Influence of organic supplements on accumulation of β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid in callus culture of Boswellia serrata Roxb.

Boswellia serrata Roxb. is a source of several bioactive triterpenoids. Boswellic acid, obtained from oleo-gum resin of the tree, is a major potentially bioactive and medicinal compound. Unrestricted exploitation of its natural resource has led to its listing among the threatened and endangered species. Accumulation of the compound through tissue culture seems a promising option. The present work was conducted to study the effect of sodium pyruvate, l-phenylalanine, glycine, ferulic acid and sucrose on the growth of callus and accumulation of four principal isomers of boswellic acids, viz. β-boswellic acid (BBA), acetyl-β-boswellic acid (ABBA), 11-keto-β-boswellic acid (KBBA) and acetyl-11-keto-β-boswellic acid (AKBBA). Callus cultures obtained from embryo explants of Boswellia serrata on Murashige and Skoog medium containing 2.5 μM 6-benzyladenine, 15 μM indole acetic acid and 200 mg l^?1 polyvinyl pyrrolidone was supplemented with varying concentrations of the supplements. Sodium pyruvate was most beneficial for the production of AKBBA (77 folds), BBA (27 folds) and ABBA (27 folds) at 10 mg l^?1 and for KBBA (47 folds) at 5 mg l^?1 when compared with control. It was closely followed by sucrose (50 g l^?1) resulting in KBBA (22-fold), AKBBA (25-fold), BBA (17-fold) and ABBA (10-fold). Glycine, l-phenylalanine and ferulic acid were relatively less effective. It can be concluded that callus cultures manipulated with different concentrations of organic supplements, sodium pyruvate or sucrose, in particular, could be considered as an alternate strategy for direct production of boswellic acid and help in the conservation of the species.     

Microbial transformation of acetyl-11-keto-β-boswellic acid and their inhibitory activity on LPS-induced NO production

The capabilities of 20 strains of fungi to transform acetyl-11-keto-β-boswellic (AKBA) were screened. And biotransformation of AKBA by Cunninghamella blakesleana AS 3.970 afforded five metabolites (1–5), while two metabolites (6, 7) were isolated from biotransformation of Cunninghamella elegans AS 3.1207. The chemical structures of these metabolites were identified by spectral methods including 2D NMR and their structures were elucidated as 7β-hydroxy-3-acety-11-keto-β-boswellic acid (1), 21β-dihydroxy-3-acety-11-keto-β-boswellic acid (2), 7β,22α-dihydroxy-3-acety-11-keto-β-boswellic acid (3), 7β,16α-dihydroxy-3-acety-11-keto-β-boswellic acid (4), 7β,15α-dihydroxy-3-acety-11-keto-β-boswellic acid (5); 7β,15α,21β-trihydroxy-3-acety-11-keto-β-boswellic acid (6) and 15α,21β-dihydroxy-3-acety-11-keto-β-boswellic acid (7). All these products are previously unknown. Their primary structure–activity relationships (SAR) of inhibition activity on LPS-induced NO production in RAW 264.7 macrophage cells were evaluated.     

Antistaphylococcal and biofilm inhibitory activities of acetyl-11-keto-β-boswellic acid from <Emphasis Type="Italic">Boswellia serrata</Emphasis>

Background  

Boswellic acids are pentacyclic triterpenes, which are produced in plants belonging to the genus Boswellia. Boswellic acids appear in the resin exudates of the plant and it makes up 25-35% of the resin. β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid have been implicated in apoptosis of cancer cells, particularly that of brain tumors and cells affected by leukemia or colon cancer. These molecules are also associated with potent antimicrobial activities. The present study describes the antimicrobial activities of boswellic acid molecules against 112 pathogenic bacterial isolates including ATCC strains. Acetyl-11-keto-β-boswellic acid (AKBA), which exhibited the most potent antibacterial activity, was further evaluated in time kill studies, postantibiotic effect (PAE) and biofilm susceptibility assay. The mechanism of action of AKBA was investigated by propidium iodide uptake, leakage of 260 and 280 nm absorbing material assays.     

Acetyl-11-keto-β-boswellic acid modulates membrane dynamics in benzo(a)pyrene-induced lung carcinogenesis

Molecular and Cellular Biochemistry - Membrane fluidity is the most important physiochemical property of cell membranes and governs its functional attributes. The current investigations were...     

