Triterpenoid carotenoids and related lipids. Triterpenoid monohydroxy- and monoglucosyloxy-carotenoids from Streptococcus faecium UNH 564P

1. The characterization of two novel triterpenoid xanthophylls occurring in Streptococcus faecium UNH 564P is described. 2. Both are derived formally, and probably biosynthetically, from the C(30) analogue of neurosporene and have been identified as 4-hydroxy-4,4'-diaponeurosporene and its glucoside, 4-d-glucopyranosyloxy-4,4'-diaponeurosporene. 3. Problems associated with the use of specific glucosidases in defining the anomerism of carotenoid glucosides are discussed.     

Pigments of Staphylococcus aureus, a series of triterpenoid carotenoids.

The pigments of Staphylococcus aureus were isolated and purified, and their chemical structures were determined. All of the 17 compounds identified were triterpenoid carotenoids possessing a C30 chain instead of the C40 carotenoid structure found in most other organisms. The main pigment, staphyloxanthin, was shown to be alpha-D-glucopyranosyl 1-O-(4,4'-diaponeurosporen-4-oate) 6-O-(12-methyltetradecanoate), in which glucose is esterified with both a triterpenoid carotenoid carboxylic acid and a C15 fatty acid. It is accompanied by isomers containing other hexoses and homologs containing C17 fatty acids. The carotenes 4,4'-diapophytoene, 4,4'-diapophytofluene, 4-4'-diapophytofluene, 4-4'-diapo-zeta-carotene, 4,4'-diapo-7,8,11,12-tetrahydrolycopene, and 4,4'-diaponeurosporene and the xanthophylls 4,4'-diaponeurosporenal, 4,4'-diaponeurosporenoic acid, and glucosyl diaponeurosporenoate were also identified, together with some of their isomers or breakdown products. The symmetrical 4,4'-diapo- structure was adopted for these triterpenoid carotenoids, but an alternative unsymmetrical 8'-apo-structure could not be excluded.     

Novel carotenoid oxidase involved in biosynthesis of 4,4'-diapolycopene dialdehyde

Biosynthesis of C(30) carotenoids is relatively restricted in nature but has been described in Staphylococcus and in methylotrophic bacteria. We report here identification of a novel gene (crtNb) involved in conversion of 4,4'-diapolycopene to 4,4'-diapolycopene aldehyde. An aldehyde dehydrogenase gene (ald) responsible for the subsequent oxidation of 4,4'-diapolycopene aldehyde to 4,4'-diapolycopene acid was also identified in Methylomonas. CrtNb has significant sequence homology with diapophytoene desaturases (CrtN). However, data from knockout of crtNb and expression of crtNb in Escherichia coli indicated that CrtNb is not a desaturase but rather a novel carotenoid oxidase catalyzing oxidation of the terminal methyl group(s) of 4,4'-diaponeurosporene and 4,4'-diapolycopene to the corresponding terminal aldehyde. It has moderate to low activity on neurosporene and lycopene and no activity on beta-carotene or zeta-carotene. Using a combination of C(30) carotenoid synthesis genes from Staphylococcus and Methylomonas, 4,4'-diapolycopene dialdehyde was produced in E. coli as the predominant carotenoid. This C30 dialdehyde is a dark-reddish purple pigment that may have potential uses in foods and cosmetics.     

Eleven New Triterpenoid Glycosides from the Roots of Ilex asprella

Asprellosides A‐K, nine new ursane‐type triterpenoid glycosides ( 1 – 9 ), and two new oleanane‐type triterpenoid glycosides ( 10 and 11 ), including six rare sulfated triterpenoid glycosides, were isolated from the roots of Ilex asprella. Their structures were determined on the basis of comprehensive spectroscopic analysis and chemical methods. Among these compounds, asprelloside B ( 2 ) and asprelloside C ( 3 ) are the first examples of triterpenoid glycosides bearing a rare 3,4‐O‐disulfo‐xylopyranosyl residue. All the saponins isolated showed no significant effects against respiratory syncytial virus (RSV) and lipopolysaccharide‐induced nitric oxide production in Raw264.7 macrophages.     

