Synthesis of the ester side chains of some potently antileukemic harringtonia alkaloids from chiral citrates

The selective reduction of one of the three carboxyl groups of two chiral citric acid derivatives to the corresponding aldehydes, under Rosenmund conditions, are reported together with the application of these aldehydes to the syntheses of the ester side chains of some potently antileukemic Cephalotaxus alkaloids e.g. anhydroharringtonine.

New alkamide and ent-kaurane diterpenoid derivatives from Senecio erechtitoides (Asteraceae)

Fractionation of a MeOH/CH2Cl2 (1/1) extract of the aerial parts of Senecio erechtitoides led to the isolation of six compounds including the hitherto unknown N-phenethylamide derivative named N-(p-hydroxyphenethyl)pentacosanamide (1), and a kauranoid derivative named derivative named ent-7-oxo-16 alpha,17-dihydroxykauran-19-oic acid (2), as well as four known compounds, ent-Kaur-16-en-19-oic acid (3), ent-7 beta-hydroxykaur-16-en-19-oic acid (4), ent-7-oxokaur-16-en-19-oic acid (5), steppogenin 4′-O-beta-d-glucoside (6). Their structures and relative configurations were elucidated on the basis of spectroscopic methods, chemical reactions, and comparison with previously known analogs. All isolates were evaluated for their antimicrobial activity and only diterpenoids were found to possess a potent inhibitor effect against the range of microorganism.

Biomimetic approach to Galbulimina type I alkaloids

On treatment with trifluoroacetic acid the tetraene precursor 23 underwent Boc deprotection, condensation and an iminium ion accelerated intramolecular Diels-Alder cycloaddition resulting in an iminium species 12, which was further converted into himbacine 1, himbeline 3 and himandravine 4, three out of four Galbulimina type I alkaloids thus providing strong evidence for the proposed biogenesis of this important family of alkaloids.

A new class of ammonium ylid for [2,3]-sigmatropic rearrangement reactions: ene-endo-spiro ylids

The first examples of sigmatropic rearrangements of ene-endo-spirocyclic, tetrahydropyridine-derived ammonium ylids are reported. Thus, spiro[6.7]-ylids rearrange primarily by a [2,3]-pathway, whereas the analogous [6.6]-ylids rearrange by [1,2]- and [2,3]-mechanisms in roughly equal proportions. This method serves as a rapid entry to the core of a range of alkaloids bearing a pyrrolo[1,2-a]azepine or octahydroindolizidine nucleus.

Comparison of the antidiabetic activity of Berberis lyceum root extract and berberine in alloxan-induced diabetic rats

Berberine has been shown to have hypoglycaemic activity in several in vitro and in vivo models, although the mechanism of action is not fully known. Berberis lyceum Royle root produces high concentrations of berberine, and in traditional medicine, the whole extract of this plant is used widely to treat diabetes. The antidiabetic activity of the ethanol root extract of Berberis lyceum was compared with pure berberine in normal and alloxan-diabetic rats using similar doses of each. The concentration of berberine in the extract was determined to be 80% dry weight with only trace amounts of other alkaloids present. The purpose of the study was to investigate the effects of berberine and a whole extract of Berberis lyceum on blood glucose and other parameters associated with diabetes, to compare the effects of the crude extract with those of pure berberine and thus validate its use as a therapeutic agent, and finally to identify any contribution of the other components of the extract to these effects. Oral administration of 50 mg/kg of Berberis extract and berberine to normal and experimental diabetic rats produced a significant (p < 0.05) reduction in blood glucose levels from days 3-7 days of treatment. Significant effects were also observed on the glucose tolerance, glycosylated haemoglobin, serum lipid profiles and body weight of experimental animals. Berberis extract and berberine demonstrated similar effects on all parameters measured, and although the extract was comparable in efficacy to berberine, it did not produce any effects additional to those shown by pure berberine. The results support the use of the extract in traditional medicine, and demonstrate that apart from being a highly cost-effective means of treating with berberine, the total extract does not appear to confer any additional benefits or disadvantages compared with the pure compound. Copyright (c) 2008 John Wiley & Sons, Ltd.

Influence of sugar type on the bioavailability of cocoa flavanols.

