Erythrocarpines A-E, new cytotoxic limonoids from Chisocheton erythrocarpus

Five new cytotoxic limonoids, erythrocarpines A-E (1-5), were isolated from the bark of Chisocheton erythrocarpus Hiern. Chemical structures, stereochemistry, and conformation were fully elucidated and characterized by 2D NMR, MS, and computational methods.     

Chisopanins A-K, 11 new protolimonoids from Chisocheton paniculatus and their anti-inflammatory activities

Eleven new protolimonoids, chisopanins A-K (1-11), were isolated from the twigs of Chisocheton paniculatus, as well as thirteen known (12-24) protolimonoids. The structures were elucidated on the basis of spectroscopic analysis, X-ray crystallographic analysis, and chemical methods. Chisopanins A and B (1 and 2) possessing uncommon hemiketal tetrahydropyran ring at C-17 showed the most potent inhibitory activities on lipopolysaccharide-stimulated inflammation factor-release with IC(50) values at 5.4 and 7.9 μM for NO, and at 26.9 and 30.7 μM for TNF-α, respectively. In addition, compounds 5-7, 9, 12, 13, and 20 were potent to inhibit NO production with IC(50) value lower than 10 μM.     

Discovery of halogenated eurypamide B analogues as inhibitors of lipid droplet accumulation in macrophages

Halogenated cyclic isodityrosine-tripeptides were synthesized as analogues of a marine natural product, eurypamide B. Although the original eurypamides showed no inhibitory activity, the new analogues were found to inhibit lipid droplet accumulation in macrophages with a low micromolar IC50 value.     

Turrianes from Kermadecia rotundifolia as new acetylcholinesterase inhibitors

Four new kermadecins, together with the known kermadecins A, B and D have been isolated from the Kermadecia rotundifolia ethyl acetate bark extract. These compounds are derivatives of the (20-membered-o,-p)cyclophane skeleton and belong to the turriane family. The structures were elucidated by mass spectrometry, extensive one- and two-dimensional NMR spectroscopy and through comparison with data reported in the literature. Isokermadecin D (2) and kermadecins D and J (7 and 4) possess significant inhibitory effect on acetylcholinesterase.     

Advances in Chemistry and Bioactivity of the Genus Chisocheton Blume

Chisocheton is one of the genera of the family Meliaceae and consists of ca. 53 species; the distribution of most of those are confined to the Indo‐Malay region. Species of broader geographic distribution have undergone extensive phytochemical investigations. Previous phytochemical investigations of this genus resulted in the isolation of mainly limonoids, apotirucallane, tirucallane, and dammarane triterpenes. Reported bioactivities of the isolated compounds include cytotoxic, anti‐inflammatory, antifungal, antimalarial, antimycobacterial, antifeedant, and lipid droplet inhibitory activities. Aside from chemistry and biological activities, this review also deals briefly with botany, distribution, and uses of various species of this genus.     

Quassinoids from Eurycoma longifolia as plant growth inhibitors.

Seven quassinoids including a new 12-epi-11-dehydroklaineanone were isolated from the leaves of Eurycoma longifolia (Simaroubaceae) as plant growth inhibitors or related compounds. The strongest activity was found in 14,15beta-dihydroxyklaineanone.     

Ellagitannins from Tuberaria lignosa as entry inhibitors of HIV

Screening of plants from the Iberian Peninsula for anti-human immunodeficiency virus (-HIV) activity revealed that aqueous extract of Tuberaria lignosa gave positive results. Following an activity-guided procedure, the crude extract was counterextracted, and the subsequent fractions obtained tested for their anti-HIV activity in vitro. The bioassay-guided fractionation of the extract afforded an ellagitannin enriched fraction (EEF) isolated for the first time from this species. This EEF exhibited antiviral activity against HIV in MT-2 infected cells, with an IC₅₀ value of 2.33 μg/ml (selectivity index greater than 21). Inhibition of HIV infection by EEF appears to be mediated by CD4 down-regulation, the main receptor for HIV entry. CXCR4 and CCR5 receptors were not affected by EEF, explaining why EEF is able to inhibit R5 and X4 infections.     

