Indole and carbazole alkaloids from Glycosmis montana with weak anti-HIV and cytotoxic activities

A diprenylated indole, (E)-3-(3-hydroxymethyl-2-butenyl)-7-(3-methyl-2-butenyl)-1H-indole (1), and six known carbazole alkaloids were isolated from the twigs and leaves of Glycosmis montana Pierre (Rutaceae). Their structures were determined on the basis of analysis of spectral evidence including 1D and 2D NMR and MS. The alkaloids (1-3) exhibited weak to moderate take in vitro inhibitory activity against HIV replication in C8166 cells, and they (as well as carbalexine A and B) had cytotoxic activity against the human leukaemia cell line CCRF-CEM.     

Quaternary isoquinoline alkaloids from Xylopia parviflora

From the quaternary alkaloidal fraction of the bark and the root of Xylopia parviflora (Annonaceae), four isoquinoline alkaloids, xylopinidine, dehydrocoreximine, N, N-dimethylanomurine and N-methylphoebine were isolated along with the known compounds, pycnarrhine, lotusine, 6,7-dimethoxy-2-methyl-isoquinolinium salt, 1,2-dehydroreticuline, (-)-phellodendrine, (+)-tembetarine, (-)-litcubine, (+)-magnoflorine, tetradehydroreticuline, (-)-oblongine, (+)-menisperine, (+)-N-methylcorydine, stepharanine, (+)-xanthoplanine, dehydrodiscretine, jatrorrhizine and palmatine. 3,4-Dihydro-6,7-dimethoxy-2-methyl-isoquinolinium and N-methylpurpuerine were isolated as natural products for the first time. Their structures were determined on the basis of spectroscopic evidence.     

Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial chemotherapy.

Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines) identified in our laboratory as potential pharmacophore for designing macrofilaricidal agents, have been explored further for identifying the pharmacophore responsible for high order of adulticidal activity. This has led to syntheses and macrofilaricidal evaluations of a number of 1-aryl-9H-pyrido[3,4-b]indole-3-carboxylate derivatives (3-7). The macrofilarical activity was initially evaluated in vivo against Acanthoeilonema viteae. Amongst all the synthesized compounds, only twelve compounds namely 3a, 3c, 3d, 3f, 4c, 4d, 4f, 5a, 6f, 6h, 6i and 7h have exhibited either > 90% micro- or macrofilaricidal activity or sterilization of female worms. These compounds have also been screened against Litomosoides carinii and of these only 3f and 5a have also been found to be active. Finally these two compounds have been evaluated against Brugia malayi. The structure activity relationship (SAR) associated with position-1 and 3 substituents in beta-carbolines have been discussed. It has been observed that the presence of carbomethoxy at position-3 and an aryl substituent at position- in beta-carbolines effectively enhance antifilarial activity particularly against A. viteae. Amongst the various compounds screened, methyl 1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (4c) has shown highest adulticidal activity and methyl 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyla te (3a) has shown highest microfilaricidal action against A. viteae at 50 mg/ kg x 5 days (i.p.). Another derivative of this compound namely 1-(4-chlorophenyl)-3-hydroxymethyl-9H-pyrido[3,4-b]indole (5a) exhibited highest activity against L. carinii at 30 mg/kg x 5 days (i.p.) and against B. malayi at 50 mg/kg x 5 days (i.p.) or at 200 mg/kg x 5 days (p.o.).     

Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity

The substituted chloroisoquinolinediones and pyrido[3,4-b]phenazinediones were synthesized, and the cytotoxic activity and topoisomerase II inhibitory activity of the prepared compounds were evaluated. Chloroisoquinolinediones have been prepared by the reported method employing 6,7-dichloroisoquinoline-5,8-dione. The cyclization to pyrido[3,4-b]phenazinediones was achieved by adding the aqueous sodium azide solution to the dimethylformamide solution of corresponding chloroisoquinoline-5,8-dione. The cytotoxicity of the synthesized compounds was evaluated by a SRB (Sulforhodamine B) assay against various cancer cell lines such as A549 (human lung cancer cell line), SNU-638 (human stomach cancer cell), Col2 (human colon cancer cell line), HT1080 (human fibrosarcoma cell line), and HL-60 (human leukemia cell line). Almost all the synthesized pyrido[3,4-b]phenazinediones showed greater cytotoxic potential than ellipticine (IC(50)=1.82-5.97 microM). In general, the cytotoxicity of the pyrido[3,4-b]phenazinediones was higher than that of the corresponding chloroisoquinolinediones. The caco-2 cell permeability of selected compounds was 0.62 x 10(-6)-35.3 x 10(-6)cm/s. The difference in cytotoxic activity among tested compounds was correlated with the difference in permeability to some degree. To further investigate the cytotoxic mechanism, the topoisomerase II inhibitory activity of the synthesized compounds was estimated by a plasmid cleavage assay. Most of compounds showed the topoisomerase II inhibitory activity (28-100%) at 200 microM. IC(50) values for the most active compound 6a were 0.082 microM. However, the compounds were inactive for DNA relaxation by topoisomerase I at 200 microM.     

