Spiroarborin, an ent-Clerodane Homodimer from Callicarpa arborea as an Inhibitor of the Eleven-Nineteen Leukemia (ENL) Protein by Targeting the YEATS Domain.

A spiro ent-clerodane homodimer with a rare 6/6/6/6/6-fused pentacyclic scaffold, spiroarborin (1), together with four new monomeric analogues (2-5), were isolated from Callicarpa arborea. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum-chemical calculations, and X-ray diffraction. A plausible biosynthetic pathway of 1 was proposed, and a biomimetic synthesis of its derivative was accomplished. Compound 1 showed a potent inhibitory effect by directly binding to the YEATS domain of the 11-19 leukemia (ENL) protein with an IC50 value of 7.3 µM. This gave a KD value of 5.0 µM, as recorded by a surface plasmon resonance binding assay.

Callicarpins, Two Classes of Rearranged ent-Clerodane Diterpenoids from Callicarpa Plants Blocking NLRP3 Inflammasome-Induced Pyroptosis.

Callicarpins A-D (1-4), possessing an unprecedented A-homoent-clerodane scaffold with a bicyclo[5.4.0]undecane ring system, and callicarpins E-G (5-7), with 5/6-fused ent-clerodane diterpenoid skeletons, were isolated from Callicarpaarborea and C. integerrim. Their structures were elucidated by comprehensive spectroscopic data, X-ray crystal diffraction, chemical derivatization, and electronic circular dichroism (ECD) data. Putative biosynthetic pathways for these callicarpins are proposed. Compounds 2, 3b, and 6-8 showed potent inhibitory effects against the NLRP3 inflammasome with IC50 values from 1.4 to 5.3 µM, and 2 significantly blocked NLRP3 inflammasome-induced pyroptosis by inhibiting Casp-1 activation and IL-1ß secretion in J774A.1 cells.

Luteolin-7-methylether from Leonurus japonicus inhibits estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19).

Leonurus japonicus (motherwort) has been widely used to treat gynecological disorders, in which estrogen is often dysregulated, for a long time in China and other Asian countries. However, the chemical constituents and mechanisms underlying the activity of this medicinal plant are not fully understood. Seventeen of forty-six tested natural products from L. japonicus showed stimulatory or inhibitory effects on estrogen biosynthesis with different potency in human ovarian granulosa-like KGN cells. Luteolin-7-methylether (XLY29) potently inhibited 17ß-estradiol production (IC50: 5.213 µM) by decreasing the expression of aromatase, the only enzyme in vertebrates that catalyzes the biosynthesis of estrogens, but had no effect on the catalytic activity of aromatase. XLY29 decreased the expression of aromatase promoter I.3/II, and suppressed the phosphorylation of cAMP response element-binding protein. XLY29 potently inhibited phosphorylation of p38 mitogen-activated protein kinase and AKT but had no effect on phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. XLY29 also decreased the serum 17ß-estradiol level and disturbed estrous cycle in mice. These results suggest that modulation of estrogen biosynthesis is a novel effect of L. japonicus, and XLY29 warrants further investigation as a new therapeutic means for the treatment of estrogen-related diseases.

Premnafulvol A: A Diterpenoid with a 6/5/7/3-Fused Tetracyclic Core and Its Biosynthetically Related Analogues from Premna fulva.

Premnafulvol A (1), a unique diterpenoid featuring a 6/5/7/3-fused tetracyclic carbon skeleton, with three biosynthetically related analogues, premnafulvols B-D (2-4), were isolated from the aerial parts of Premna fulva. Structures of 1-4 were established by a combination of extensive spectroscopic analyses, quantum chemical calculations, and X-ray crystallography. Plausible biosynthetic pathways of 1-4 were proposed. Interestingly, 2 and 3 exhibited opposite effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells by modulating the expression of aromatase.

In Vitro Human Dihydroorotate Dehydrogenase Inhibitory, Anti-inflammatory and Cytotoxic Activities of Alkaloids from the Seeds of Nigella glandulifera.

