New antioxidative phenolic glycosides isolated from Kokuto non-centrifuged cane sugar

Nine compounds, 3-hydroxy-4,5-dimethoxyphenyl-beta-D-glucopyranoside (1), beta-D-fructfuranosyl-alpha-D-(6-vanilloyl)-glucopyranoside (2), beta-D-fructfuranosyl-alpha-D-(6-syringyl)-glucopyranoside (3), 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxy-1-(E)-propenyl)-2-methoxyphenoxy]propyl-beta-D-glucopyranoside (4), 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxy-1-(E)-propenyl)-2,6-dimethoxyphenoxy] propyl-beta-D-glucopyranoside (5), dehydrodiconiferyl alcohol-9'-beta-D-glucopyranoside (6), 4-[ethane-2-[3-(4-hydroxy-3-methoxyphenyl)-2-propen]oxy]-2,6-dimethoxyphenyl-beta-D-glucopyranoside (7), 4-[ethane-2-[3-(4-hydroxy-3-methoxyphenyl)-2-propen]oxy]-2-methoxyphenyl-beta-D-glucopyranoside (8), and 3-hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-2-[4-(3-hydroxy-1-(E)-propenyl)-2,6-dimethoxyphenoxy]propyl-beta-D-glucopyranoside (9), were isolated from Kokuto non-centrifuged cane sugar. Their structures were elucidated by spectroscopic evidence, mainly based on the NMR technique. Among them, seven new glycosides were identified. The 2-deoxyribose oxidation method was used to measure their antioxidative activity. All of these compounds showed antioxidative activities.     

Phenolic constituents from the core of kenaf (Hibiscus cannabinus)

Four lignans, boehmenan H [2-(4-hydroxy-3-methoxyphenyl)-5-[3-(4-hydroxy-3-methoxycinnamoyloxy)propyl]-3-hydroxymethyl-7-methoxybenzodihydrofuran], boehmenan K [2-(4-hydroxy-3-methoxyphenyl)-5-[3-(4-hydroxycinnamoyloxy)-1-propenyl]-3-(4-hydroxy-3-methoxycinnamoyloxymethyl)-7-methoxybenzodihydrofuran], threo-carolignan H [threo-1-(4-hydroxy-3-methoxyphenyl)-2-[4-[3-(4-hydroxy-3-methoxycinnamoyloxy)propyl]-2-methoxyphenoxy]-1,3-propanodiol], and threo-carolignan K [threo-1-(4-hydroxy-3-methoxyphenyl)-3-(4-hydroxy-3-methoxycinnamoyloxy)-2-[4-[3-(4-hydroxycinnamoyloxy)-1-propenyl]-2-methoxyphenoxy]-1-propanol] as well as several other lignans, aldehydes and a tyramine derivative were isolated from the acetone extract of core of kenaf (Hibiscus cannabinus). All the structures were established by spectroscopic methods. The hitherto unreported 13C NMR spectra of some compounds are also presented and discussed. 2D NMR techniques have allowed the revision of certain previously reported 13C NMR assignments of some scarce naturally occurring compounds.     

Synthesis of 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole derivatives and their effects on neuronal cell death

Novel 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole analogs were synthesized by either of the following two pathways: (1) a sequence of Knoevenagel condensation of oxindole with (4-dimethylamino)cinnamaldehyde–hydrogenation, or (2) alkylation of oxindole dianion with [(4-dimethylamino)phenyl]alkyl halides. Subsequent alkylation at C-3 and/or N-1 of the oxindole skeleton by anion-based methods provided additional substituted derivatives for structure-activity relationship studies. Their effects on neuronal cell death induced by oxidative stress were evaluated by lactate dehydrogenase assay. Compounds with the alkyl chain length of 2–4 significantly suppressed the neuronal cell death. No significant change occurred in the activity by substitution with less-polar groups. The stereochemistry at C-3 of the oxindole core was also irrelevant for the neuroprotective effects of these compounds.     