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.     

4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: potent, nonsteroidal androgen receptor agonists.

A series of human androgen receptor (hAR) agonists based on 4-alkyl-; 4,4-dialkyl-; and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinoline was synthesized and evaluated in competitive receptor binding assays and an androgen receptor cotransfection assay in a mammalian cell background. A number of compounds in this series demonstrated activity equal to or better than dihydrotestosterone in both assays and represent a novel class of compounds for use in androgen replacement therapy.     

Tetrahydroisoquinoline alkaloids of the Mexican columnar cactus Pachycereus Weberi

Eight tetrahydroisoquinoline alkaloids have been crystallized and identified from the nonphenolic and phenolic extracts of the giant Mexican cereoid cactus, Pachycereus weberi (Coult.) Br. and R. The identities were established as 5,6,7-trimethoxy-1,2,3,4- tetrahydroisoquinoline (nortehuanine) 1; 7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (lemaireocercine) 2; 7-methoxy-1, 2,3,4-tetrahydroisoquinoline (weberidine) 3; 5,6,7,8-tetramethoxy-1,2,3,4-tetrahydroisoquinoline (weberine) 4; 6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline (heliamine) 5; 2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (N- methylheliamine or oxymethyl-corypalline) 6; 2-methyl-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline (tehuanine) 7; and 1,2-dimethyl-6,7-dimethoxy-8-hydroxy-1,2,3,4-tetrahydroisoquinoline (pellotine) 8. Compounds 1- 4 have not been identified previously as natural compounds, while compounds 5-8 are previously known cactus alkaloids.     

Isoquinoline and isoindole alkaloids from Menispermum dauricum

Three isoquinoline alkaloids and an isoindole alkaloid, along with eight known compounds, were isolated from the roots of Menispermum dauricum (Menispermacese). The alkaloids were characterized as 7-hydroxy-6-methoxy-1(2H)-isoquinolinone, 6,7-dimethoxy-N-methyl-3,4-dioxo-1(2H)-isoquinolinone, 1-(4-hydroxybenzoyl)-7-hydroxy-6-methoxy-isoquinoline and 6-hydroxy-5-methoxy-N-methylphthalimide, on the basis of spectral evidence including 1D- and 2D-NMR and MS analyses.     

Quinoline alkaloids and cytotoxic lignans from Haplophyllum tuberculatum

Three quinoline alkaloids and two lignan lactones were isolated from Haplophyllum tuberculatum. Physicochemical and spectral evidence established the structures of two of the alkaloids as a new quinoldione, 3-(1′,1′-dimethylallyl)-3-(3″,3″-dimethylallyl)-1,2,3,4-tetrahydro-2,4-quinoldione and the known 4-(3′,3′-dimethylallyloxy)-3-(3″,3″-dimethylallyl)-2(1H)-quinolone. The former was shown to undergo facile [3,3]-sigmatotropic transformation into the latter. The remaining compounds were identified as the known Polygamain, kusunokinin and 1-methyl-2-n-nonyl-4(1H)-quinolone.     

A dopamine- and octopamine-sensitive adenylate cyclase in the nervous system of Octopus vulgaris

• 1.1. Adenylate cyclase activity was assayed in the optic lobe of Octopus vulgaris.
• 2.2. Both octopamine and dopamine stimulate the octopus adenylate cyclase, apparently by competing with the same receptor site.
• 3.3. (±)-2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene-HBr (6,7-ADTN) and a number of phenylethanolamine derivatives stimulate the octopus adenylate cyclase activity.
• 4.4. The dopamine D-1 antagonists R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH-23390) and (±)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SKF-83566) are unable to antagonize the effects of dopamine and octopamine, and similarly ineffective is the agonist (±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol-HCl (SKF-38393).
• 5.5. No detectable binding of labelled SCH-23390 occurs on membrane preparations from octopus optic lobe.