Design, synthesis, and SAR studies of novel polycyclic acids as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Starting from high throughput screening hit 2-adamantyl acetic acid 3, a series of polycyclic acids have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD-1. Structure-activity relationships of two different regions of the chemotype (polycyclic ring and substituents on quaternary carbon) are discussed.     

Characterization of isoflavonoids as inhibitors of β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from Moraxella catarrhalis: Kinetics,spectroscopic, thermodynamics and in silico studies

Backgroud

β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) is an essential component of type II fatty acid biosynthesis (FAS II) pathway in bacteria. It performs dehydration of β-hydroxyacyl-ACP to trans-2-acyl-ACP in the elongation cycle of the FAS II pathway. FabZ is ubiquitously expressed and has uniform distribution, which makes FabZ an excellent target for developing novel drugs against pathogenic bacteria.

Production of poly(3-hydroxyalkanoates) from α, ω-alkanedioic acids and hydroxylated fatty acids by Alcaligenes sp.

Summary Poly(3-hydroxybutyrate) (P(3HB)) was produced from a series of , -alkanedioic acids of both even and odd carbon numbers by the Alcaligenes sp. AK201. In contrast, copolymers of 3HB and 3-hydroxyvalerate(P(3HB-co-3HV)) were produced from hydroxylated fatty acids of even carbon numbers such as 12-hydroxystearate and 2-hydroxyoctanoate. The biosynthetic pathways to poly(3-hydroxyalkanoates)(P(3HA)) are discussed.     

Synthesis and structural studies of new analogues of PTH(1–11) containing Cα-tetra-substituted amino acids in position 8

The N-terminal 1–34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses characteristic of the native intact PTH. Recently, analogues of PTH(1–11) fragments with helicity-enhancing substitutions have been demonstrated to yield potent analogues of PTH(1–34). The work describes the synthesis, biological activity and structure of analogues of the best modified PTH sequence H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH₂ (I). In particular, the effect of the Ala/Aib substitution at positions 1 and 3 as well as of the replacement of Nle in position 8 with d-Nle, l-(αMe)-Nle and d-(αMe)-Nle was studied. The resulting peptides were characterized structurally by CD spectroscopy, solution NMR and MD, and in vitro for activity with respect to the cognate receptor, parathyroid hormone receptor.     

A New Peptide-N 4-(acetyl-β-glucosaminyl)asparagine Amidase from Soybean (Glycine max) Seeds: Purification and Substrate Specificity

We report here the isolation and characterization of a peptide-N ⁴-(acetyl-β-glucosaminyl) asparagine amidase (peptide: N-glycanase) from soybean (Glycine max) seeds. The enzyme was purified to homogeneity with 6.5% yield from defatted soybean meal extract by ion-exchange chromatography, gel filtration, hydroxyapatite chromatography, and hydrophobic chromatography. The purified enzyme, designated PNGase-GM, had the apparent molecular mass of 93 kDa by SDS-PAGE and 90 kDa by gel filtration, indicating this PNGase is a monomeric protein. The enzyme showed maximal activity at pH 4.5-5.0. PNGase-GM was capable of hydrolyzing the β-aspartylglycosylamine linkage (GlcNAcβ1→Asn) of various glycopeptide substrates bearing high-mannose type, hybrid type, and xylose/fucose-containing plant complex type N-glycan units, while this amidase was far less active on the glycopeptides bearing sialylated animal complex-type glycans.     

Synthesis,enzyme kinetics and computational evaluation of N-(β-d-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors

All possible isomers of N-β-d-glucopyranosyl aryl-substituted oxadiazolecarboxamides were synthesised. O-Peracetylated N-cyanocarbonyl-β-d-glucopyranosylamine was transformed into the corresponding N-glucosyl tetrazole-5-carboxamide, which upon acylation gave N-glucosyl 5-aryl-1,3,4-oxadiazole-2-carboxamides. The nitrile group of the N-cyanocarbonyl derivative was converted to amidoxime which was ring closed by acylation to N-glucosyl 5-aryl-1,2,4-oxadiazole-3-carboxamides. A one-pot reaction of protected β-d-glucopyranosylamine with oxalyl chloride and then with arenecarboxamidoximes furnished N-glucosyl 3-aryl-1,2,4-oxadiazole-5-carboxamides. Removal of the O-acetyl protecting groups by the Zemplén method produced test compounds which were evaluated as inhibitors of glycogen phosphorylase. Best inhibitors of these series were N-(β-d-glucopyranosyl) 5-(naphth-1-yl)-1,2,4-oxadiazol-3-carboxamide (K_i = 30 μM), N-(β-d-glucopyranosyl) 5-(naphth-2-yl)-1,3,4-oxadiazol-2-carboxamide (K_i = 33 μM), and N-(β-d-glucopyranosyl) 3-phenyl-1,2,4-oxadiazol-5-carboxamide (K_i = 104 μM). ADMET property predictions revealed these compounds to have promising oral drug-like properties without any toxicity.     