Synthesis of some newer derivatives of substituted quinazolinonyl-2-oxo/thiobarbituric acid as potent anticonvulsant agents

5-[1'-[3"-Aminoacetyl-2"-methyl-6",8"-dihalosubstitutedquinazolin-4"(3"H)-onyl]-thiosemicarbazido]-2-oxo/thiobarbituric acids 3a-3h and 5-[2'-amino-5'-[3"-aminomethylene-2"-methyl-6",8"-dihalosubstitutedquinazolin-4"(3"H)-onyl]-1',3',4'-thiadiazol-2'-yl]-2-oxo/thiobarbituric acid 5a-5h were prepared by incorporating 1-[3'-aminoacetyl-2'-methyl-6",8"-dihalosubstituted-quinazolin-4'(3'H)-onyl]-thiosemicarbazides 2a-2d and 2-amino-5-[3'-aminomethylene-2'-methyl-6',8'-dihalosubstituted-quinazolin-4'(3'H)-onyl]-1,3,4-thiadiazoles 4a-4 h respectively at 5(th) position of 2-oxo/thiobarbituric acids (via Mannich reaction). All the newly synthesized compounds were screened for their anti-convulsant activity in MES and PTZ models and were compared with standard drugs phenytoin sodium and sodium valproate. Interestingly, these compounds were found to be devoid of sedative and hypnotic activities when tested. Out of the compounds studied, the most active compound 5h, that is 5-[2'-amino-5'-[3"-aminomethylene-2"-methyl-6",8"-dibromoquinazolin-4"(3"H)-onyl]-1',3',4'-thiadiazol-2'-yl]-2-thiobarbituric acid showed activity (90%) more potent than the standard drug.     

Benzofurans and another constituent from seeds of Styrax officinalis

The benzofuran constituents of the seeds of Styrax officinalis were investigated. From the hexane extract, two new constituents named 5-(3"benzoyloxypropyl)-7-methoxy-2-(3',4'-methylenedioxyphenyl)-benzofuran (5) and 4-[3"-(1c-methylbutanoyloxy)propyl]-2-methoxy-(3',4'-methylenedioxyphenyl)-1a, 5b-dihydrobenzo-[3,4]-cyclobutaoxirene (6) were isolated together with four known compounds, 5-[3"-(1c-methylbutanoyloxy)propyl]-7-methoxy-2-(3',4'-dimethoxyphenyl)-benzofuran (4), 5-[3"-(1c-methylbutanoyloxy)propyl]-7- methoxy-2-(3',4'-methylenedioxyphenyl)-benzofuran (3), 5-(3"-acetoxypropyl)-7-methoxy2-(3',4'-methylenedioxphenyl)-benzofuran (2) and 5-(3"-hydroxypropyl)-7-methoxy-2-(3',4'-met hylenedioxyphenyl)-benzofuran (1). Although the compounds 1, 2, and 3 have been isolated previously from the seeds of Styrax obassia, this is the first record of their isolation from seeds of Styrax officinalis. The structures of the isolated compounds were established by 1D- and 2D-NMR (HMBC, HMQC, COSY), FABMS and high-resolution ESI FTMS.     

牛心朴子须根的化学成分研究

从采自宁夏的萝摩科鹅绒藤属植物牛心朴子 (CynanchumkomaroviiAl.Iljinski.)须根的乙醇提取物中分离鉴定了十个非C2 1 甾体类化合物 :β D 呋喃果糖基 (2→ 1) α D [6 O 芥子酰基 ] 吡喃葡萄糖甙 (1) ,β D (3 O 芥子酰基 ) 呋喃果糖基 (2→ 1) α D [6 O 芥子酰基 ] 吡喃葡萄糖甙 (2 ) ,[6 O β D 吡喃葡萄糖基 (1→ 6 ) β D 吡喃葡萄糖基 1,2 双氧 (4 羟基 3,5 二甲氧基肉桂酰 ) (3) ,7 脱甲氧基娃儿藤碱 (4) ,9 羟基 芳樟醇 3 O β D 吡喃木糖基 (1→ 6 ) β D 吡喃葡萄糖甙 (5 ) ,(2E ,6R) 2 ,6 二甲基 2 ,7 辛二烯 1,6 二醇 (6 ) ,[(+) 丁香素 ](7) ,4′ O demethylepiyangambin(8) ,4′ 羟基 2′ 甲氧基苯乙酮 (9) ,(2S ,3S ,4R ,12E) N [2′ (R) 羟基二十二碳烷基 ] 1,3,4 三羟基 2 酰胺 二十碳烷基 12 烯 (10 )。除化合物 4和 9外 ,其余化合物均为首次从该植物中分离得到。     