Novel skeleton terpenes from Celastrus hypoleucus with anti-tumor activities

Celahypodiol 1, an unusual 17-membered carbon diterpenoid with a novel skeleton, and a new triterpenoid 12-oleanene-3beta,6alpha-diol 2, together with four known compounds furreginol 3, suigol 4, 20(30)-lupene-3beta, 29-diol 5, and 20(29)-lupene-1beta,3beta-diol 6, were isolated from the stalks of Celastrus hypoleucus (Oliv.) Warb. Their structures were established by means of spectroscopic analysis, including 2D NMR. The new compounds exhibited anti-tumor activities against a panel of human tumor cell lines.     

A novel sequence for phytoene dehydrogenation in Rhodospirillum rubrum

Differences between the absorption spectra of zeta-carotene (7,8,7',8'-tetrahydrolycopene) and the corresponding conjugated heptaene from diphenylamine-inhibited cultures of Rhodospirillum rubrum have been rationalized by the identification of the latter compound as the unsymmetrical isomer, 7,8,11,12-tetrahydrolycopene. The structures of the other conjugated polyene hydrocarbons, phytoene, phytofluene and neurosporene, have been confirmed and a novel pathway for the dehydrogenation of phytoene to lycopene in these bacteria is described.     

Neurosporene is the major carotenoid accumulated by Rhodobacter viridis JA737

The carotenoid, neurosporene, is of commercial importance due to its use as an antioxidant and UV-B radiation protector. It is usually obtained from fruits and vegetables. Although some bacterial mutants can accumulate neurosporene, these are unstable. A recently-isolated, natural and stable neurosporene accumulating, phototrophic purple non-sulfur bacterium Rhodobacter viridis JA737 is described that accumulates neurosporene as the major (98 %) carotenoid up to ~7 mg g dry cell^?1 and at 7.3 mg l^?1.     

Jessic acid and related acid triterpenoids from combretum elaeagnoides

A novel triterpenoid acid, jessic acid, was extracted from the leaves of Combretum elaeagnoides, where it was found together with its methyl ester and its α-L-arabinopyranoside, all three compounds occurring in significantly large amounts. Jessic acid is 1α,3β-dihydroxy-23-oxo-24-methylenecycloartan-30-oic acid.     

苦丁茶化学成分的研究

从苦丁茶叶中分离鉴定出四种成份,其中之一经鉴定为一新五环三萜内酯,暂命名为苦丁茶甙元(kudinchagenin);其他三种成份分别鉴定为α-香树脂、β-谷甾醇和鸟苏酸。     

Novel 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methylbenzofuran derivatives as selective alpha(2C)-adrenergic receptor antagonists

The synthesis of a series of 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-arylbenzofuran and 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methylbenzofuran-2-carboxamide derivatives as novel alpha(2C)-adrenergic receptor antagonists are described. Their affinity at three different human alpha(2)-adrenergic receptors is reported, and some of these compounds exhibited high affinity for the alpha(2C)-adrenergic receptor with high subtype selectivity. Among them, compound 10e has been found to show the anti-L-dopa-induced dyskinetic activity in marmosets. The structure-activity relationship of these compounds is also discussed.     

Loranthol: A new pentacyclic triterpenoid from Loranthus grewinkii

Loranthol (VIII) has been shown by chemical and physical methods to be lup-20(30)-en-3β,7β-diol, a new triterpenoid of the lupane series. The stereochemistry was established by its degradation to the parent hydrocarbon, lup-20(30)-ene.     

Anti-HIV activity of natural triterpenoids and hemisynthetic derivatives 2004–2009

The continued advance of HIV-AIDS makes the development of relatively inexpensive, freely accessible, and mechanistically more diverse antiviral therapies an urgent need. Natural products are, directly or indirectly, an important potential source of compounds meeting these conditions. A review of the recent literature indicates that some hemisynthetic triterpenoid derivatives, particularly belonging to the lupane, oleanane and ursane series, may be nearing a stage where they can be used to complement existing therapeutic approaches. On the other hand, although some natural derivatives of tetracyclic terpenoid families have revealed many novel structures and some promise as anti-HIV substances, their chemical modification to improve their potency and selectivity remains practically untouched. While ongoing work with the more ‘classical’ pentacyclic triterpenoids will continue to be a fertile field for HIV-AIDS drug discovery, the other structural groups offer unprecedented opportunities for the development of additional substances with useful properties and for the discovery of novel targets for antiviral therapy.     