Iron-induced oxidation of (all-E)-β-carotene under model gastric conditions: kinetics,products, and mechanism

The stability of (all-E)-β-carotene toward dietary iron was studied in a mildly acidic (pH 4) micellar solution as a simple model of the postprandial gastric conditions. The oxidation was initiated by free iron (Fe^II, Fe^III) or by heme iron (metmyoglobin, MbFe^III). Fe^II and metmyoglobin were much more efficient than Fe^III at initiating β-carotene oxidation. Whatever the initiator, hydrogen peroxide did not accumulate. Moreover, β-carotene markedly inhibited the conversion of Fe^II into Fe^III. β-Carotene oxidation induced by Fe^II or MbFe^III was maximal with 5–10 eq Fe^II or 0.05–0.1 eq MbFe^III and was inhibited at higher iron concentrations, especially with Fe^II. UPLC/DAD/MS and GC/MS analyses revealed a complex distribution of β-carotene-derived products including Z-isomers, epoxides, and cleavage products of various chain lengths. Finally, the mechanism of iron-induced β-carotene oxidation is discussed. Altogether, our results suggest that dietary iron, especially free (loosely bound) Fe^II and heme iron, may efficiently induce β-carotene autoxidation within the upper digestive tract, thereby limiting its supply to tissues (bioavailability) and consequently its biological activity.     

Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1)

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.     

Stereoconservative and stereoselective syntheses of rare and non-naturalα-amino acids from (S)-aspartic acid and (S)-malic acid

Summary A new strategy for stereoconservative and stereoselective syntheses of several types of amino acids starting from-functional carboxylic acids employing hexafluoroacetone as protecting and activating reagent is described. Outstanding features of this new method are the mild reaction conditions and the high yields for introduction and cleavage of the protective group allowing sensitive functional groups in the side chain to survive. Furthermore, the new concept results in saving of synthetic steps.     

Substrate effects on the mechanism of enantioselective hydrogenation using ruthenium bis(phosphine) complexes as catalyst: A mechanistic investigation of the hydrogenation of α,β-unsaturated acids and esters based on deuterium labeling studies

The mechanism of ruthenium-bis(phosphine) catalyzed enantioselective hydrogenation of olefins was examined using [Ru((R)-BINAP)(H)(MeCN)_n(sol)_3 − n]BF₄ (n = 0–3, sol = solvent used in reaction) as catalyst. Tiglic and angelic acids were used as standard α,β-unsaturated acid substrates; (Z)-methyl α-acetamidocinnamate and dimethyl itaconate were used as standard α,β-unsaturated ester substrates. Isotopic labeling studies (deuterium scrambling) indicate that two distinct mechanisms are in operation for α,β-unsaturated acids versus α,β-unsaturated esters. In each case, 5-membered metallocycle intermediates are formed via olefin-hydride insertion. The mechanisms, however, deviate primarily in the activation of dihydrogen, which is strongly affected by the nature of the substrate. Hydrogenation of α,β-unsaturated acids proceed via heterolytic cleavage of dihydrogen, whereas hydrogenation of α,β-unsaturated esters proceed via homolytic cleavage of dihydrogen. A full discussion of the mechanisms is presented.     

Comparative properties of Aβ1–42, Aβ11–42, and [Pyr11]Aβ11–42 generated from O-acyl isopeptides

The use of water-soluble O-acyl isopeptides enabled us to investigate the biochemical properties of Aβ11–42 species, by preparing highly concentrated stock solutions after a pretreatment. Aβ11–42 and [Pyr¹¹]Aβ11–42 showed comparable aggregation capability and cytotoxicity, suggesting that the pyroglutamate modification at Glu¹¹ does not have a crucial role in these events. However, given that Aβ11–42 is converted to [Pyr¹¹]Aβ11–42 by a glutamyl cyclase in vivo, the potential aggregative and cytotoxic nature of [Pyr¹¹]Aβ11–42 that was observed in the present study provides valuable insights into the pathological functions of pyroglutamate-modified Aβ species in Alzheimer’s disease.