Chemical and anti-platelet constituents from Formosan Zanthoxylum simulans

A pyrrole alkaloid, pyrrolezanthine [5-hydroxymethyl-1-[2-(4-hydroxyphenyl)-ethyl]-1H-pyrrole-2-carbaldehyde]; a lignan, (-)-simulanol [4- [3-hydroxymethyl-5-((E)-3-hydroxypropenyl)-7-methoxy-2,3-dihydrobenzofuran-2-yl]-2,6-dimethoxy-phenol] and a monocyclic gamma-pyrone, zanthopyranone [3,5-dimethoxy-2-methyl-pyran-4-one], together with 28 known compounds were isolated from the stem wood of Formosan Zanthoxylum simulans. Their structures were determined through spectral analyses. Among the isolates, 11 compounds showed anti-platelet aggregation activity in vitro.     

1,2,4]Triazole derivatives as 5-HT(1A) serotonin receptor ligands.

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.     

Commercially processed dry ginger (Zingiber officinale): composition and effects on LPS-stimulated PGE2 production

Using techniques previously employed to identify ginger constituents in fresh organically grown Hawaiian white and yellow ginger varieties, partially purified fractions derived from the silica gel column chromatography and HPLC of a methylene chloride extract of commercially processed dry ginger, Zingiber officinale Roscoe, Zingiberaceae, which demonstrated remarkable anti-inflammatory activity, were investigated by gas chromatography-mass spectrometry. In all, 115 compounds were identified, 88 with retention times (R(t)) >21 min and 27 with <21 min. Of those 88 compounds, 45 were previously reported by us from fresh ginger, 12 are cited elsewhere in the literature and the rest (31) are new: methyl [8]-paradol, methyl [6]-isogingerol, methyl [4]-shogaol, [6]-isoshogaol, two 6-hydroxy-[n]-shogaols (n=8 and 10), 6-dehydro-[6]-gingerol, three 5-methoxy-[n]-gingerols (n=4, 8 and 10), 3-acetoxy-[4]-gingerdiol, 5-acetoxy-[6]-gingerdiol (stereoisomer), diacetoxy-[8]-gingerdiol, methyl diacetoxy-[8]-gingerdiol, 6-(4'-hydroxy-3'-methoxyphenyl)-2-nonyl-2-hydroxytetrahydropyran, 3-acetoxydihydro-[6]-paradol methyl ether, 1-(4'-hydroxy-3'-methoxyphenyl)-2-nonadecen-1-one and its methyl ether derivative, 1,7-bis-(4'-hydroxy-3'-methoxyphenyl)-5-methoxyheptan-3-one, 1,7-bis-(4'-hydroxy-3'-methoxyphenyl)-3-hydroxy-5-acetoxyheptane, acetoxy-3-dihydrodemethoxy-[6]-shogaol, 5-acetoxy-3-deoxy-[6]-gingerol, 1-hydroxy-[6]-paradol, (2E)-geranial acetals of [4]- and [6]-gingerdiols, (2Z)-neral acetal of [6]-gingerdiol, acetaldehyde acetal of [6]-gingerdiol, 1-(4-hydroxy-3-methoxyphenyl)-2,4-dehydro-6-decanone and the cyclic methyl orthoesters of [6]- and [10]-gingerdiols. Of the 27 R(t)<21 min compounds, we had found 5 from fresh ginger, 20 others were found elsewhere in the literature, and two are new: 5-(4'-hydroxy-3'-methoxyphenyl)-pent-2-en-1-al and 5-(4'-hydroxy-3'-methoxyphenyl)-3-hydroxy-1-pentanal. Most of the short R(t) compounds are probably formed by thermal degradation during GC (which mimics cooking) and/or commercial drying. The concentrations of gingerols, the major constituents of fresh ginger, were reduced slightly in dry ginger, while the concentrations of shogaols, the major gingerol dehydration products, increased.     