Anti-AIDS agents. Part 57: Actein, an anti-HIV principle from the rhizome of Cimicifuga racemosa (black cohosh), and the anti-HIV activity of related saponins

Actein (1), a tetracyclic triterpenoid from the rhizome of Cimicifuga racemosa (black cohosh), and 82 related triterpenoid and steroidal saponins isolated from higher plants were evaluated for anti-HIV activity as a continuing study to discover potential anti-AIDS agents from natural products. Actein showed potent activity and another twelve saponins showed moderate activity. The active compounds included two steroidal, seven tetracyclic triterpenoid, and four pentacyclic triterpenoid compounds.     

A new triterpenoid from the fern Adiantum lunulatum and evaluation of antibacterial activity

A new triterpenoid, 22,29xi-epoxy-30-norhopane-13beta-ol (1) was isolated together with six known compounds viz., fern-9(11)-en-6alpha-ol. fern-9(11)-ene, fern-9(11)-en-25-oic acid, fern-9(11)-en-28-ol, filicenol-B, adiantone and oxidation product of fern-9(11)-en-6alpha-ol obtained as 6-oxofern-9(11)-ene from the whole plant of Adiantum lunulatum, and their structures were elucidated by means of spectroscopic analysis and antibacterial evaluation of these compounds were conducted.     

N-(3-Acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives as potent vanilloid receptor agonists and analgesics

A series of N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives were investigated as vanilloid receptor ligands in an effort to discover a novel class of analgesics. The proposed pharmacophore model of resiniferatoxin. which includes the C20 homovanillic moiety, the C3-carbonyl and the orthoester phenyl ring as key pharmacophoric groups, was utilized as a guide for drug design. The compounds were synthesized after several steps from diethylmalonate and evaluated in vitro in a receptor binding assay and in a capsaicin-activated channel assay. Additional evaluation of analgesic activity, anti-inflammatory activity and pungency was conducted in animal models by the writhing test, the ear edema assay, and the eye-wiping test, respectively. Among the new compounds, 23 and 28 were found to be the most potent receptor agonists of the series with Ki values of 19 nM and 11 nM, respectively. Their strong in vitro potencies were also reflected by an excellent analgesic profile in animal tests with ED50 values of 0.5 microg kg for 23 and 1.0 microg/kg for 28. Relative to capsaicin these compounds appear to be ca. 600 and 300 times more potent. Both 23 and 28 were found to be less pungent than capsaicin based on the eye-wiping test. However, the compounds did not show significant anti-inflammatory activity. A molecular modeling study comparing the energy-minimized structures of resiniferatoxin and 35 demonstrated a good correlation in the spatial disposition of the corresponding key pharmacophores. The thioureas described in this investigation, which were designed as simplified resiniferatoxin surrogates, represent a novel class of potent vanilloid receptor agonists endowed with potent analgesic activity and reduced pungency.     

Discovery of small molecule human C5a receptor antagonists

A novel series of small molecule C5a antagonists is reported. In particular, in vitro metabolic studies and solution based combinatorial synthesis are demonstrated as useful tools for the rapid identification of antagonists with low in vitro clearance. Members of this series specifically inhibited the binding of ¹²⁵I-labeled C5a to human recombinant C5a receptor (C5aR). In functional cell assays these compounds displayed surmountable antagonism against C5a and did not demonstrate any detectable agonist activity.     

Slr1293 in Synechocystis sp. strain PCC 6803 Is the C-3',4' desaturase (CrtD) involved in myxoxanthophyll biosynthesis

