Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap.

Drawing inspiration from the structural resemblance between a natural product N-(3-carboxypropyl)-2-acetylpyrrole and phenylbutyric acid, a pioneer HDAC inhibitor evaluated in clinical trials, we embarked on the design and synthesis of a novel array of HDAC inhibitors containing an N-linked 2-acetylpyrrole cap by utilizing the pharmacophore fusion strategy. Among them, compound 20 exhibited potential inhibitory activity on HDAC1, and demonstrated notable potency against RPMI-8226 cells with an IC50 value of 2.89 ± 0.43 µM, which was better than chidamide (IC50 = 10.23 ± 1.02 µM). Western blot analysis and Annexin V-FTIC/propidium iodide (PI) staining showed that 20 could enhance the acetylation of histone H3, as well as remarkably induce apoptosis of RPMI-8226 cancer cells. The docking study highlighted the presence of a hydrogen bond between the carbonyl oxygen of the 2-acetylpyrrole cap group and Phe198 of the HDAC1 enzyme in 20, emphasizing the crucial role of introducing this natural product-inspired cap group. Molecular dynamics simulations showed that the docked complex had good conformational stability. The ADME parameters calculation showed that 20 possesses remarkable theoretical drug-likeness properties. Taken together, these results suggested that 20 is worthy of further exploration as a potential HDAC-targeted anticancer drug candidate.

Immunosuppressive Breviane Spiroditerpenoids from Penicillium bialowiezense Isolated from a Medicinal Plant.

Breviane spiroditerpenoids are a small group of structurally interesting and complex meroterpenoids. This work focused on an endophytic fungus Penicillium bialowiezense ZBWPQ-27 that was isolated from a medicinal plant Euphorbia neriifolia, leading to the isolation of 15 breviane spiroditerpenoids with four types of polycyclic systems (1-6 and 9-17), and two new carotane sesquiterpenoids (7 and 8). The structures including absolute configurations of the new compounds 1-8 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the misassigned NMR data of several resonances of the 5-methyl-TAL motif (E ring) in those of known brevianes (9-15) were corrected by spectroscopic data analysis. Biological tests revealed that brevianes with the type A ring system (6/6/6/5/6) showed moderate to significant immunosuppressive activities, and compound 11 displayed the most potent inhibitory activities against concanavalin A (ConA)-induced T cell proliferation (IC50 4.1 ± 0.2 µM) and lipopolysaccharide (LPS)-induced B cell proliferation (IC50 4.6 ± 0.2 µM), with good SI values of 28 ± 2 and 25 ± 4, respectively.

Anti-Inflammatory Salicin Derivatives from the Barks of Salix tetrasperma.

The genus Salix L. is traditionally used in folk medicine to alleviate pain caused by various kinds of inflammation. In the present study, 10 undescribed salicin derivatives along with 5 known congeners were isolated from the barks of Salix tetrasperma, and their structures were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, and chemical conversions. Compounds 4-6 significantly inhibited NO production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, and the most active 4 obviously suppressed the production of IL-1ß and IL-6 and decreased iNOS and COX-2 expression in a dose-dependent manner. Further Western blotting analysis revealed that the anti-inflammatory mechanism of 4 is possibly mediated through the MAPK and NF-κB signaling pathways.

Monoterpenoid indole alkaloids from Alstonia scholaris and their Toxoplasma gondii inhibitory activity.

Nine previously unreported various types of monoterpenoid indole alkaloids, together with seven known analogues were isolated from the stem barks of Alstonia scholaris through a silica gel free methodology. The structures of 1-9 were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Compound 1 is a modified echitamine-type alkaloid with a novel 6/5/5/7/6/6 hetero hexacyclic bridged ring system, and 8 and 9 exist as a zwitterion and trifluoroacetate salt, respectively. The anti-Toxoplasma activity of all isolates on infected Vero cells were evaluated, which revealed that compound 14 at 0.24 µM displayed potent activity. This study expanded the structural diversity of alkaloids of A. scholaris, and presented their potential application in anti-Toxoplasma drug development.