Homoisoflavonoids and xanthones from the tubers of wild and in vitro regenerated Ledebouria graminifolia and cytotoxic activities of some of the homoisoflavonoids

Eleven homoisoflavonoids and two xanthones were isolated and characterized from the bulbs of Ledebouria graminifolia. Five of the homoisoflavonoids are new compounds and were identified as: 5-hydroxy-7-methoxy-3-(4'-hydroxybenzyl)-4-chromanone, 5-hydroxy-6,7-dimethoxy-3-(4'-hydroxybenzyl)-4-chromanone, 5,7,8-trimethoxy-3-(4'-hydroxybenzyl)-4-chromanone, 5-hydroxy-3',4',7-trimethoxyspiro[2H-1-benzopyran-7'-bicyclo[4.2.0]octa-trien]-4-one, 5,7-dihydroxy-3',4'-dimethoxyspiro[2H-1-benzopyran-7'-bicyclo[4.2.0]octa-trien]-4-one. Structures were elucidated by extensive 1D, and 2D NMR spectroscopy and HRMS. A method for tissue culture was developed and the bulbs of mature plants were found to contain all the compounds isolated from the wild specimens of L. graminifolia.     

Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues

A series of lipophilic diaromatic derivatives of the glia-selective GABA uptake inhibitor (R)-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol [(R)-exo-THPO, 4] were synthesized via reductive amination of 3-ethoxy-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-one (9) or via N-alkylation of O-alkylatedracemic 4. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation or primary cultures of mouse cortical neurons and glia cells (astrocytes), as well as HEK cells transfected with cloned mouse GABA transporter subtypes (GAT1-4). The activity against isoniazid-induced convulsions in mice after subcutaneous administration of the compounds was determined. All of the compounds were potent inhibitors of synaptosomal uptake the most potent compound being (RS)-4-[N-(1,1-diphenylbut-1-en-4-yl)amino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (17a, IC50 = 0.14 microM). The majority of the compounds showed a weak preference for glial, as compared to neuronal, GABA uptake. The highest degree of selectivity was 10-fold corresponding to the glia selectivity of (R)-N-methyl-exo-THPO (5). All derivatives showed a preference for the GAT1 transporter, as compared with GAT2-4, with the exception of (RS)-4-[N-[1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl]-N-methylamino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (28d), which quite surprisingly turned out to be more potent than GABA at both GAT1 and GAT2 subtypes. The GAT1 activity was shown to reside in (R)-28d whereas (R)-28d and (S)-28d contributed equally to GAT2 activity. This makes (S)-28d a GAT2 selective compound, and (R)-28d equally effective in inhibition of GAT1 and GAT2 mediated GABA transport. All compounds tested were effective as anticonvulsant reflecting that these compounds have blood-brain barrier permeating ability.     

Indole alkoloids from Nauclea officinalis with weak antimalarial activity

Five indole alkaloids (naucleofficines A-E) were isolated from the stems (with bark) of Nauclea officinalis: (E)-2-(1-beta-d-glucopyranosyloxybut-2-en-2-yl)-3-(hydroxymethyl)-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (1), (E)-1-propenyl-12-beta-d-glucopyranosyloxy-2,7,8-trihydro-indolo[2,3-a]pyran[3,4-g]quinolizin-4,5(13H)-dione (2), (E)-2-(1-hydroxybut-2-en-2-yl)-11-beta-d-glucopyranosyloxy-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (3), (E)-1-propenyl-4-hydroxy-2,4a,7,8,13b,14,14a-hepthydro-(4alpha,4abeta,13balpha,14abeta)indolo[2,3-a]pyran[3,4-g]quinolizin-5(13H)-one (4) and 1-(1-hydroxyethyl)-10-hydroxy-7,8-dihydro-indolo[2,3-a]pirydine[3,4-g]quinolizin-5(13H)-one (10-hydroxyangustoline) (5), together with two known compounds, naucleidinal (6) and angustoline (7). All of the structures of the seven compounds above were elucidated by spectroscopic methods including use of 1D- and 2D-NMR spectroscopic analyses. Compounds 2 and 3 are rare examples of monoterpene indole alkaloids with a glucopyranosyloxy group attached to position C-12. In vitro activity screening of the above seven compounds showed weak to moderate inhibitory activity against Plasmodium falciparum.     