     

Cytotoxic lignans from Larrea tridentata

Six lignans, including the cyclolignan 3,4'-dihydroxy-3',4'-dimethoxy-6,7'-cyclolignan, were isolated from the flowering tops of Larrea tridentata. Additionally the flavanone, (S)-4',5-dihydroxy-7-methoxyflavanone, was isolated for the first time from L. tridentata or any member of the family Zygophyllaceae. All of the compounds were assessed for their growth inhibitory activity against human breast cancer, human colon cancer and human melanoma cell lines. The lignans had IC50 values of 5-60 microM with the linear butane-type lignans being the most potent, and it was found that colon cancer cells were the least sensitive cell type tested. The relative potency of linear butane type lignans against human breast cancer appears to correlate positively with the number of O-methyl groups present on the molecule.     

Synthesis and evaluation of pharmacological profile of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides

In previous studies we identified several 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives displaying potent anticonvulsant effects in different animal models of epilepsy. With the aim to deepen the structure–activity relationships (SAR) for this class of compounds and identify novel anticonvulsant agents we synthesized a series of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides. The new compounds incorporate the main features of the above-mentioned anticonvulsants and a sulfonamide function capable to inhibit the enzyme carbonic anhydrase (CA, EC 4.2.1.1), which represents an attractive target in epilepsy. Pharmacological effects were evaluated in vivo against audiogenic seizures in DBA/2 mice and in vitro against several CA isoforms. Some of the new molecules showed anticonvulsant properties better than topiramate, but weak inhibitory activity and low selectivity in enzymatic assay.     

油丹生物碱的研究

从油丹中分到6种生物碱,其中4种经理化常数及光谱测定,鉴定为：番荔枝宁,杏黄罂粟碱,多略发宁及1－（4－甲氧基苄基）,6,7－亚甲二氧基1,2,3,4－四氢异喹啉生物碱。     

(+)-12alpha-Hydroxysophocarpine, a new quinolizidine alkaloid and related anti-HBV alkaloids from Sophora flavescens

(+)-12alpha-Hydroxysophocarpine (8), a new quinolizidine alkaloid was isolated from the roots of Sophora flavescens, together with 10 known quinolizidine alkaloids, (+)-oxymatrine (1), (+)-matrine (2), (+)-9alpha-hydroxymatrine (3), (+)-allomatrine (4), (+)-oxysophocarpine (5), (-)-sophocarpine (6), (-)-9alpha-hydroxysophocarpine (7), (+)-lehmannine (9), (-)-13,14-dehydrosophoridine (10), and (-)-anagyrine (11). Their structures were elucidated by spectroscopic methods, and the stereochemistry of 8 was confirmed by X-ray analysis. These alkaloids were tested for anti-hepatitis B virus (HBV) activity in vitro, compounds 5, 6, 9, and 10 showed significant anti-HBV activity with inhibitory potency against HBsAg secretion at 48.3-79.3% and that against HBeAg secretion at 24.6-34.6%.     

Enantioselective Dynamic Process Reduction of α- and β-Tetralone and Stereoinversion of Resulting Alcohols in a Selected Strain Culture

α-Tetralone and β-tetralone were subjected to biotransformation by 14 fungal strains. Enantiomeric purity of the products depended on the reaction time. 3-Day transformation of α-tetralone in Absidia cylindrospora culture gave S-(+)-1,2,3,4-tetrahydro-1-naftol of 92 % ee, whereas longer biotransformation time resulted in decrease of ee value. 3-Day transformation of β-tetralone by the same strain gave predominantly S-(-)-1,2,3,4-tetrahydro-2-naftol, whereas after 9 days of the reaction, the R-enantiomer with 85 % ee was isolated. Transformation of β-tetralone by Chaetomium sp. KCh 6651 gave pure (S)-(-)-1,2,3,4-tetrahydro-2-naftol in high yield at the concentration of 1 g/l. In this process, a non-selective carbonyl reduction was observed, followed by a selective oxidation of the R-alcohol.     