Biflavones from Ginkgo biloba as inhibitors of human thrombin

Ginkgo Biloba leaf extract has been widely used for the prevention and treatment of thrombosis and cardiovascular disease in both eastern and western countries, but the bioactive constituents and the underlying mechanism of anti-thrombosis have not been fully characterized. The purpose of this study was to investigate the inhibitory effects of major constituents in Ginkgo biloba on human thrombin, a key serine protease regulating the blood coagulation cascade and the processes of thrombosis. To this end, a fluorescence-based biochemical assay was used to assay the inhibitory effects of sixteen major constituents from Ginkgo biloba on human thrombin. Among all tested natural compounds, four biflavones (ginkgetin, isoginkgetin, bilobetin and amentoflavone), and five flavonoids (luteolin, apigenin, quercetin, kaempferol and isorhamnetin) were found with thrombin inhibition activity, with the IC₅₀ values ranging from 8.05 μM to 82.08 μM. Inhibition kinetic analyses demonstrated that four biflavones were mixed inhibitors against thrombin-mediated Z-GGRAMC acetate hydrolysis, with the K_i values ranging from 4.12 μM to 11.01 μM. Molecular docking method showed that the four biflavones could occupy the active cavity with strong interactions of salt bridges and hydrogen bonds. In addition, mass spectrometry-based lysine labeling reactivity assay suggested that the biflavones could bind on human thrombin at exosite I rather than exosite II. All these findings suggested that the biflavones in Ginkgo biloba were naturally occurring inhibitors of human thrombin, and these compounds could be used as lead compounds for the development of novel thrombin inhibitors with improved efficacy and high safety profiles.     

Porphyrin derivatives as inhibitors for acetylcholinesterase from Drosophila melanogaster

The cure for Alzheimer''s disease (AD) is still unknown. According to Cholinergic hypothesis, Alzheimer''s disease is caused by the reduced synthesis of the neurotransmitter, Acetylcholine. Regional cerebral blood flow can be increased in patients with Alzheimer''s disease by Acetylcholinesterase (AChE) inhibitors. In this regard, Tetraphenylporphinesulfonate (TPPS), 5,10,15,20- Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS) and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinatoIron(III) nitrosyl Chloride (FeNOTPPS) were investigated as candidate compounds for inhibition of Acteylcholinesterase of Drosophila melanogaster (DmAChE) by use of Molecular Docking. The results show that FeNOTPPS forms the most stable complex with DmAChE.     

Oleuropein and derivatives from olives as Tau aggregation inhibitors

Tau isoforms constitute a family of microtubule-associated proteins that are mainly expressed in neurons of the central nervous system. They promote the assembly of tubulin monomers into microtubules and modulate their stability, thus playing a key structural role in the distal portion of axons. In Alzheimer's disease and related tauopathies, Tau aggregation into fibrillary tangles contributes to intraneuronal and glial lesions. We report herein the ability of three natural phenolic derivatives obtained from olives and derived food products to prevent such Tau fibrillization in vitro, namely hydroxytyrosol, oleuropein, and oleuropein aglycone. The latter was found to be more active than the reference Tau aggregation inhibitor methylene blue on both wild-type and P301L Tau proteins, inhibiting fibrillization at low micromolar concentrations. These findings might provide further experimental support for the beneficial nutritional properties of olives and olive oil as well as a chemical scaffold for the development of new drugs aiming at neurodegenerative tauopathies.     

Pseudo-peptides derived from isomannide as potential inhibitors of serine proteases

Summary. Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.     

Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PL^pro) than against 3-chymotripsin-like protease (3CL^pro); therefore, we investigated their structural features that were responsible for this selectivity. Compound 4 was the most potent inhibitor of PL^pro with an IC₅₀ value of 3.7?μM. The active compounds displayed kinetic behaviors, and the binding constants of their interaction with PL^pro were determined from surface plasmon resonance analysis. Our results suggest B. papyrifera constituents as promising candidates for development into potential anti-coronaviral agents.     

