Potent inhibitory effects of N-aryl S-alkylthiocarbamate derivatives on the dopa oxidase activity of mushroom tyrosinase

This study reports the potent inhibitory effect of N-aryl S-alkylthiocarbamate derivatives on mushroom tyrosinase (MT) activity. N-Aryl S-alkylthiocarbamate derivatives were found to exhibit a potent inhibitory effect on the dopa (3,4-dihydroxyphenylalanine) oxidase activity of mushroom tyrosinase. Most of the N-aryl S-alkylthiocarbamate derivatives (compounds from A to J) exhibited higher inhibitory effects than kojic acid (IC50=318 microM), a well known tyrosinase inhibitor. Tyrosinase was the most inhibited by S-phenetyl N-phenylthiocarbamate (compound E, IC50=7.25 microM), and this inhibition was 44 times stronger than that of kojic acid. Compound E exhibited 95.0% of inhibition at 100 microM. A kinetic study of MT inhibition by compound E using the Lineweaver-Burk plots analysis was performed. And the kinetics profiles observed suggest that compound E competitively inhibits MT.     

Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity

The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 microM) vs 9 (IC50 > 200 microM). Structure-activity studies of a series of carbocyclic analogues 6a-i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (-)-quinic acid is also described.     

Inhibition on HIV-1 integrase activity and nitric oxide production of compounds from Ficus glomerata

An ethanol Ficus glomerata wood extract and its purified components were investigated for their HIV-1 integrase (IN) and nitric oxide (NO) inhibitory activities. From bioassay-guided isolation, five compounds: beta-sitosterol-D-glucoside (1), aloe-emodin (2), genistein (3), 1,3,6-trihydroxy-8-methyl-anthraquinone (4) and 3-(1-C-beta-D-glucopyranosyl)-2,6-dihydroxy-5-methoxybenzoic acid (5) were isolated. Among the tested samples, at concentrations of 100 microM; compound 2 showed 31.9% inhibition of HIV-1 IN, followed by 4 (19.5%), whereas other compounds were inactive. With regard to the inhibitory effect on NO production, 3 possessed the highest activity with an IC50 value of 27.5 microM, followed by 4 (IC50 = 34.7 microM) and 2 (IC50 = 41.8 microM), respectively. This is the first time that compounds 2-5 have been isolated from Ficus glomerata.     

Inhibition of urease activity by dipeptidyl hydroxamic acids.

A series of dipeptidyl hydroxamic acids (H-X-Gly-NHOH: X = amino acid residues) was synthesized, and the inhibitory activity against Jack bean and Proteus mirabilis ureases [EC 3.5.1.5] was examined. A number of H-X-Gly-NHOH inhibited Jack bean urease with an I50 of the order of 10(-6) M and inhibited Proteus mirabilis urease with an I50 of the order of 10(-5) M. The inhibition against Jack bean urease was more potent than that with the corresponding aminoacyl hydroxamic acids (H-X-NHOH).     

Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies

A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences. Tyrosinase inhibition study of these compounds and their structure-activity relationship (SAR) were also investigated. The compounds exhibited potent to mild inhibition activity against the enzyme. Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme tyrosinase, as compared to the standard tyrosinase inhibitors kojic acid (IC50=16.67 microM) and L-mimosine (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes.     

Syntheses and biological activity of amamistatin B and analogs

Amamistatins A and B, natural products isolated from a strain of Nocardia, showed growth inhibition against three human tumor cell lines (IC(50) 0.24-0.56 microM). Structurally related mycobactins affect the growth of both mycobacterial and human cells through interference with iron chelation. To further probe the biological activity of this class of compounds, the total syntheses of amamistatin B and two analogs were completed, and the synthetic samples were screened for tumor cell growth inhibition, HDAC inhibition, and Mycobacterium tuberculosis growth inhibition. Amamistatin B (15) and diastereomer 18 were both active against MCF-7 cells (IC(50) 0.12-0.20 microM), and less so against PC-3 cells (IC(50) 8-13 microM). Amamistatin B only moderately inhibited the growth of M. tuberculosis (MIC 47 microM) but showed growth promotion of Mycobacterium smegmatis and other bacteria.     