Tetrahydro-beta-carboline alkaloids that occur in foods and biological systems act as radical scavengers and antioxidants in the ABTS assay

Tetrahydro- β-carboline alkaloids that occur in foods such as wine, seasonings, vinegar and fruit products (juices, jams) acted as good radical scavengers (hydrogen- or electron donating) in the ABTS (2,2'-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) assay, and therefore, they could contribute to the beneficial antioxidant capacity attributed to foods. In contrast, the fully aromatic β-carbolines norharman and harman did not show any radical scavenger activity in the same assay. During the reaction with ABTS^.++ radical cation, tetrahydro- β-carboline-3-carboxylic acid such as 1-methyl-1,2,3,4-tetrahydro- β-carboline-3-carboxylic acid (MTCA) and 1-methyl-1,2,3,4-tetrahydro- β-carboline-1,3-dicarboxylic acid (MTCA-COOH) were converted to harman, whereas 1,2,3,4-tetrahydro- β-carboline-3-carboxylic acid (THCA) and 1,2,3,4-tetrahydro- β-carboline-1,3-dicarboxylic acid (THCA-COOH) afforded norharman. These results suggest that food and naturally-occurring tetrahydro- β-carboline alkaloids if accumulated in tissues, as reported elsewhere, might exhibit antioxidant activity.     

Anthraquinones from Hedyotis capitellata

Four new furanoanthraquinones, 2-hydroxymethyl-3,4-[2'-(1-hydroxy-1-methylethyl)-dihydrofurano]-8-hydroxyanthraquinone, 2-hydroxymethyl-3,4-[1'-hydroxy-2'-(1-hydroxy-1-methylethyl)-dihydrofurano]-8-hydroxyanthraquinone, 2-hydroxymethyl-3,4-[2'-1-hydroxy-1-methylethyl)-dihydrofurano]anthraquinone and 2-methyl-3,4-[2'-(1-hydroxy-1-methylethyl)-dihydrofurano] anthraquinone or capitellataquinone A-D and four known anthraquinones, rubiadin, anthragallol 2-methyl ether, alizarin 1-methyl ether and digiferruginol, together with scopoletin were isolated from the stems of Hedyotis capitellata Wall (Rubiaceae). Lucidin-3-O-beta-glucoside was isolated from the roots of the plant. Characterization of the new compounds was carried out by extensive NMR studies using FGCOSY, FGHMQC, FGHMBC and DEPT-135 in addition to other spectroscopic methods.     

Tetrahydro-β-carboline Alkaloids that Occur in Foods and Biological Systems Act as Radical Scavengers and Antioxidants in the ABTS Assay

Tetrahydro- &#103 -carboline alkaloids that occur in foods such as wine, seasonings, vinegar and fruit products (juices, jams) acted as good radical scavengers (hydrogen- or electron donating) in the ABTS (2,2'-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) assay, and therefore, they could contribute to the beneficial antioxidant capacity attributed to foods. In contrast, the fully aromatic &#103 -carbolines norharman and harman did not show any radical scavenger activity in the same assay. During the reaction with ABTS^.++ radical cation, tetrahydro- &#103 -carboline-3-carboxylic acid such as 1-methyl-1,2,3,4-tetrahydro- &#103 -carboline-3-carboxylic acid (MTCA) and 1-methyl-1,2,3,4-tetrahydro- &#103 -carboline-1,3-dicarboxylic acid (MTCA-COOH) were converted to harman, whereas 1,2,3,4-tetrahydro- &#103 -carboline-3-carboxylic acid (THCA) and 1,2,3,4-tetrahydro- &#103 -carboline-1,3-dicarboxylic acid (THCA-COOH) afforded norharman. These results suggest that food and naturally-occurring tetrahydro- &#103 -carboline alkaloids if accumulated in tissues, as reported elsewhere, might exhibit antioxidant activity.     

Abietane diterpenoids from the roots of some Mexican Salvia species (Labiatae): chemical diversity, phytogeographical significance, and cytotoxic activity

From the roots of some Mexican Salvia species, classified in subgenus Jungia, several diterpenoids belonging to abietane (i.e., 3-7), salvifolane (9-->20,10-->6)-diabeoabietane) (i.e., 2), and totarane (i.e., 10) carbocyclic skeletons were isolated together with two 20-nor- and one 6,7-secoabietane derivatives, 1 and 9, and 8, respectively. While compounds 2-10 were previously known from different sources, compound 1 is a new 20-norabietane derivative, whose structure was deduced by spectroscopic means and confirmed by X-ray-diffraction analysis. The phytogeographical significance of the distribution of 20-norabietanic diterpenoids in the genus suggested an evolutionary link between the Chinese and New-World Salvias. Compounds 2 and 8 were tested for cell-growth inhibition activity against several human cancer cell lines and human normal lymphocytes, while 2 showed a moderate cytotoxic activity, 8 exhibited a moderate yet selective activity against leukemia cell line.