Diterpenoids from Euphorbia lactea and their anti-HIV-1 activity.

Nine undescribed diterpenoids, euphlactenoids A-I (1-9), including four ingol-type diterpenoids (1-4) with a 5/3/11/3-tetracyclic framework and five ent-pimarane-type diterpenoids (5-9), together with thirteen known diterpenoids (10-22), were identified from the leaves and stems of Euphorbia lactea Haw. The structures and absolute configurations of compounds 1-9 were unequivocally elucidated on the basis of spectroscopic analysis, ECD calculations and single crystal X-ray diffraction. Compounds 3 and 16 showed anti-HIV-1 effects with IC50 values of 1.17 µM (SI = 16.54) and 13.10 µM (SI = 1.93), respectively.

Diterpenoids from Sauropus spatulifolius Leaves with Antimicrobial Activities.

As a plant used in both food and medicine, Sauropus spatulifolius is consumed widely as a natural herbal tea, food source, and Chinese medicine. Inspired by its extensive applications, we conducted a systematic phytochemical study of the leaves of S. spatulifolius. Thirteen new diterpenoids, sauspatulifols A-M (1-13), including four ent-cleistanthane-type diterpenoids (1-4), eight 15,16-di-nor-ent-cleistanthane-type diterpenoids (5-12), and one 17-nor-ent-pimarane-type diterpenoid (13) as well as one known diterpenoid, cleistanthol (14), were isolated. All of these diterpenoids feature a 2α,3α-dihydroxy unit within the A ring, and their structures were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Compound 14 displayed moderate inhibitory activity against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, and Shigella flexneri with the same minimum inhibitory concentration value of 12 µg/mL as well as activity against vesicular stomatitis virus and influenza A virus.

Isolation, Characterization, and Possible Anti-Alzheimer's Disease Activities of Bisabolane-Type Sesquiterpenoid Derivatives and Phenolics from the Rhizomes of Curcuma longa.

One new bisabolane-type sesquiterpenoid, together with four known bisabolane-type sesquiterpenoid derivatives and seven phenolics, was isolated from the rhizomes of Curcuma longa. Their structures were elucidated by extensive spectroscopic (IR, HR-ESI-MS, and NMR) data analysis. The possible anti-Alzheimer's disease (AD) activities of the isolated compounds were also evaluated using Caenorhabditis elegans AD pathological model, and 1ß-hydroxybisabola-2,10-dien-4-one had the highest possible anti-AD activity.

Narjatamanins A and B, a pair of novel epimers possessing a 2,3-seco-iridoid skeleton with an unusual 1,10-oxygen bridge from Nardostachys jatamansi and evaluation of their effects on worm paralysis in AD C. elegans.

Narjatamanins A (1) and B (2), a pair of epimers possessing a novel 2,3-seco-iridoid skeleton with an unusual 1,10-oxygen bridge, were isolated from the whole plants of Nardostachys jatamansi. Their structures were elucidated by a combination of various spectroscopic methods, including HRESIMS, IR and 1D and 2D NMR techniques. The absolute configurations of 1 and 2 were established by electronic circular dichroism (ECD) calculations. The pharmacological activities of 1 and 2 to alleviate AD-like symptoms were also evaluated using the Caenorhabditis elegans Alzheimer's disease (AD) pathological model, and narjatamanins A (1) and B (2) showed statistically significant delay in the worm paralysis phenotype of AD-like symptoms.

Four novel sesquiterpenoids with their anti-Alzheimer's disease activity from Nardostachys chinensis.

