Jun-Sheng Zhang

Natural nitric oxide (NO) inhibitors from Aristolochia mollissima

Six new sesquiterpenoids, aristomollins A–F (1–6), and 24 known analogues (7–30) were isolated from the leaves and stems of Aristolochia mollissima. Their structures were elucidated by spectroscopic analysis, and the absolute configurations of compounds 2–5 were determined by the chemical correlations and quantum chemical ECD calculations. Compound 1 represented an unprecedented 5,6-seco-4,5-cyclohumulane skeleton. All the compounds were examined for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 microglial cells, and compounds 4, 9, 28, and 30 exhibited pronounced inhibition of NO production with IC50 values in the range of 5.7–9.9 μM, being more active than the positive control, quercetin (IC50 = 15.7 μM).

Bioactive Cembranoids from the South China Sea Soft Coral Sarcophyton elegans

Four new cembranoids, sarcophelegans A–D (1–4) and six known analogues (5–10) were isolated from the South China Sea soft coral Sarcophyton elegans. Their structures were elucidated through detailed spectroscopic analysis, and the absolute configuration of 1 was confirmed by single-crystal X-ray diffraction. The antimigratory potential of compounds 1–10 were evaluated and compounds 2 and 6 were found to inhibit human breast tumor MDA-MB-231 cell migration at 10 μM.

Anti-inflammatory sesquiterpenoids from the Traditional Chinese Medicine Salvia plebeia : Regulates pro-inflammatory mediators through inhibition of NF-κB and Erk1/2 signaling pathways in LPS-induced Raw264.7 cells

ETHNOPHARMACOLOGICAL RELEVANCE Salvia plebeia R. Brown, a traditional Chinese medicinal herb, has been used to treat inflammatory diseases such as cough, hepatitis, and diarrhea for a long history. AIM OF THE STUDY The aim of the present study was to isolate and identify potential anti-inflammatory agents from the herb of S. plebeia, which may have contributed to its folk pharmacological use in the treatment of inflammatory diseases. MATERIAL AND METHODS The aerial parts of S. plebeia were extracted with 95% ethanol and separated by silica gel, RP-C18, Sephadex LH-20, and HPLC. The structures of the isolated compounds were elucidated by extensive spectroscopic analysis (MS, NMR, and X-ray). Anti-inflammatory activities of all compounds were evaluated by the model of LPS-induced up-regulated of NO in Raw264.7 macrophages. The expression levels of cytokine (TNF-α) and proteins (iNOS and COX-2) were assessed by ELISA kit and Western blotting analysis, respectively. Furthermore, the influences of salviplenoid A (1) on NF-κB and MAPK signaling pathways were determined by Western blotting analysis and immunofluorescence assay. RESULTS Six new (1-6, salviplenoids A-F) and ten known (7-16) sesquiterpenoids were isolated from the herb of S. plebeia. The absolute configurations of compounds 1, 2, and 7 were determined by X-ray diffraction. The new eudesmane-type sesquiterpenoid, salviplenoid A (1), significantly decreased the release of NO and TNF-α and the expression of proteins iNOS and COX-2. In addition, the biochemical mechanistic study indicated that 1 regulated the NF-κB dependent transcriptional activity through inhibiting the nuclear translocation of p50/p65 dimer and decreasing the phosphorylation of IκB and Erk1/2. CONCLUSIONS Among all sesquiterpenoids isolated from S. plebeian, the new salviplenoid A (1) exhibited the most potent anti-inflammatory activity in LPS-induced Raw264.7 cells via inhibition of NF-κB and Erk1/2 signaling pathways.

Design, Synthesis, and Biological Evaluation of Novel Selenium-Containing Isocombretastatins and Phenstatins as Antitumor Agents

Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl(phenyl)selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC50 values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4) represented the most active compound with IC50 values of 2-34 nM against 12 cancer cell lines, including two drug-resistant cell lines. Importantly, its phosphate salt, 11ab, inhibited tumor growth in xenograft mice models with inhibitory rate of 72.9% without apparent toxicity, which was better than the reference compounds isoCA-4P (inhibitory rate 52.2%) and CA-4P (inhibitory rate 47.6%). Mechanistic studies revealed that 11a is a potent tubulin polymerization inhibitor, which could arrest cell cycle at G2/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, 11a could serve as a promising lead for the development of highly efficient anticancer agents.