Flavonols from Pterogyne nitens and their evaluation as myeloperoxidase inhibitors

A myeloperoxidase inhibitory kaempferol derivative, namely pterogynoside (1), was isolated from fruits of Pterogyne nitens, along with six known flavonols, kaempferol, afzelin, kaempferitrin, quercetin, isoquercetrin and rutin. The structures of all compounds were elucidated primarily from 1D and 2D NMR spectroscopic analyses, as well as by high resolution mass spectrometry. All flavonols were screened to identify secondary metabolites as potential myeloperoxidase (MPO) inhibitors, and at concentrations of 0.50–50 nM, quercetin (5), isoquercitrin (6) and rutin (7) exhibited strong inhibitory effects with IC₅₀ values of 1.22 ± 0.01, 3.75 ± 0.02 and 3.60 ± 0.02, respectively. The MPO activity detected for the new derivative 1 was markedly decreased (IC₅₀ 10.3 ± 0.03) when compared with known flavonols 5–7, and interestingly increased when tested against ABTS scavenging activity.     

New hydroxypyrimidinone-containing sulfonamides as carbonic anhydrase inhibitors also acting as MMP inhibitors

A set of benzenesulfonamide (BSA) derivatives bearing a hydroxypyrimidinone (HPM) moiety were synthesized and investigated for their inhibitory activity against several carbonic anhydrase (CA, EC 4.2.1.1) isozymes. They all revealed to be very potent inhibitors (nanomolar order) of the cytosolic CA I and II isozymes, but especially of the transmembrane, tumor-associated CA IX isozyme, a beneficial feature for a potential antitumor effect of these compounds. Further structure optimization aimed at improving the specificity of CA inhibition and enhancing their matrix metalloproteinase (MMP) inhibitory activity may also lead to new compounds with an attractive dual mechanism of action as antitumor agents.     

Heteroarylisopropylamines as MAO inhibitors

The in vitro monoamine oxidase inhibitory (MAOI) activities of 11 heteroarylisopropylamines vis-à-vis MAO-A and MAO-B were described and interpreted in terms of possible interactions with the enzyme active site. Molecular dynamics simulations allowed a comparison between the most active MAO-A inhibitor of the series, the 1-(2-benzofuryl)-2-aminopropane, and the specific, analogous MAO-A substrate serotonin.     

Poly-beta-hydroxybutyrate accumulation in Nostoc muscorum: effects of metabolic inhibitors

Poly-beta-hydroxybutyrate (PHB) accumulation in Nostoc muscorum was studied in presence of various metabolic inhibitors. Supplementation of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) was found to suppress PHB accumulation in phosphate-limited N. muscorum under photoautotrophic growth condition. PHB accumulation increased up to 21% and 17% from an initial PHB content of 8.5% of dry weight, respectively, under carbonylcyanide m-chlorophenylhydrazone (CCCP) and dicyclohexylcarbodiimide (DCCD) treatment, whereas 2,4 -dinitrophenol (DNP) supplementation depicted insignificant effect on PHB pool of the test cyanobacterium. Supplementation of l-methionine-dl-sulfoximine (MSX) and azaserine was also found to increase PHB accumulation in N(2) -fixing and NH(4)(+) -grown N. muscorum, but not in NO(3)(-) -grown cells. The stimulatory action of monofluoroacetate on PHB accumulation was suppressed in presence of alpha-ketoglutarate and DCMU. Interestingly, 2,3 -butanedione supplementation was not only found inhibitory for accumulation of PHB in P-deficient, N-deficient and chemoheterotrophically grown N. muscorum but suppression of PHB synthesis was also evident in control cultures in presence of 2,3 -butanedione. The possible mechanisms are discussed.     

Aminomethylpyridines as DPP-IV inhibitors

In a novel series of DPP-IV inhibitors, a large increase of inhibitory activity was achieved by optimisation of aromatic substituents and conformational restriction.     

'Beta-lactams' as beta-lactamase inhibitors

The application of inhibitors to block the beta-lactamase destruction of penicillins and cephalosporins by resistant bacteria is a potentially useful way of improving the efficacy of established compounds. Certain semi-synthetic penicillins and cephalosporins have been found to be competitive inhibitors of selected beta-lactamases but an examination of streptomycete culture fluids has revealed two new types of beta-lactam compound: clavulanic acid, which is a progressive inactivator of a wide range of beta-lactamases, and the olivanic acids, which are both broad-spectrum antibiotics and potent beta-lactamase inhibitors. Penicillanic acid sulphone and 6-beta-bromopenicillanic acid have been shown to be significant inhibitors of beta-lactamase. The chemotherapeutic application of these compounds is discussed.