When grown at high light intensity, more than a quarter of the total carotenoids in the unicellular cyanobacterium Synechocystis consists of myxoxanthophyll, a polar carotenoid glycoside. The biosynthetic pathway of myxoxanthophyll is unknown but is presumed to involve a number of enzymes, including a C-3',4' desaturase required to add one double bond to generate 11 conjugated double bonds in the monocyclic myxoxanthophyll. A candidate for this desaturase is Slr1293, which was identified by genome similarity searching. To determine whether Slr1293 is a desaturase recognizing neurosporene and lycopene, slr1293 was expressed in Escherichia coli strains accumulating neurosporene or lycopene. Confirming such a desaturase function for Slr1293, these E. coli strains accumulated 3',4'-didehydroneurosporene and 3',4'-didehydrolycopene, respectively. Indeed, deletion of slr1293 in Synechocystis provides further evidence that Slr1293 is a desaturase recognizing neurosporene: In the slr1293 deletion mutant, neurosporene was found to accumulate and was further processed to produce neurosporene glycoside. Neurosporene hereby becomes a primary candidate to be the branch point molecule between carotene and myxoxanthophyll biosynthesis in this cyanobacterium. The slr1293 gene was concluded to encode a C-3',4' desaturase that is essential for myxoxanthophyll biosynthesis, and thus it was designated as crtD. Furthermore, as Slr1293 appears to recognize neurosporene and to catalyze the first committed step on the myxoxanthophyll biosynthesis pathway, Slr1293 plays a pivotal role in directing a portion of the precursor pool for carotenoid biosynthesis toward myxoxanthophyll biosynthesis in Synechocystis sp. strain PCC 6803.     

Chemical constituents from the fruits of Melia azedarach (Meliaceae)

A new apotirucallane-type triterpenoid, 3α-benzoate triterpenoid A (1), along with six known triterpenoids (2–7), one aromatic ester (8) and eight lignans (9–16), were isolated from the fruits of Melia azedarach Linn. The structure of 1 was determined by spectral analyses, including HR-ESI-MS, 1D NMR (¹H NMR and ¹³C NMR) and 2D NMR (HSQC and HMBC) analyses. 10, 11 and 16 were reported for the first time from the family Meliaceae, 8 was identified from the genus Melia for the first time, and 2, 3, 5, 7, 9 and 12–15 were obtained from M. azedarach for the first time. The chemotaxonomic significance of these compounds is discussed.     

Bioactive triterpenoid saponins and phenolic compounds against glioma cells

A total of 54 natural origin compounds were evaluated for their activity in inhibiting the proliferation of glioma cells. Results showed that four Aesculus polyhydroxylated triterpenoid saponins (3–6), six Gleditsia triterpenoid saponins (7–12), and five phenolic compounds (43–46, 51) had dose-dependent activity suppressing the proliferation of both C6 and U251 cells. Structure–activity relationship analysis suggested that the acetyl group at C-28 for the Aesculus saponins and the monoterpenic acid moiety for the Gleditsia saponins could be critical for the activity of these active compounds. Aesculioside H (4), gleditsioside A (7), and feuric acid 3,4-dihydroxyphenethyl ester (FADPE, 46) were the three most active compounds from the different types of the active compounds and induced apoptosis and necrosis in glioma cells.     

The effect of methyl jasmonate on triterpene and sterol metabolisms of Centella asiatica, Ruscus aculeatus and Galphimia glauca cultured plants

Considering that exogenously applied methyl jasmonate can enhance secondary metabolite production in a variety of plant species and that 2,3-oxidosqualene is a common precursor of triterpenes and sterols in plants, we have studied Centella asiatica and Galphimia glauca (both synthesizing triterpenoid secondary compounds) and Ruscus aculeatus (which synthesizes steroidal secondary compounds) for their growth rate and content of free sterols and respective secondary compounds, after culturing with or without 100 microM methyl jasmonate. Our results show that elicited plantlets of G. glauca and to a higher degree C. asiatica (up to 152-times more) increased their content of triterpenoids directly synthesized from 2,3-oxidosqualene (ursane saponins and nor-seco-friedelane galphimines, respectively) at the same time as growth decreased. In contrast, the free sterol content of C. asiatica decreased notably, and remained practically unaltered in G. glauca. However, in the case of R. aculeatus, which synthesizes steroidal saponins (mainly spirostane type) indirectly from 2,3-oxidosqualene after the latter is converted to the plant phytosterol-precursor cycloartenol, while the growth rate and free sterol content clearly decreased, the spirostane saponine content was virtually unchanged (aerial part) or somewhat lower (roots) in presence of the same elicitor concentration. Our results suggest that while methyl jasmonate may be used as an inducer of enzymes involved in the triterpenoid synthesis downstream from 2,3-oxidosqualene in both C. asiatica and G. glauca plantlets, in those of C. asiatica and R. aculeatus it inhibited the enzymes involved in sterol synthesis downstream from cycloartenol.