Polycyclic polyprenylated acylphloroglucinols: natural phosphodiesterase-4 inhibitors from Hypericum sampsonii

Chemical investigation of the aerial parts of Hypericum sampsonii led to the isolation of seven new polycyclic polyprenylated acylphloroglucinols, hypersampsonones A–G (1–7), together with 23 known analogs (8–30). Their structures including the absolute configurations were elucidated by combined spectroscopic analysis, quantum chemical ECD calculations, and chemical methods. Compound 1 represents an unprecedented cyclocitral monoterpene-coupled bicyclo[3.3.1]nonane skeleton, while 2 features an unusual hexahydrofuro[2,3-b]furan-diepoxy ring system fused in a tricyclo[4.3.1.15,7]undecane skeleton. All the compounds were screened by using tritium-labeled adenosine 3′,5′-cyclic monophosphate ([3H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 1, 18–19, 21, and 25–30 exhibited inhibition with IC50 values less than 10 μM, in which compound 19 represented the most active compound (IC50 = 0.64 μM), being comparable to the positive control, rolipram (IC50 = 0.62 μM).

Natural diarylfluorene derivatives: isolation, total synthesis, and phosphodiesterase-4 inhibition

In our previous study, selaginpulvilins A–D (1–4) featuring an unprecedented 9,9-diphenyl-1-(phenylethynyl)-9H-fluorene skeleton were identified as potent phosphodiesterase-4 (PDE4) inhibitors from Selaginella pulvinata. In the current work, a large-scale reinvestigation of the same plant led to the isolation of six additional new analogues, selaginpulvilins E–J (5–10), among which 5 features a rare 6-(4-hydroxyphenyl)-2H-pyran-2-one unit. Compounds 5–10 exhibited remarkable inhibitory activities against PDE4 with IC50 values in the range of 0.22–1.38 μM. The first total synthesis of selaginpulvilins A–F (1–6) was developed in 7–11 steps involving a Friedel–Crafts reaction as the key reaction, which provides a feasible access to this scaffold.

New prenylated coumarins from the stems of Toddalia asiatica

Eight new prenylated coumarins (1a/1b, 2a/2b, and 3–6) including two pairs of enantiomers (1a/1b and 2a/2b), a new phenolic acid derivative, methyl (E)-3,4-bis(4-hydroxyphenyl)-4-oxobut-2-enoate (7), and 33 known compounds (8–40) were isolated from the stems of Toddalia asiatica. Their structures were established from spectroscopic data and by chemical methods. The absolute configurations of two pairs of enantiomers (1a/1b and 2a/2b) were determined by X-ray diffraction analysis together with ECD and specific optical rotation calculations. The inhibitory effects of selected compounds against phosphodiesterase-4 (PDE4) were evaluated, and compounds 12, 19, 21–23, 26, 34, and 35 exhibited PDE4 inhibition activities with IC50 values less than 10 μM.

New lanostane-type triterpenoids from the fruiting body of Ganoderma hainanense

Five new lanostane-type triterpenoids, ganoderenses A-E (1-5), two new lanostane nor-triterpenoids, ganoderenses F and G (6 and 7), along with 13 known analogues (8-20) were isolated from the fruiting body of Ganoderma hainanense. Their structures were determined by combined chemical and spectral methods, and the absolute configurations of compounds 1 and 13 were confirmed by single crystal X-ray diffraction. All compounds were evaluated for inhibitory activity against thioredoxin reductase (TrxR), a potential target for cancer chemotherapy with redox balance and antioxidant functions, but were inactive.

Biscembranoids and Cembranoids from the Soft Coral Sarcophyton elegans

Two novel biscembranoids, sarelengans A and B (1 and 2), five new cembranoids, sarelengans C–G (3–7), along with two known cembranoids (8 and 9) were isolated from the South China Sea soft coral Sarcophyton elegans. Their structures were determined by spectroscopic and chemical methods, and those of 1, 4, 5, and 6 were confirmed by single crystal X-ray diffraction. Compounds 1 and 2 represent the first example of biscembranoids featuring a trans-fused A/B-ring conjunction between the two cembranoid units. Their unique structures may shed light on an unusual biosynthetic pathway involving a cembranoid-∆8 rather than the normal cembranoid-∆1 unit in the endo-Diels-Alder cycloaddition. Compounds 2 and 3 exhibited potential inhibitory effects on nitric oxide production in RAW 264.7 macrophages, with IC50 values being at 18.2 and 32.5 μM, respectively.

A new bisabolane sesquiterpenoid and a new abietane diterpenoid from Cephalotaxus sinensis

Abstract Phytochemical investigation of Cephalotaxus sinensis has led to the isolation of a new bisabolane sesquiterpenoid (1), a new abietane diterpenoid (2), and 13 known compounds (3–15). Their structures were elucidated by extensive spectroscopic analysis (MS, UV, IR, and NMR).