Phosphorus-based SAHA analogues as histone deacetylase inhibitors

[structure: see text] Three analogues of suberoyl anilide hydroxamic acid (SAHA) with phosphorus metal-chelating functionalities were synthesized as inhibitors of histone deacetylases (HDACs). The compounds showed weak activity for HeLa nuclear extracts (IC(50) = 0.57-6.1 mM), HDAC8 (IC(50) = 0.28-0.41 mM), and histone-deacetylase-like protein (HDLP, IC(50) = 0.33-1.9 mM), suggesting that the transition state of HDAC is not analogous to zinc proteases. Antiproliferative activity against A2780 cancer cells (IC(50) = 0.11-0.12 mM), comparable to SAHA (0.15 mM), was observed.     

Hydantoin derivatives of L- and D-amino acids: synthesis and evaluation of their antiviral and antitumoral activity

3,5-Disubstituted hydantoin (1,3-imidazolidinedione) derivatives 5a-h were prepared by base induced cyclization of the corresponding N-(1-benzotriazolecarbonyl)-L- and D-amino acid amides 4a-h. Compounds 5a-h were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, 3-benzhydryl-5-isopropyl hydantoin (5a) showed a weak but selective inhibitory effect against vaccinia virus (EC(50) = 16 microg/mL; selectivity index: 25). 3-Cyclohexyl-5-phenyl hydantoin (5g) showed inhibitory activity against cervical carcinoma (HeLa, IC(50) = 5.4 microM) and breast carcinoma (MCF-7, IC(50) = 2 microM), but also cytotoxic effects towards human normal fibroblasts (WI 38). On the contrary, the 3-benzhydryl-5-phenyl substituted hydantoin derivative 5h showed moderate inhibitory activity towards HeLa, MCF-7, pancreatic carcinoma (MiaPaCa-2), lung carcinoma (H 460) and colon carcinoma (SW 620) (IC(50) = 20-23 microM), but no effect on WI 38.     

Synthesis and aldose reductase inhibitory activity of triazine derivatives possessing acetic acid group.

N-Acetic acid derivatives of 6-aryl-pyrazolo-triazin-4-ones were synthesized for evaluation as new aldose reductase inhibitors. The intrinsic activity of each compound was assessed by measuring the inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All the prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-6) M less than or equal to IC50 less than or equal to 10(-4) M). Furthermore, biological activity (log 1/IC50) for most of the data sets could be correlated directly to electronic and steric parameters. Finally, spatial configuration of the most active derivative 6c (IC50 = 2 x 10(-6) M) was compared with that of tolrestat and with pharmacophor requirements of the aldose reductase inhibitor site using a molecular modeling system.     

Probing sponge-derived terpenoids for human 15-lipoxygenase inhibitors

A human 15-lipoxygenase (15-HLO) assay has been employed to discover new marine-sponge-derived bioactive compounds. Extracts from two different sponges, Jaspis splendens (order Choristida, family Jaspidae) and Suberea sp. (order Verongida, family Aplysinellidae), exhibited potent IC(50) values of 0.4 and 0.1 microg/mL, respectively. Both are sources of terpenoids, and the former is a known source of (+)-jasplakinolide (7), which is inactive as a 15-HLO inhibitor. The terpenoids included (+)-(5S,6S)-subersin (1, IC(50) > 100 microM), (-)-(5R,10R)-subersic acid (2, IC(50) = 15 microM), jaspaquinol (3, IC(50) = 0.3 microM), and (-)-jaspic acid (4, IC(50) = 1.4 microM). Structure elucidations and lipoxygenase activity studies of these compounds are reported.     

Phenolic constituents from the heartwood of Artocapus altilis and their tyrosinase inhibitory activity

From the MeOH extract of the heartwood of Artocapus altilis, thirteen phenolic compounds have been isolated, namely curcumin (1), desmethoxycurcumin (2), retrodihydrochalcone (3), apigenin (4), tangeretin (5), nobiletin (6), O-methyldehydrodieugenol (7), dehydrodieugenol (8), beta-hydroxypropiovanillone (9), p-coumaric acid (10), p-hydroxybenzaldehyde (11), vanillin (12), and vanillic acid (13). This is the first report on the presence of these compounds in the heartwood of A. altilis. Compounds 1, 2, and 10 showed more potent tyrosinase inhibitory activities, with IC50 values ranging from 2.3 to 42.0 microM, than the positive control kojic acid (IC50, 44.6 microM). The most active compound, p-coumaric acid (10) (IC50, 2.3 microM), was 22 times more active in tyrosinase inhibitory activity than kojic acid.     