Four new dolabellane-type diterpene alkaloids, glandulamines A - D (1:  - 4: ), together with twelve known compounds (5:  - 16: ), were isolated from the seeds of Nigella glandulifera using repeated column chromatography and semipreparative HPLC. The structures of 1:  - 16: were elucidated based on NMR data analysis, HRMS experiments and other spectroscopic interpretations. The absolute configuration of 5: was determined by single-crystal X-ray diffraction data for the first time. Compounds 10: and 12: showed human dihydroorotate dehydrogenase inhibitory activity with IC50 values of 61.1 ± 5.3 and 45.9 ± 3.0 µM, respectively. Molecular docking of the active compound 12: and positive control teriflunomide on the inhibitor-binding site of human dihydroorotate dehydrogenase was subsequently performed to visualize the interaction pattern. In addition, compounds 8: and 10: exhibited inhibitory effects against lipopolysaccharide-induced nitric oxide production with inhibition rates of 61 and 41%, respectively, at the concentration of 10 µM. Compounds 9: and 12: showed cytotoxic activities with cell viability varying from 29 ~ 57% at 100 µM against T98G, U87, U251, and GL261 glioma cancer cell lines. These data provide new insights on the pharmacologically active compounds of this plant widely used in folk medicine.

Isolation, Characterization, and Structure-Activity Relationship Analysis of Abietane Diterpenoids from Callicarpa bodinieri as Spleen Tyrosine Kinase Inhibitors.

Species belonging to the genus Callicarpa are used traditionally in Chinese medicine for the treatment of inflammation, rheumatism, and pain. Investigation of the leaves and twigs of Callicarpa bodinieri resulted in the isolation of nine new abietane diterpenoids, bodinieric acids A-I (1-9), along with six known compounds (10-15). The structures of 1-9 were elucidated on the basis of the interpretation of their HRESIMS and NMR data and by ECD calculations. To explore the potential therapeutic target of this plant for immune-mediated disease, the inhibitory activities of the isolates obtained were determined against 13 kinase enzymes. Eight compounds exhibited moderate inhibitory effects on spleen tyrosine kinase (SYK), and the IC50 values of compounds 2 and 6 were 7.2 and 10.7 µM, respectively. In addition, a preliminary structure-activity relationship of this scaffold was analyzed with both molecular docking and a 3D-QSAR pharmacophore model.

Isolation, identification and bioactivities of abietane diterpenoids from Premna szemaoensis.

Investigation of the leaves and stems of Premna szemaoensis resulted in the isolation of twelve new abietane diterpenoids, szemaoenoids A-L (1-12), together with four known abietane diterpenoids (13-16). The structures involved two rearranged-abietane skeletons: 17(15 → 16)-abeo-abietane (7, 10-12, 14 and 15) and 17(15 → 16),18(4 → 3)-diabeo-abietane (1-6, 13 and 16). The structures of the new compounds were established mainly by analyzing NMR and HRESIMS data. The absolute configurations of 1, 3 and 10 were confirmed by single crystal X-ray diffraction analysis. In bioactivity assays, compounds 11, 12, 14 and 15 were active against two human colon cancer cell lines (HCT-116 and HT-29) with IC50 values ranging from 8.8 to 34.3 µM, and compounds 10, 13 and 14 exhibited effective free radical scavenging activity with IC50 values ranging from 35.6 to 41.5 µM by DPPH experiment.

Highly oxygenated lanostane-type triterpenoids and their bioactivity from the fruiting body of Ganoderma gibbosum.

Eight new highly oxygenated lanostane triterpenes, gibbosic acids A-H (1-8), along with three known ones (9-11), were isolated from the fruiting body of Ganoderma gibbosum. The structures of new isolates were assigned by NMR and HRESIMS experiments. The absolute configurations of 1 were further confirmed by single crystal X-ray diffraction data and computational ECD methods. Immunoregulatory effect and anti-inflammatory activities of these compounds were screened in murine lymphocyte proliferation assay and in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, respectively. Compound 2 exhibited immunostimulatory effect both in lymphocyte proliferation assay without any induction and ConA-induced mitogenic activity of T-lymphocyte, and the proportion of lymphocyte proliferation at the concentration of 0.1µM are 20.01% and 21.40%, respectively.

Two new phenolic compounds from the seeds of Machilus yunnanensis.

Chemical constituents investigation on the seeds of Machilus yunnanensis led to two new phenolic compounds 8-O-acetyl-phenylethanoid-4-O-ß-D-glucopyranoside (1) and (E)-2,3-bis(4-hydroxyphenyl)acrylaldehyde (2), together with 16 known compounds. Their structures were elucidated on the basis of spectroscopic data analysis (IR, MS, 1D, and 2D NMR). Meanwhile, compounds 1-3, 6-13, 17, and 18 were evaluated for vasorelaxant effects on the rat endothelium-intact thoracic aorta rings precontracted with phenylephrine (PE) or KCl. The bioassay results showed that compound 17 had significant vasorelaxant effect on the endothelium-intact thoracic aorta rings precontracted with KCl.