HIV-1 Tat interactions with cellular 7SK and viral TAR RNAs identifies dual structural mimicry.

The HIV Tat protein competes with the 7SK:HEXIM interaction to hijack pTEFb from 7SK snRNP and recruit it to the TAR motif on stalled viral transcripts. Here we solve structures of 7SK stemloop-1 and TAR in complex with Tat's RNA binding domain (RBD) to gain insights into this process. We find that 7SK is peppered with arginine sandwich motifs (ASM)-three classical and one with a pseudo configuration. Despite having similar RBDs, the presence of an additional arginine, R52, confers Tat the ability to remodel the pseudo configuration, required for HEXIM binding, into a classical sandwich, thus displacing HEXIM. Tat also uses R52 to remodel the TAR bulge into an ASM whose structure is identical to that of the remodeled ASM in 7SK. Together, our structures reveal a dual structural mimicry wherein viral Tat and TAR have co-opted structural motifs present in cellular HEXIM and 7SK for productive transcription of its genome.

Analgesic principle from Curcuma amada.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma amada has been used as a folk medicine for the treatment of rheumatic disorders in the northern part of Bangladesh and has also used for the treatment of inflammation and fever in the Ayurvedic and Unani systems of medicine. Aim of the study was to investigate the analgesic principle of the MeOH extract of the rhizome of Curcuma amada by an in vivo bioassay guided chromatographic separation and purification, and the structure elucidation of the purified compound by spectroscopic methods. MATERIALS AND METHODS: Dried powder of Curcuma amada rhizomes was extracted with MeOH. The analgesic activity of the crude extract and its chromatographic fractions as well as the purified compound itself was evaluated by the acetic acid induced writhing method and the formalin induced licking test in Swiss albino mice. The MeOH extract was separated by chromatographic methods and the pure active compound was purified by crystallization in hexanes. The structure of the pure compound was then elucidated by spectroscopic methods. RESULTS: The MeOH extract of Curcuma amada exhibited 41.63% and 45.53% inhibitions in the acetic acid induced writhing method at doses of 200mg/kg and 400mg/kg, respectively. It also exerted 20.43% and 28.50% inhibitions in early phase at doses of 200mg/kg and 400mg/kg, respectively, and 30.41% and 42.95% inhibitions in late phase at doses of 200mg/kg and 400mg/kg, respectively in the formalin induced licking test. Vacuum Liquid Chromatography (VLC) of crude extract yielded five fractions and Fr. 1 was found to have the most potent analgesic activity with inhibitions of 36.96% in the acetic acid induced writhing method and 47.51% (early phase), 39.50% (late phase) in the formalin induced licking test at a dose of 200mg/kg. Column chromatography of Fr. 1 on silica gel generated seven fractions (SF. 1-SF. 7). SF. 2 showed the most potent activity with inhibition of 49.81% in the acetic acid induced writhing method at a dose of 100mg/kg. Crystallization of SF. 2 yielded (1) (zederone, 520mg). It showed statistically significant inhibitions of 38.91% and 52.14% in the acetic acid induced writhing method at doses of 20mg/kg and 40mg/kg, respectively. Moreover, it also showed statistically significant inhibitions of 27.79% and 29.93% (early phase) and of 38.24% and 46.08% (late phase) in the formalin induced licking test at doses of 20mg/kg and 40mg/kg, respectively. CONCLUSION: Isolation and characterization of zederone (1) as analgesic principle of Curcuma amada corroborate its use in Ayurvedic, Unani and folk medicines for the treatment of rheumatic disorders and also contributing to its pharmacological validation.

Fungal transformation of cedryl acetate and α-glucosidase inhibition assay, quantum mechanical calculations and molecular docking studies of its metabolites.

The fungal transformation of cedryl acetate (1) was investigated for the first time by using Cunninghamella elegans. The metabolites obtained include, 10ß-hydroxycedryl acetate (3), 2α, 10ß-dihydroxycedryl acetate (4), 2α-hydroxy-10-oxocedryl acetate (5), 3α,10ß-dihydroxycedryl acetate (6), 3α,10α-dihydroxycedryl acetate (7), 10ß,14α-dihydroxy cedryl acetate (8), 3ß,10ß-cedr-8(15)-ene-3,10-diol (9), and 3α,8ß,10ß -dihydroxycedrol (10). Compounds 1, 2, and 4 showed α-glucosidase inhibitory activity, whereby 1 was more potent than the standard inhibitor, acarbose, against yeast α-glucosidase. Detailed docking studies were performed on all experimentally active compounds to study the molecular interaction and binding mode in the active site of the modeled yeast α-glucosidase and human intestinal maltase glucoamylase. All active ligands were found to have greater binding affinity with the yeast α-glucosidase as compared to that of human homolog, the intestinal maltase, by an average value of approximately -1.4 kcal/mol, however, no significant difference was observed in the case of pancreatic amylase.

Studies on α-glucosidase inhibition and anti-glycation potential of Iris loczyi and Iris unguicularis.