The beneficial effects of cocoa on vascular function are mediated by the absorption of monomeric flavanols into the circulation from the small intestine. As such, an understanding of the impact of the food matrix on the delivery of flavanols to the circulation is critical in assessing the potential vascular impact of a food. In the present study, we investigated the impact of carbohydrate type on flavanol absorption and metabolism from chocolate. A randomised, double-blind, three-arm cross-over study was conducted, where fifteen volunteers were randomly assigned to either a high-flavanol (266 mg) chocolate containing maltitol, a high-flavanol (251 mg) chocolate with sucrose or a low-flavanol (48 mg) chocolate with sucrose. Test chocolates were matched for micro- and macronutrients, including the alkaloids theobromine and caffeine, and were similar in taste and appearance. Total flavanol absorption was lower after consumption of the maltitol-containing test chocolate compared with following consumption of its sucrose-containing equivalent (P = 0·002). Although the O-methylation pattern observed for absorbed flavanols was unaffected by sugar type, individual levels of unmethylated ( - )-epicatechin metabolites, 3'-O-methyl-epicatechin and 4'-O-methyl-epicatechin metabolites were lower for the maltitol-containing test chocolate compared with the sucrose-containing equivalent. Despite a reduction in the total plasma pool of flavanols, the maximum time (T max) was unaffected. The present data indicate that full assessment of intervention treatments is vital in future intervention trials with flavanols and that carbohydrate content is an important determinant for the optimal delivery of flavanols to the circulation.

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid Loci

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses.

New furoquinoline alkaloid and flavanone glycoside derivatives from the leaves of Oricia suaveolens and Oricia renieri (Rutaceae)

Fractionation of the methanol extract of the leaves of Oricia renieri and Oricia suaveolens (Rutaceae) led to the isolation of 13 compounds including the hitherto unknown furoquinoline alkaloid named 6,7-methylenedioxy-5-hydroxy-8-methoxydictamnine (1) and a flavanone glycoside named 5-hydroxy-40-methoxy-7-O-[a-Lrhamnopyranosyl(1000→500)-b-D-apiofuranosyl]-flavanoside (2), together with 11 known compounds (3–13). The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral data and comparison. All compounds isolated were examined for their activity against human carcinoma cell lines. The alkaloids 1, 5, 12, 13 and the phenolic 2, 8, 11 tested compounds exhibited non-selective moderate cytotoxic activity with IC50 8.7–15.9mM whereas compounds 3, 4, 6, 7, 9 and 10 showed low activity.

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

Cinchona alkaloids with a free 6'-OH functionality are being increasingly used within asymmetric organocatalysis. This fascinating class of bifunctional catalyst offers a genuine alternative to the more commonly used thiourea systems and because of the different spacing between the functional groups, can control enantioselectivity where other organocatalysts have failed. In the main, this review covers the highlights from the last five years and attempts to show the diversity of reactions that these systems can control. It is hoped that chemists developing asymmetric methodologies will see the value in adding these easily accessible, but underused organocatalysts to their screens.

Production of bioactive diterpenoids in the Euphorbiaceae depends on evolutionarily conserved gene clusters

The Euphorbiaceae produce a diverse range of diterpenoids, many of which have pharmacological activities. These diterpenoids include ingenol mebutate, which is licensed for the treatment of a precancerous skin condition (actinic keratosis), and phorbol derivatives such as resiniferatoxin and prostratin, which are undergoing investigation for the treatment of severe pain and HIV, respectively. Despite the interest in these diterpenoids, their biosynthesis is poorly understood at present, with the only characterized step being the conversion of geranylgeranyl pyrophosphate into casbene. Here, we report a physical cluster of diterpenoid biosynthetic genes from castor (Ricinus communis), including casbene synthases and cytochrome P450s from the CYP726A subfamily. CYP726A14, CYP726A17, and CYP726A18 were able to catalyze 5-oxidation of casbene, a conserved oxidation step in the biosynthesis of this family of medicinally important diterpenoids. CYP726A16 catalyzed 7,8-epoxidation of 5-keto-casbene and CYP726A15 catalyzed 5-oxidation of neocembrene. Evidence of similar gene clustering was also found in two other Euphorbiaceae, including Euphorbia peplus, the source organism of ingenol mebutate. These results demonstrate conservation of gene clusters at the higher taxonomic level of the plant family and that this phenomenon could prove useful in further elucidating diterpenoid biosynthetic pathways.