α-Glucosidase Inhibition by Usnic Acid Derivatives

This study investigated a set of new potential antidiabetes agents. Derivatives of usnic acid were designed and synthesized. These analogs and nineteen benzylidene analogs from a previous study were evaluated for enzyme inhibition of α-glucosidase. Analogs synthesized using the Dakin oxidative method displayed stronger activity than the pristine usnic acid (IC₅₀>200 μM). Methyl (2E,3R)-7-acetyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethylidene)-3,5-dimethyl-2,3-dihydro-1-benzofuran-3-carboxylate ( 6b ) and 1,1′-(2,4,6-trihydroxy-5-methyl-1,3-phenylene)di(ethan-1-one) ( 6e ) were more potent than an acarbose positive control (IC₅₀ 93.6±0.49 μM), with IC₅₀ values of 42.6±1.30 and 90.8±0.32 μM, respectively. Most of the compounds synthesized from the benzylidene series displayed promising activity. (9bR)-2,6-Bis[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 1c ), (9bR)-3,7,9-trihydroxy-8,9b-dimethyl-2,6-bis[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 1g ), (9bR)-2-acetyl-6-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2d ), (9bR)-2-acetyl-6-[(2E)-3-(3-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2e ), (6bR)-8-acetyl-3-(4-chlorophenyl)-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3e ), (6bR)-8-acetyl-6,9-dihydroxy-5,6b-dimethyl-3-phenyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3h ), (6bR)-3-(2-chlorophenyl)-8-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 4b ), and (9bR)-6-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-2-[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 5c ) were the most potent α-glucosidase enzyme inhibitors, with IC₅₀ values of 7.0±0.24, 15.5±0.49, 7.5±0.92, 10.9±0.56, 1.5±0.62, 15.3±0.54, 19.0±1.00, and 12.3±0.53 μM, respectively.     

柯拉斯那沉香中2-(2-苯乙基)色酮类化学成分研究

为研究柯拉斯那(Aquilaria crassna Pierre ex Lecomte)沉香的化学成分。实验采用多种柱色谱方法从该沉香中分离得到9个2-(2-苯乙基)色酮类化合物,通过现代波谱学技术分别鉴定为6-甲氧基-2-[2-(3′-羟基-4′-甲氧基苯基)乙基]色酮(1)、5-羟基-6-甲氧基-2-[2-(3′-羟基-4′-甲氧基苯基)乙基]色酮(2)、tetrahydrochromone F(3)、6-甲氧基-2-[2-(3′-甲氧基-4′-羟基苯基)乙基]色酮(4)、6-甲氧基-7-羟基-2-[2-(4′-甲氧基苯基)乙基]色酮(5)、6,7-二甲氧基-2-[2-(3′-羟基-4′-甲氧基苯基)乙基]色酮(6)、6,7-二甲氧基-2-[2-(4′-甲氧基苯基)乙基]色酮(7)、6-羟基-2-[2-(4′-羟基苯基)乙基]色酮(8)、5-羟基-2-[2-(2′-羟基苯基)乙基]色酮(9)。化合物2、3和5～9均为首次从柯拉斯那所得沉香中分离得到。采用MTT法对单体化合物的细胞毒活性进行测试,测试结果表明,化合物1,2和4具有微弱的细胞毒活性。     

除臭大蒜口服液的GC／MS分析

应用GC/MS联用技术,对除臭大蒜口服液进行了检测,定性鉴定了25种含硫有机化合物。二烯丙基硫醚、甲基烯丙基三硫醚、3-乙烯基-1,2-二硫杂-5-环己烯、2-乙烯基-1,3-二硫杂-5-环己烯和二烯丙基三硫醚是主要组分;二烯丙基四硫醚、烯丙基四硫化氢、2-和3-(2’,3’-二硫杂-5’-己烯基)-3,4-二氢-2H-噻喃、2-(2’-[3’,4’-二氢-2H噻喃基])-1,3-二硫杂-5-环己烯和3-(2’-[3’,4’-二氢-2H-噻喃基])-1,2-二硫杂-5-环己烯是次要组分。最后4种次要组分在大蒜油和大蒜口服液中的鉴定在国内尚属首次。     

Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones

Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed.     

