Nine undescribed guaiane sesquiterpenoids named linderaguaianoids A-I, together with thirteen reported analogues, were isolated from the roots of Lindera glauca. Their structures were fully elucidated by spectroscopic techniques, single-crystal X-ray diffraction experiments, and quantum chemical calculations. Linderaguaianoid A is characterized as a rare 5/5/6/5-caged tetracyclic sesquiterpenoid with a [5.3.1.14,11.01,5]dodecane scaffold. Linderaguaianoids B-C and E are uncommon guaiane-type norsesquiterpenoids. Among these compounds, pseudoguaianelactone A inhibits hypoxia-inducible factor-1α activity, suppresses macrophage-mediated inflammatory response, and alleviates liver injury in LPS/D-GalN-induced acute liver injury mice, suggesting that it may emerge as a potent lead for the development of therapeutic agent against acute liver injury.

The beta-carboline scaffold and amide bond have great potential for drug discovery as consisting in many marketed pharmaceuticals and drug candidates. Compared to the chemical method, enzymatic synthesis of amide with nontoxicity and mild reaction conditions has received great attention. In this study, the amide bond synthetase MarA was characterized, and a series of novel amide-containing beta-carboline analogues were synthesized by MarA-catalyst. Compound 5b having fluorine substitution, and compound 5n possessing an N-methyl substituent, showed excellent anti-myocardial fibrosis effects, which were found to be superior to the positive control drug, captopril. Our study provides MarA as a new green biocatalytic strategy for the synthesis of new beta-carboline analogues with anti-fibrotic properties.

Twelve undescribed meroterpenoids possessing bicyclic polyprenylated acylphloroglucinol (BPAP) scaffold, (±)-lancasternoids A-D and lancasternoids E-H, together with fourteen known analogues, were isolated from Hypericum lancasteri (Hypericaceae) and structurally characterized. (±)-Lancasternoids A-D are the first examples of bicyclo[3.2.1]octane-type BPAP meroterpenoids present as enantiomeric pairs, while (±)-lancasternoids A-C incorporate an unprecedented 5-oxatetracyclo[7.5.1.04,9.01,11]pentadecane system. Lancasternoids E-H are two pairs of epimers with [3.3.1]-type BPAP scaffold. Some of the isolates showed inhibition in hypoxia-inducible factor-1α (HIF-1α) responsive element (HRE) luciferase assay, and uraloidin A further decreased the lipopolysaccharide (LPS)-induced pro-inflammatory factor IL-1β expression level in RAW 264.7 cells.

Two undescribed cardiac glycosides, strasperoside K (1) and L (2), together with five known analogs (3-7), were isolated from Streblus asper Lour. Their structures were elucidated on the basis of spectroscopic analysis and chemical methods. The inhibitory activities of isolated compounds against porcine epidemic diarrhea virus (PEDV) and six strains of pathogenic bacteria were evaluated.

Ten enantiomeric pairs of meroterpenoids were isolated from Rhododendron capitatum Maxim. Among them, (+/-)-capitanoids A-F, (+)-ranhuadujuanine B, (-)-rubiginosin G, and (-)-anthopogochromene B are undescribed compounds. Their structures were fully established by spectroscopic techniques, X-ray crystallographic analyses, modified Mosher's method, and ECD calculation. (+/-)-Capitanoid A are the first pair of meroterpenoids possessing an unusual 6/7/5 heterocyclic system characterized by a 1,2,3,3a, 10,10a-hexahydrobenzo [b]cyclopenta[e][1,4]dioxepine motif. (+/-)-Capitanoid F are a pair of meroterpenoids with a tris-normonoterpene moiety that are discovered from the genus Rhododendron for the first time. (+/-)-Rubiginosin G, (+/-)-anthopogochromene B, and (-)-rhodonoid B showed inhibition in hypoxia-inducible factor-1α (HIF-1α) responsive element (HRE) luciferase assay. Furthermore, (+)-anthopogochromene B and (-)-rhodonoid B exhibited suppressive effects on macrophage-mediated inflammatory response by downregulating the pro-inflammatory factor IL-1β expression level and secretion.

Ten undescribed cardiac glycosides, strasperosides A -J, together with twelve known analogues, were isolated from Streblus asper Lour. Their structures were elucidated on the basis of spectroscopic analysis, electronic circular dichroism data, and chemical methods. These cardiac glycosides showed diversity in steroid skeleton and sugar moiety. Strasperosides A and B are a pair of unusual stereoisomers featuring different orientation of the lactone motif. Ten cardiac glycosides demonstrated potent antiviral effects on HSV-1 in vitro with the IC50 values from 0.19 +/- 0.08 to 1.03 +/- 0.25 mu M and the therapeutic indices from 66.61 +/- 5.08 to 326.75 +/- 11.75.

PCSK9 has been recognized as an efficient target for hyperlipidemia and related cardiovascular/cerebrovascular diseases. However, PCSK9 inhibitors in the clinic are all biological products, and no small molecules are available yet. In the current work, we discovered that the crude extract of Euphorbia esula (E. esula) promoted LDL uptake in vitro and then obtained 8 new and 12 known jatrophane diterpenoids by activity-guided isolation. After summarized their structure-activity relationship of PCSK9 inhibition, we selected compound 11 (C11) with potent activity and high abundance to investigate its mechanism and in vivo efficacy. Mechanistically, C11 bound with HNF1 alpha to influence its nuclear distribution and subsequently inhibit PCSK9 transcription, thereby enhancing LDLR and promoting LDL uptake. Moreover, C11 demonstrated obvious lipid-lowering activity in HFD mouse model. In conclusion, we first revealed the novel application of E. esula in the discovery of a lipid-lowering candidate and highlighted the potential of C11 in the treatment of hyperlipidemia.

