Anti-inflammatory Alkaloids, Papaversomni A, a Hexacyclic-Membered Morphinan, and Two Pairs of <i>E</i> / <i>Z</i> Nonseparable Stereoisomers, Papaversomni C and Sinoracutinal, from <i>Papaver somniferum</i>

Five new alkaloids, including papaversomnis A-C (<b>1</b>, <b>3</b>, and <b>4</b>), sinoracutinal (<b>5</b>), and ethoxyepiglaudine (<b>6</b>), along with two known alkaloids, <b>2</b> and <b>7</b>, were discovered from <i>Papaver somniferum</i>. <b>1</b> has unprecedented 6/6/6/6/5/5-fused hexacyclic framework, representing a novel type of morphinan, whereas <b>4</b> and <b>5</b> are two pairs of <i>E</i>/<i>Z</i> nonseparable stereoisomers. Their stereochemistries were identified via single crystal X-ray diffraction analysis, the exciton chirality method evaluation of ECD, comparison of the experimental and calculated ¹H and ¹³C NMR, and ECD data. <b>1</b> and <b>2</b> exhibited stronger anti-inflammatory effects on NO production in lipopolysaccharide-stimulated RAW 264.7 macrophages, with IC₅₀ values of 16.63 ± 0.83 and 12.78 ± 0.95 μM, respectively, than the positive control, with IC₅₀ value of 22.10 ± 0.63 μM. Western blotting analysis displayed that <b>1</b> and <b>2</b> could inhibit the expression of iNOS and COX-2 as key mediators in the inflammatory responses.