AIMS: One of the aims of this research work is the isolation and identification of various constituents of two medicinally important plants (Iris loczyi and Iris unguicularis). Secondly, the prime aim is the biological evaluation of these natural products to discover new potential inhibitors of α-glucosidase enzyme and protein glycation. MAIN METHODS: Plants of the genus Iris contain a variety of secondary metabolites. Chromatographic techniques were applied for the isolation of different compounds from Iris loczyi and Iris unguicularis. All the isolated compounds were screened for their α-glucosidase enzyme inhibition and antiglycation potential. KEY FINDINGS: It is shown in the results that two compounds (Kaempferol and 8-Methoxyeriodictyol) isolated from plant Iris unguicularis and compounds (Arborinone and 5,7-dihydroxy-2',6-dimethoxyisoflavone) isolated from plant Iris loczyi possess promising activity against α-glucosidase enzyme as compare to acarbose which is used as a standard α-glucosidase inhibitor in this study. A flavanone (2',5-dihydroxy-6,7-methylenedioxy) isolated from Iris loczyi was explored as most active anti-glycating agent. SIGNIFICANCE: α-Glucosidase enzyme is a therapeutic target to treat carbohydrate mediated diseases. In this study various inhibitors of α-glucosidase are identified which might be important for the management of diabetes. Similarly, antiglycation agents may have application for the management of late diabetic complications.

Duboscic acid: a potent α-glucosidase inhibitor with an unprecedented triterpenoidal carbon skeleton from Duboscia macrocarpa.

Duboscic acid (1), a triterpenoid with a unique carbon backbone, was isolated from Duboscia macrocarpa Bocq. It is the first member of a new class of triterpenoids, for which the name "dubosane" is proposed. Duboscic acid has a potent α-glucosidase inhibition, and its structure was unambiguously deduced by a single-crystal X-ray diffraction study.

Alpha-glucosidase and tyrosinase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones.

Sixteen new and one known metabolites 4-20 were obtained by incubation of tibolone (1) and hydroxytibolones (2 and 3) with various fungi. Their structures were elucidated by means of a homo and heteronuclear 2D NMR and by HREI-MS techniques. The relative stereochemistry was deduced by 2D NOESY experiment. Metabolites of tibolone (1) exhibited significant inhibitory activities against alpha-glucosidase and tyrosinase enzymes. Hydroxylations at C-6, C-10, C-11, C-15 positions and alpha,beta-unsaturation at C-1/C-2, C-4/C-5 showed potent inhibitory activities against these enzymes.

Alpha-glucosidase inhibitors ellagic acid derivatives with immunoinhibitory properties from Terminalia superba.

Fractionation of stem barks of Terminalia superba yielded two new ellagic acid derivatives, 3,4'-di-O-methylellagic acid 3'-O-beta-D-xylopyranoside (1) and 4'-O-galloy-3,3'-di-O-methylellagic acid 4-O-beta-D-xylopyranoside (2) together with known 3,3'-di-O-methylellagic acid, ellagic acid and 3,3'-di-O-methylellagic acid 4'-O-beta-D-xylopyranoside. Compounds (1) and (2) showed significant alpha-glucosidase inhibition activity and possessed significant immunoinhibitory activities with no cytotoxic effects.

Bioactive aristolactams from Piper umbellatum.

Four alkaloids named piperumbellactams A-D (1-4) were isolated from branches of Piper umbellatum together with known N-hydroxyaristolam II (5), N-p-coumaroyl tyramine (6), 4-nerolidylcatechol (7), N-trans-feruloyltyramine, E-3-(3,4-dihydroxyphenyl)-N-2-[4-hydroxyphenylethyl]-2-propenamide, beta-amyrin, friedelin, apigenin 8-C-neohesperidoside, acacetin 6-C-beta-d-glucopyranoside, beta-sitosterol, its 3-O-beta-d-glucopyranoside and its 3-O-beta-d-[6'-dodecanoyl]-glucopyranoside. Glycosidase inhibition, antioxidant and antifungal activities of these compounds were evaluated. Compounds 1-3 showed moderate alpha-glucosidase enzyme inhibition with IC50 values 98.07+/-0.44, 43.80+/-0.56 and 29.64+/-0.46, respectively. In DPPH radical scavenging assay, compounds 2, 3 and 6 showed potent inhibitory activity while compounds 4, 5 and 7 showed potent antifungal activity.

Microbial transformation of oleanolic acid by Fusarium lini and alpha-glucosidase inhibitory activity of its transformed products.

The biotransformation of a pentacyclic triterpene, oleanolic acid (1), with Fusarium lini afforded two oxidative metabolites, 2alpha,3beta-dihydroxyolean-12-en-28-oic acid (2), and 2alpha,3beta,11beta-trihydroxyolean-12-en-28-oic acid (3). Metabolite 3 was found to be a new compound. The structures were characterized on the basis of spectroscopic studies. These metabolites exhibited a potent inhibition of alpha-glucosidase enzyme.

alpha-Glucosidase inhibitory activity of triterpenoids from Cichorium intybus.

