile (J2) viability; exposure to 36 μg/mL for 24 h induced 100% paralysis of J2 (EC = 47.5 μg/mL). Gymnoascole acetate suppressed M. incognita egg hatch relative to controls by >90% at 133 μg/mL after 7 days of exposure. The numbers of root galls and J2 in both soil and roots were significantly reduced (p = 0.05) by treatment with 2-200 μg/mL gymnoascole acetate/kg soil, compared to untreated control plants; nematode suppression increased with gymnoascole acetate concentration. This study demonstrated the nematotoxicity of gymnoascole acetate and indicates that it might be a potential biobased component in integrated management of M. incognita.