Nardochinins A-D (1-4), four novel sesquiterpenoids, along with four known ones were isolated from the underground parts of Nardostachys chinensis Batal in ethanol. Their structures were determined by extensive spectroscopic methods and single-crystal X-ray diffraction. Nardochinin A (1) possessed a norsesquiterpene skeleton with an unusual 3/6/5/5 tetracyclic ring system, which had not appeared in natural products. Nardochinins B (2) and C (3) were the first time found naturally occurring sesquiterpenoids with a 4,5-seco-nardosinane skeleton. Besides, compound 3 represented an unprecedented 4,5-seco-nardosinane type norsesquiterpenoid with losing an isopropenyl at C-6 compared with 2 in the structural framework. Nardochinin D (4) was a novel, highly oxygenated valerenane-type sesquiterpenoid possessing a rare 3,12-epoxy group and an unusual 9,11-epoxy group. The anti-Alzheimer's disease (AD) activities of 1-4 were also evaluated using the Caenorhabditis elegans AD pathological model, and nardochinin B (2) had the highest anti-AD activity.

Norcrassin A, a novel C16 tetranorditerpenoid, and bicrotonol A, an unusual dimeric labdane-type diterpenoid, from the roots of Croton crassifolius.

A novel C16 tetranorditerpenoid, norcrassin A (1), and an unusual dimeric labdane-type diterpenoid, bicrotonol A (2), were isolated from the roots of Croton crassifolius. Norcrassin A (1) featured a new carbon skeleton with an unprecedented 5/5/5/6 tetracyclic system. Bicrotonol A (2) possessed an unusual tetrahydroxypyran ring linkage connecting two labdane diterpenoid monomers. The structures of all compounds, including the absolute configuration, were elucidated by the interpretation of their NMR spectroscopic data, high resolution mass spectrometry, and single-crystal X-ray diffraction. A plausible biosynthetic pathway of 1 is proposed. The anti-Alzheimer's Disease (AD) activities of 1 and 2 are also evaluated using the AD pathological model.

Cytotoxic and antibacterial activities of iridoids and sesquiterpenoids from Valeriana jatamansi.

Three new iridoids, valejatanins A-C (1-3), and one new natrual iridoid (4), together with four known sesquiterpenoids (5-8), were isolated from the roots of Valeriana jatamansi Jones. Compounds 3 and 4 are C(4)-epimers. Their structures were elucidated by extensive spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and by comparison of their NMR data with those of related compounds. The absolute configuration of 5 was determined for the first time by single-crystal X-ray diffraction analysis with Cu-Kα irradiation. The cytotoxic activities of all compounds were evaluated against HT29, K562 and B16 cancer cell lines in vitro by MTT assay. Valejatanin A (1) showed noteworthy cytotoxic activities with IC50 values of 22.17, 15.26, 3.53µg/mL against three cancer cell lines. The antibacterial activities of all compounds against bacteria were tested in vitro. Compound 6 exhibited antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa.

Phenolic compounds from Bletilla striata.

Two new malic acid derivatives, namely eucomic acid 1-methyl ester (2) and 6'''-acetylmilitaline (7), together with ten known compounds (1, 3-6, 8-12), were isolated from the dry tubers of Bletilla striata (Thunb.) Reichb. F., a perennial traditional Chinese medicinal herb, which was used for the treatment of pneumonophthisis, pneumonorrhagia, tuberculosis, and hemorrhage of the stomach or lung. Their structures were elucidated by spectroscopic analyses, including 1D-, 2D-NMR, and HR-ESI-MS.

Eremophilane-type Sesquiterpenes from the Leaves of Ligularia virgaurea.

A phytochemical study of the ethanolic extract of the leaves of Ligularia virgaurea led to the isolation of a new eremophilane-type sesquiterpene lactone, (4S,5R,6S,8S,lR)-6ß-angeloyloxy-eremophil-7(l l)-en-10ßH-8α,12-olide (1), along with a known eremophilane-type sesquiterpene, (4S,5R,6S,lOS)-6ß- angeloyloxy-10ßH-furanoeremophil-9-one (2). Their structures were elucidated by extensive spectroscopic methods, including ID and 2D nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry experiments, and the absolute configurations were confirmed by single-crystal X-ray diffraction analysis using the anomalous scattering of Cu Ka radiation.