Two new triterpenoids, 18alpha,19beta-20(30)-taraxasten-3beta,21alpha-diol (cichoridiol) (1) and 17-epi-methyl-6-hydroxyangolensate (intybusoloid) (2), were obtained from the methanolic extract of seeds of Cichorium intybus along with 11 known compounds, lupeol (3), friedelin (4), beta-sitosterol (5), stigmasterol (6), betulinic acid (7), betulin (8), betulinaldehyde (9), syringic acid (10), vanillic acid (11) 6,7-dihydroxycoumarin (12), and methyl-alpha-D-galactopyranoside (13). Compounds 1, 1a, and 11 showed a good alpha-glucosidase inhibitory activity.

Further cytotoxic sesquiterpene lactones from Elephantopus mollis KUNTH.

Three new sesquiterpene lactones, (4betaH)-5alpha-hydroxy-8alpha-(2-methylbut-2-enoyloxy)-2-oxo-1(10),11(13)-guaiadien-12,6alpha-olide (1), (4betaH)-8alpha-(2-methylbut-2-enoyloxy)-2-oxo-1(5),10(14),11(13)-guaiatrien-12,6alpha-olide (2) and 2,5-epoxy-2beta-hydroxy-4alpha-methoxy-8alpha-(2-methylbut-2-enoyloxy)-4(15),10(14),11(13)-germacratrien-12,6alpha-olide (3), have been isolated from roots and stems of Elephantopus mollis together with two known sesquiterpene lactones (4, 5). The identification of the isolates was accomplished by spectroscopic methods. Compounds (1-5) exhibited significant cytotoxic activities against mouse neuroblastoma B104 cells.

alpha-Glucosidase inhibitory pentacyclic triterpenes from the stem bark of Fagara tessmannii (Rutaceae).

In addition to fatty acids, a mixture of sterols (beta-sitosterol, stigmasterol, campesterol and stigmastanol), lupeol, arctigenin methylether, sesamin, vanillic acid (1), 2,6-dimethoxy-1,4-benzoquinone (2), betulinic acid and two pentacyclic triterpene acetates were isolated from Fagara tessmannii Engl. They were identified as 3beta-acetoxy-16beta-hydroxybetulinic acid (3a) and 3beta,16beta-diacetoxybetulinic acid (3b), and their structures were established using 1 and 2D NMR spectra and by comparison with published data. Two derivatives of the compounds were prepared. Some isolated compounds were evaluated for their antifungal and antibacterial activities. Compounds 1 and 3a showed significant inhibition of alpha-glucosidase.

Alpha-glucosidase inhibitory and antioxidant acridone alkaloids from the stem bark of Oriciopsis glaberrima ENGL. (Rutaceae).

The CH2Cl2/MeOH extract of the stem bark of Oriciopsis glaberrima ENGL. afforded four new acridone alkaloids namely oriciacridone C, D, E and F along with six known compounds: atalaphyllidine, oleanolic acid, butulinic acid, beta-sitosterol, stigmasterol, glucoside of stigmasterol and one synthetically known acridone: 1,3,5-trihydroxy-4-prenylacridone. The structures were established on the basis of MS, 1D and 2D NMR experiments. The acridones 1, 4 and 5 showed potent activity against alpha-glucosidase, while the acridones 1-5 showed moderate free radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH).

Alpha-glucosidase inhibitory anthranols, kenganthranols A-C, from the stem bark of Harungana madagascariensis.

One new prenylated 1,4-anthraquinone and three new prenylated anthranols, named kengaquinone (1) and kenganthranols A (2), B (3), and C (4), were isolated from a hexane extract of the stem bark of Harungana madagascariensis. Six known compounds including anthraquinones, anthrones, and xanthones were also isolated and identified. The structures of the new compounds were determined by analysis of spectroscopic data and comparison with data of previously known analogues. Some isolated compounds (3-5, 7-11) were evaluated for their alpha-glucosidase inhibition activity. Compounds 3, 4, 8, and 11 showed significant activity, whereas compounds 7, 9, and 10 were inactive in this test.

Alpha-glucosidase inhibitory constituents from Duranta repens.

Three C-alkylated flavonoids 7-O-alpha-D-glucopyranosyl-3,5-dihydroxy-3'-(4"-acetoxyl-3"-methylbutyl)-6,4'-dimethoxyflavone (1), 7-O-alpha-D-glucopyranosyl-3,4'-dihydroxy-3'-(4"-acetoxyl-3"-methylbutyl)-5,6-dimethoxyflavone (2), 3,7,4'-trihydroxy-3'-(8"-acetoxy-7"-methyloctyl)-5,6-dimethoxyflavone (3) and a trans-clerodane type diterpenoid (-)-6beta-hydroxy-5beta,8beta,9beta,10alpha-cleroda-3,13-dien-16,15-olid-18-oic acid (4) are reported from Duranta repens along with (+)-hardwickiic acid (5) and (+)-3,13-clerodadien-16,15-olid-18-oic acid (6), isolated for the first time from this species. Their structures were established on the basis of the spectral methods, especially two dimensional (2D) NMR spectroscopy.