Three new formyl phloroglucinol meroterpenoids, eumaidials A-C (1–3), were isolated from the leaves of Eucalyptus globulus subsp. maidenii, along with ten known analogues (4–13). Their chemical structures were determined by various spectral data and electronic circular dichroism calculations. Eumaidial A (1) is the first β-caryophyllene-based formyl phloroglucinol meroterpenoids from the genus Eucalyptus. Compounds 1–4 and 10 exhibited ATP-citrate lyase inhibitory activities, and compounds 2 and 3 suppressed the hepatocyte lipogenesis.

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 dif-fraction,and computational approaches.Both compounds showed anti-inflammatory activity in vitro.Compounds 1 and 2 could de-crease the lipopolysaccharide(LPS)-/nigericin-induced IL-1β release in THP-1 cells.Both compounds also showed inhibition in hypox-ia-inducible factor-1α(HIF-1α)pathway luciferase reporter assay.

Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain.

As a both edible and medicinal plant, Hypericum patulum (Hypericaceae) is used as a natural herbal tea, scented tea, and folk medicine. In this study, eight undescribed bicyclic polyprenylated acylphloroglucinol-related meroterpenoids named hyperpatins A–H, along with eight known ones, were isolated from this plant. Their structures were elucidated on the basis of spectroscopic techniques, chemical method, X-ray crystallographic experiments, and electronic circular dichroism analyses. Hyperpatins A–H possess a characteristic pyran ring system diversely fused with the bicyclo[3.3.1]nonane-2,4,9-trione core, and hyperpatins C and D incorporate a unique α,β-unsaturated aldehyde moiety. Some of the isolates exhibited potent inhibitory effects on death-associated protein kinase-related apoptosis-inducing kinase 2 with IC50 values ranging from 2.60 ± 0.29 to 17.93 ± 3.08 μM. This is the first report of DRAK2 inhibitory activity for acylphloroglucinol-related meroterpenoids. The most active molecule hyperpatins C showed binding affinity with DRAK2 by hydrogen-bond and hydrophobic interactions in molecular docking and promoted the glucose-stimulated insulin secretion ability of primary islets.

Two enantiomeric pairs of macrocyclic acylphloroglucinols (1a/1b and 2a/2b) with an unprecedented carbon skeleton featuring a bicyclo[12.3.1]octadecane core, together with an undescribed biogenetically related long-chain acylphloroglucinol (3), were isolated from Syzygium szemaoense. Their structures were fully established by spectroscopic method, X-ray crystallographic analysis, and ECD calculation. Compounds 1b and 2a/2b exhibited inhibition against death-associated protein kinase-related apoptosis inducing protein kinase 2 (DRAK2) and ATP citrate lyase (ACLY), respectively.

Undescribed enantiomeric pairs of acylphloroglucinol related meroterpenoids with 11/5/6 spiro-heterocyclic systems were isolated from Hypericum kouytchense.

Abstract Two new maytansinoids, N-methyltreflorine (1) and methyltrewiasine (2), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3 – 5). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1 and 2 was determined by X-ray crystallographic analysis. Compounds 1 – 5 exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 – 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1 and 4 also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1 and 2 significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

Five undescribed enantiomeric pairs of acylphloroglucinol-monoterpene meroterpenoids ((+)-/(−)-eucateretins A−E) resolved by chiral-phase HPLC were obtained from the leaves of Eucalyptus tereticornis Smith, along with nine known analogues. Their structures were elucidated by spectroscopic methods and ECD calculations. This is the first report of meroterpenoid enantiomers from this plant. Some of the isolates, (−)-eucateretin A, (+)-/(−)-eucateretins E, 7′α-eucalrobusone X, eucalrobusone X, and robustadial B, exhibited inhibitory effects on ATP citrate lyase, and 7′α-eucalrobusone X significantly suppressed the hepatocyte lipogenesis.

Three novel dimeric sesquiterpenoids named sarglanoids A-C (1-3), two undescribed monomeric sesquiterpenoids named sarglanoids D (4) and E (5), and seven known compounds (6-12), were isolated and characterized from Sarcandra glabra. Compound 1 represents the first heterodimeric sesquiterpenoid composed of a eudesmane and an eremophilane moiety. Compound 2 possesses two eremophilane monomers featuring an undescribed dimerization pattern. Compound 3 is a symmetric eudesmane dimer with a rare 1,4-epoxy bridge. The structures of 1-5 were fully identified by spectroscopic methods and single-crystal X-ray diffraction experiments. Compounds 3 and 6 suppressed the LPS-triggered inflammatory responses in RAW 264.7 cells.

Comprehensive Summary 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‐ κ B) pathway inhibition. The NF‐ κ B inhibitors further suppressed the lipopolysaccharide (LPS)‐induced inflammatory responses in RAW 264.7 cells.

Two new oleanane-triterpenoid saponins, clinograsaponins A (1) and B (2), together with twelve known ones (3-14), were isolated from the whole herb of Clinopodium gracile (Bentham) Matsumura. Their structures were determined by spectroscopic analysis and chemical method. All the isolated compounds were evaluated for their activities against ATP-citrate lyase (ACLY) and nuclear factor kappa B (NF-κB).

Three unprecedented dimeric clerodane diterpenoids, dodovisdimers A-C (1-3), along with six known clerodane monomers (4-9), were isolated from Dodonaea viscosa. Compounds 1-3 may be biosynthetically formed via an intermolecular Diels-Alder [4+2] cycloaddition between the coexisting monomers 4-7. The structures of these clerodanes were characterized by spectroscopic techniques, X-ray crystallographic study, and ECD calculations. Some isolates exerted antiviral effects on human influenza A virus (H3N2) in vitro.