Antihepatitis B virus constituents of Solanum erianthum

Eleven compounds were isolated from the methanolic extract of the leaves of Solanum erianthum D. Don, including five alpha-linolenic acid analogs, alpha-linolenic acid (1), 13S-hydroxy-9(Z),11(E)-octadecadienoic acid (2), 9S-hydroxy-10(E),12(Z), 15(Z)-octadectrienoic acid (3), 9(Z),11(E)-octadecadienoic acid (4), and octadecanoic acid (5); two benzofuran-type lactones, loliolide (6) and dihydroactinidiolide (7); two steroidal alkaloids, solasonine (8) and solamargine (9); a flavonol glycoside, camelliaside C (10); and a flavone, 5-methoxy-(3,4"-dihydro-3",4"-diacetoxy)-2",2'-dimethylpyrano-(7,8:5",6")-flavone (11). Among these isolated compounds, 9 showed the most potent activity against HBsAg, with an IC50 of 1.57 microM, followed by 8 (IC50 is 5.89 microM). In the testing against HBeAg, 11 was the only active compound with an IC50 of 36.11 microM. Compound 9 also revealed strong inhibition of DNA replication towards HBV and its IC50 was 2.17 microM. However, alpha-linolenic acid (1) showed a prominent selected index (SI), both in anti-HBsAg and inhibition of DNA replication with SI values of 7.75 and 7.18, respectively. This is the first report that unsaturated fatty acid 1, steroidal alkaloid glycoside 9 and flavone 11, all showed excellent activity against HBV. These results provide lead candidates in the development of anti-HBV drugs from natural sources.     

Depigmenting activity and low cytotoxicity of alkoxy benzoates or alkoxy cinnamte in cultured melanocytes

To obtain effective and safe topical depigmenting agents, we synthesized hydroxybenzoates, alkoxybenzoates, and 3,4,5-trimethoxycinnamate containing a thymol moiety and screened then for high-level inhibitory activity against melanin synthesis in cultured melanocytes. Eight compounds were tested for their depigmenting effect and cytotoxicity using a murine melanocyte cell line. We found that 3,4,5-trialkoxybenzoates and 3,4,5-trimethoxycinnamate, synthesized by conjugating 3,4,5-trialkoxybenzoic acids and 3,4,5-trimethoxycinnmic acid with thymol, showed a potent depigmenting effect and low cytotoxicity. Compound 4h, 5-methyl-2-(methylethyl)phenyl (2E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoate, showed the most potent depigmenting effect (IC50=10 microM) with low cytotoxicity (IC50=200 microM).     

Cinnamoylphenethyl amides from Polygonum hyrcanicum possess anti-trypanosomal activity

A methanolic extract from aerial parts of Polygonum hyrcanicum (Polygonaceae) showed high activity against Trypanosoma brucei rhodesiense (IC50 = 3.7 microg/mL). Bioassay-guided fractionation of the extract resulted in isolation of cinnamoylphenethyl amides, including N-trans-caffeoyltyramine (1), N-trans-p-coumaroyltyramine (7), and N-trans-feruloyltyramine (8) as the main active constituents (IC50s ranging from 2.2 to 13.3 microM). Some structurally related, but less active compounds, such as cannabisin B (2), tyrosol (3), p-coumaric acid (4), ferulic acid (5), and N-cis-feruloyltyramine (6) were also identified, along with N-trans-3,4-dimethoxycinnamoyldopamine (9). Cytotoxicity of the active compounds in L6 cells was determined, and selectivity indices (SI) of 7.9 to 33.4 were calculated.     

Relationship of electrochemical oxidation of catechins on their antioxidant activity in microsomal lipid peroxidation.