Antibacterial bromophenols from the marine red alga Rhodomela confervoides

Two bromophenols, together with three known compounds, were isolated from the methanolic extract of the marine alga, Rhodomela confervoides. By means of MS and NMR spectroscopic analyses, they were identified as 3-bromo-4-[2,3-dibromo-4,5-dihydroxyphenyl] methyl-5-(hydroxymethyl) 1,2-benzenediol (1) and 3-bromo-4-[2,3-dibromo-4,5-dihydroxyphenyl] methyl-5- (ethoxymethyl) 1,2-benzenediol (2). Three known compounds were also isolated, namely 3-bromo-4-[2,3-dibromo-4,5-dihydroxyphenyl] methyl-5-(methoxymethyl) 1,2-benzenediol (3), 4,4'- methylenebis [5,6-dibromo-1,2-benzenediol] (4) and bis (2,3-dibromo-4,5-dihydroxybenzyl) ether (5). Compound 5 was the most active against five strains of bacteria with the MIC less than 70 microg/ml, while compounds 2, 3 and 4 exhibited moderate activity.     

Synthesis and in vivo evaluation of ¹⁸F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters

The purpose of this study was to synthesize two new positron emission tomography (PET) probes, N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-[1?F]fluoroethoxy-9-oxo-4-acridine carboxamide ([1?F]3) and quinoline-3-carboxylic acid [2-(4-{2-[7-(2-[1?F]fluoroethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethyl}phenylcarbamoyl)-4,5-dimethoxyphenyl]amide ([1?F]4), and to evaluate the potential of these PET probes for assessing the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). [1?F]3 and [1?F]4 were synthesized by 1?F-alkylation of each O-desmethyl precursor with [1?F]2-fluoroethyl bromide for injection as PET probes. In vitro accumulation assay showed that treatment with P-gp/BCRP inhibitors (1 and 2) enhanced the intracellular accumulation capacity of P-gp- and BCRP-overexpressing MES-SA/Dx5 cells. In PET studies, the uptake (AUC(brain[0-)?? (min])) of [1?F]3 and [1?F]4 in wild-type mice co-injected with 1 were approximately sevenfold higher than that in wild-type mice, and the uptake of [1?F]3 and [1?F]4 in P-gp/Bcrp knockout mice were eight- to ninefold higher than that in wild-type mice. The increased uptake of [1?F]3 and [1?F]4 was similar to that of parent compounds ([11C]1 and [11C]2) previously described, indicating that radioactivity levels in the brain after injection of [1?F]3 and [1?F]4 are related to the function of drug efflux transporters. Also, these results suggest that the structural difference between parent compounds ([11C]1 and [11C]2) and fluoroethyl analogs ([1?F]3 and [1?F]4) do not obviously affect the potency against drug efflux transporters. In metabolite analysis of mice, the unchanged form in the brain and plasma at 60 min after co-injection of [1?F]4 plus 1 were higher (95% for brain; 81% for plasma) than that after co-injection of [1?F]3 plus 1. [1?F]4 is a promising PET probe to assess the function of drug efflux transporters.     

Antibacterial and cytotoxic activity of prenylated bicyclic acylphloroglucinol derivatives from Hypericum amblycalyx

Two new bicyclic acylphloroglucinol derivatives, hypercalyxone A (1-[5,7-dihydroxy-2-methyl-3-(3-methyl-but-2-enyl)-2-(4-methyl-pent-3-enyl)-chroman-8-yl]-2-methyl-propan-1-one, 1) and B (1-[5,7-dihydroxy-2-methyl-3-(3-methyl-but-2-enyl)-2-(4-methyl-pent-3-enyl)-chroman-8-yl]-2-methyl-butan-1-one, 2), have been isolated from the petroleum ether extract of the aerial parts of Hypericum amblycalyx, together with two further compounds (1-[5,7-dihydroxy-2-methyl-2-(4-methyl-pent-3-enyl)-chroman-8-yl]-2-methyl-propan-1-one, 3 and 1-[5,7-dihydroxy-2-methyl-2-(4-methyl-pent-3-enyl)-chroman-8-yl]-2-methyl-butan-1-one, 4), which have been described only as semi-synthetic products. In addition, the known triterpene lup-20(29)-en-3-one was obtained. Structure elucidation was based on 1D and 2D NMR studies, as well as on data derived from mass spectrometry. The four acylphloroglucinol derivatives were evaluated for their cytotoxic and antibacterial activity. All compounds showed moderate cytotoxic activity against KB and Jurkat T cancer cells. Especially compounds 3 and 4 exhibited a strong antibacterial activity against different Gram-positive strains.     

Inhibition of mast cell leukotriene release by thiourea derivatives

Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcERI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were seven active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 microM and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects.