Highly Aromatic Norditerpenoid Heterodimers and Monomers from Trigonostemon fragilis

Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.

Isoprenylated Flavonoids with PTP1B Inhibition from Macaranga denticulata

Three new C-methylated and isoprenylated chalcone derivatives,dentichalcones A–C(1–3),together with six known compounds(4–9),were isolated from the twigs and leaves of Macaranga denticulata.Their structures were elucidated by spectroscopic analysis,including 1D,2D NMR,and MS data.The known compounds,(2E)-1-(5,7-dihydroxy-2,2,6-trimethyl-2H-benzopyran-8-yl)-3-(4-methoxyphenyl)-2-propen-1-one(4),(2E)-1-(5,7-dihydroxy-2,2-dimethyl-2H-benzopyran-8-yl)-3-phenyl-2-propen-1-one(5),laxichalcone(6),macarangin(7),bonanniol A(8),and bonannione A(9),showed inhibitory activities against protein tyrosine phosphatase 1B(PTP1B)in vitro.Graphical Abstract Three new C-methylated and isoprenylated chalcone derivatives,dentichalcones A–C(1–3),together with six known compounds,were isolated from the twigs and leaves of Macaranga denticulata.Some compounds showed inhibitory activities against PTP1B in vitro.

A new class of potent liver injury protective compounds: Structural elucidation, total synthesis and bioactivity study

A new class of potent liver injury protective compounds,phychetins A-D(1-4)featuring an unique 6/6/5/6/5 pentacyclic framework,were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus.Compounds 2-4 are three pairs of enantiomers that were initially obtained in a racemic manner,and were further separated by chiral HPLC preparation.Compounds 1-4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step.A bioinspired total synthesis strategy was thus designated,and allowed the effective syntheses of compounds 2-4 in high yields.Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1β.Notably,compound 4,the most active enantiomeric pair in vitro,displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice,which could serve as a promising lead for the development of acute liver injury therapeutic agent.

Alkaloid Constituents of Ficus hispida and Their Antiinfammatory Activity

Four new alkaloids,fcuhismines A-D(1-4),together with three known ones,were isolated from Ficus hispida.Their structures were elucidated by spectroscopic analysis and chemical method.The new compounds represent the frst amine alkaloids with a rhamnosyl moiety(1-2)or with a N-oxide motif(2-4)from the genus Ficus.Compound 2 showed potent inhibitory efect in nuclear factor-κB(NF-κB)pathway luciferase assay with IC_(50) value of 0.52±0.11μM.

Study on the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease based on molecular docking

Objective:To explore the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease(AD)based on molecular docking.Methods:22 major components of Radix et Rhizoma Rhei were screened from TCMSP and related literatures,which docked with the key targets of NLRP3/Caspase-1/GSDMD signaling pathway.NLRP3,Caspase-1,GSDMD inhibitors MCC950,ML132 and LDC7559 were used as positive control to analyze the docking results.Results:The docking results showed that the main components of Radix et Rhizoma Rhei had different degrees of binding with NLRP3,Caspase-1 and GSDMD targets,and the potential active components were mutanochrome and physciondiglucoside.Conclusion:Molecular docking predicts that the main components of Radix et Rhizoma Rhei may act on NLRP3/Caspase-1/GSDMD signaling pathway,and the active components may be mutanochrome and physciondiglucoside,which provides theoretical basis for revealing the anti-inflammatory mechanism and active components of Radix et Rhizoma Rhei in the treatment of AD.

Hyperlanins A and B, Two Highly Rearranged Meroterpenoids from Hypericum lancasteri

Hyperlanins A(1)and B(2),two highly rearranged polycyclic polyprenylated acylphloroglucinol(PPAP)-related meroterpenoids based on different new carbon skeletons,were isolated from Hypericum lancasteri.Compound 1 incorporates an unprecedented 5/6/7/5 ring system featuring a 3,13-dioxatetracyclo[9.2.1.12.5.01.8]pentadecane core.Compound 2 possesses a unique compact 6/6/5/6/6/5/6 ring system with a caged tetracyclo[6.2.1.13.8.05,11]dodecane motif.Their structures were established by spectroscopic data,X-ray diffraction,and computational approaches.Both compounds showed anti-inflammatory activity in vitro.Compounds 1 and 2 could decrease the lipopolysaccharide(LPS)-/nigericin-induced IL-1βrelease in THP-1 cells.Both compounds also showed inhibition in hypoxia-inducible factor-1α(HIF-1αa)pathway luciferase reporter assay.

Assessment of right ventricular strain in children with repaired tetralogy of Fallot using speckle tracking imaging

To the Editor: Tetralogy of Fallot (TOF) was first surgically repaired in 1955. Initial TOF repairs were performed using a trans-annular right ventricular outflow tract patch to relieve the obstruction. However, this procedure resulted in long-standing pulmonary valve regurgitation and increased right ventricular (RV) volume, causing arrhythmias and sudden death.[1] Thus, pulmonary annulus preservation became the most prevalent surgical strategy for TOF repair, possibly causing a mix of pulmonary stenosis and pulmonary valve regurgitation. Currently, clinicians concerned with RV function decrease during the long-term follow-up use of cardiac magnetic resonance imaging (CMR) to predict the appropriate timing of interventions for valve sparing. Although CMR techniques have evolved as the reference standard for assessing RV volumes and function during the last two decades, routinely monitoring the progression of repaired tetralogy of Fallot (rTOF) RV dysfunction remains difficult.

cis-Clerodane Diterpenoids with Structural Diversity and Anti-inflammatory Activity from Tinospora crispa

Twelve new cis-clerodane diterpenoids, designated as crispinoids A—L (1—12), together with three known analogues (13—15), were isolated from Tinospora crispa. Their structures were fully assigned by comprehensive spectroscopic techniques, single-crystal X-ray diffraction experiments, and electronic circular dichroism (ECD) analyses. The isolated clerodanes displayed diverse heterocyclic frameworks including 6/6/6-, 6/5/6/6-, 6/6/5-, 6/6-, and 6/5/6-fused ring systems. Some of the isolates showed ATP-citrate lyase (ACLY) and nuclear factor kappa B (NF-κB) pathway inhibition. The NF-κB inhibitors further suppressed the lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells.

Discovery of Novel Long-Chain Alkenyl Diacid Derivatives as ACLY Inhibitors

ATP citrate lyase(ACLY)synthesizes cytosolic acetyl coenzyme A(acetyl-CoA),an essential biosynthetic precursor for lipid synthesis and the acetyl donor required for protein acetylation.The aberrant expression and activity of ACLY has been documented in multiple human cancers.ETC-1002 is an indirect ACLY inhibitor,and it has recently been approved by the FDA as an additional therapeutic option in high-risk hypercholesterolemia patients unable to meet goals with standard therapy.In this work,we identified a series of novel long-chain alkenyl diacids as potent direct ACLY inhibitors,and comprehensive structure-activity relationship analysis showed that compound 18f was the most potent ACLY inhibitor with an IC50 value of 1.5μmol/L.Subsequent ester formation of 18f gave a new series of compounds such as 25f that maintained ACLY inhibitory activity and improved antitumor cell proliferation effects.