The oxidation potentials of catechins were measured by employing flow-through column electrolysis. The oxidation potentials of catechins were shown to depend on their structures. At the same time, the antioxidant activity of catechins on NADPH-dependent lipid peroxidation in rat liver microsomes was evaluated. Catechins showed a 50% inhibition of lipid peroxidation in the concentration range of 10-51 microM. Among those studied, galloylated catechins exhibited stronger antioxidant activities than those of nongalloylated catechins. A quantitative relationship has been obtained to describe the antioxidant activity of catechins: log IC50 (microM)= 1.56+2.49E1/2 (V)-0.29 logP (r=0.907), where IC50 represents the concentration for 50% inhibition of lipid peroxidation, E1/2 represents the half-wave potential of the first oxidation wave, and P represents the octanol/water partition coefficient. This relationship suggested two important characteristics determining catechin antioxidant activity, namely the ease of oxidation and the lipophilicity.     

Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity

A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic analyses by a Lineweaver-Burk plot clearly indicated that piperine competitively inhibited MAO-A and MAO-B with Ki values of 19.0+/-0.9 microM and 3.19+/-0.5 microM, respectively. The inhibition by piperine was found to be reversible by dialysis of the incubation mixture. In addition, the immobility times in the tail suspension test were significantly reduced by piperine, similar to that of the reference antidepressant fluoxetine, without accompanying changes in ambulation when assessed in an open-field. These results suggest that piperine possesses potent antidepressant-like properties that are mediated in part through the inhibition of MAO activity, and therefore represent a promising pharmacotherapeutic candidate as an antidepressant agent.     

Stimuli-responsive polyguanidino-oxanorbornene membrane transporters as multicomponent sensors in complex matrices

We introduce guanidinium-containing synthetic polymers based on polyguanidino-oxanorbornenes (PGONs) as anion transporters in lipid bilayers that can be activated and inactivated by chemical stimulation. According to fluorogenic anion export experiments with vesicles, PGON transporters are most active in neutral bilayers near their phase transition, with EC50's in the nanomolar range. Six times higher effective transporter concentrations were measured with aminonaphthalene-1,3,6-trisulfonate than with 5(6)-carboxyfluorescein, demonstrating the importance of anion binding for transport and excluding nonspecific efflux. Negative surface potentials efficiently annihilate transport activity, while inside-negative membrane potentials slightly increase it. These trends demonstrate the functional importance of counterions to hinder the binding of hydrophilic counterions and to minimize the global positive charge of the transporter-counterion complexes. Strong, nonlinear increases in activity with polymer length reveal a significant polymer effect. Overall, the characteristics of PGONs do not match those of similar systems (for example, polyarginine) and hint toward an interesting mode of action, clearly different from nonspecific leakage caused by detergents. The activity of PGONs increases in the presence of amphiphilic anions such as pyrenebutyrate (EC50 = 70 microM), while several other amphiphilic anions tested were inactive. PGONs are efficiently inactivated by numerous hydrophilic anions including ATP (IC 50 = 150 microM), ADP (IC50 = 460 microM), heparin (IC50 = 1.0 microM), phytate (IC50 = 0.4 microM), and CB hydrazide (IC50 = 26 microM). The compatibility of this broad responsiveness with multicomponent sensing in complex matrices is discussed and illustrated with lactate sensing in sour milk. The PGON lactate sensor operates together with lactate oxidase as a specific signal generator and CB hydrazide as an amplifier for covalent capture of the pyruvate product as CB hydrazone (IC50 = 1.5 microM).     

Inhibition of gastric H+, K(+)-ATPase activity by compounds from medicinal plants

H+, K(+)-ATPase enzyme is a therapeutic target for the treatment of gastric disturbances. Several medicinal plants and isolated compounds inhibit the acid gastric secretion through interaction with the proton pump. In order to add new properties to some natural constituents, five compounds, a benzylated derivative of vincoside, a diterpene (abietic acid) and three alkaloids (cephaeline, vinblastine and vindoline), were tested for their activities on gastric H+, K(+)-ATPase isolated from rabbit stomach. All the compounds inhibited H+, K(+)-ATPase activity with varied potency. The IC50 value for benzylvincoside was 121 (50-293) microM, and for abietic acid 177 (148-211) microM. The alkaloids cephaeline, vinblastine and vindoline inhibited the H+, K(+)-ATPase activity with IC50 values of 194, 761 and 846 microM, respectively. The results suggest that benzylvincoside, abietic acid and cephaeline can be important sources for the development of anti-secretor agents.