Lupin Alkaloids Research Articles

Total Synthesis of the Lupin Alkaloid Cytisine: Comparison of Synthetic Strategies and Routes

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Stereochemistry, Syntheses and Biological Activity of Lupine Alkaloids-from Studies on the Leguminous Plants Growing Mainly in Japan

Lupine alkaloids have been studied from the viewpoints of biosynthesis, biotechnology, chemotaxonomy, and biological activity, on the basis of the chemical investigation of the leguminous plants of the 28 species belonging to the 9 genera, which mainly grow in Japan. The results obtained have been comprehensively reviewed by authors. This review describes the stereochemistry of lupine alkaloids and focuses on the conformational flexibility of nitrogen-fused systems such as quinolizidine and indolizidine, syntheses of new unusual types of alkaloids from known lupine alkaloids, and pharmacological activity of lupine alkaloids, especially kappa-opioid receptor-mediated antinociceptive effects of matrine-type lupine alkaloids.

Indolizidine and quinolizidine alkaloids

This review covers the isolation, structure determination, synthesis, chemical transformations and biological activity of indolizidine and quinolizidine alkaloids. Included in the review are the hydroxylated indolizidines lentiginosine, swainsonine, castanospermine and their analogues; alkaloids from animal sources, including ants, amphibians and beetles; indolizidine alkaloids from the genera Polygonatum, Prosopis and Elaeocarpus; indolizidine and phenanthroindolizidine alkaloids; alkylquinolizidine alkaloids, including myrtine, epimyrtine, plumerinine and Lycopodium metabolites; Lythraceae and Nuphar alkaloids; lupine alkaloids; and alkaloids from marine sources. 150 references are cited.

A Flexible Strategy for the Synthesis of Tri‐ and Tetracyclic Lupin Alkaloids: Synthesis of (+)‐Cytisine, (±)‐Anagyrine, and (±)‐Thermopsine

A Flexible Strategy for the Synthesis of Tri‐ and Tetracyclic Lupin Alkaloids: Synthesis of (+)‐Cytisine, (±)‐Anagyrine, and (±)‐Thermopsine

A Flexible Strategy for the Synthesis of Tri‐ and Tetracyclic Lupin Alkaloids: Synthesis of (+)‐Cytisine, (±)‐Anagyrine, and (±)‐Thermopsine

Sequenzieller Ringschluss: Eine allgemeine Synthesestrategie für den Aufbau der Lupinalkaloide wurde entwickelt. Ein Teil der Strategie ist die sequenzielle Bildung der N1-C10- und C6-C7-Bindungen, die in allen Verbindungen dieser Naturstoffklasse vorkommen. Die Allgemeingültigkeit des Ansatzes wird mit der Synthese von (+)-Cytisin, (±)-Anagyrin und (±)-Thermopsin belegt (siehe Schema). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2006/z504015_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Hypoglycemic Effects of Multiflorine Derivatives in Normal Mice

(-)-Multiflorine isolated from leguminous plants produces a hypoglycemic effect when administered to mice with streptozotocin-induced diabetes. (-)-Multiflorine has an enaminone-type conjugation on the A ring, which is unusual in lupine alkaloids. Proceeding on the assumption that the A-B ring is responsible for the hypoglycemic effect, several compounds bearing the quinolizidin-2-one ring system were synthesized, and their hypoglycemic effects were examined. In addition, tricyclic compounds bearing 4-pyridone were synthesized, and their hypoglycemic effects were examined. The hypoglycemic effect of a 4-pyridone-type compound was similar to that of (-)-multiflorine as measured by oral glucose tolerance testing in normal mice. No hypoglycemic effect of a 4-piperidone-type compound was observed. These results indicate that compounds possessing double bond(s) in the A ring of multiflorine may be lead compounds for a new type of diabetes drug.

Astonishing diversity of natural surfactants: 6. Biologically active marine and terrestrial alkaloid glycosides

This review article presents 209 alkaloid glycosides isolated and identified from plants, microorganisms, and marine invertebrates that demonstrate different biological activities. They are of great interest, especially for the medicinal and/or pharmaceutical industries. These biologically active glycosides have good potential for future chemical preparation of compounds useful as antioxidants, anticancer, antimicrobial, and antibacterial agents. These glycosidic compounds have been subdivided into several groups, including: acridone; aporphine; benzoxazinoid; ergot; indole; enediyne alkaloidal antibiotics; glycosidic lupine alkaloids; piperidine, pyridine, pyrrolidine, and pyrrolizidine alkaloid glycosides; glycosidic quinoline and isoquinoline alkaloids; steroidal glycoalkaloids; and miscellaneous alkaloid glycosides.

The influence of the dietary inclusion of the alkaloid gramine, on rainbow trout ( Oncorhynchus mykiss) growth, feed utilisation and gastrointestinal histology

This study examined the influence of the alkaloid gramine, when included in diets for rainbow trout. Quinolizidine alkaloids have been suggested as a potential anti-nutritional problem with the use of lupin ( Lupinus sp.) meals in aquaculture diets. The findings from the present study show that above a critical threshold, the alkaloid gramine does have a strong anti-palatability effect. The effect is noted at a minimum gramine concentration of 500 mg/kg of diet, though not at 100 mg/kg. A continuing strong anti-palatability response is noted at higher inclusion levels and at the highest gramine inclusion concentration examined in this study (10,000 mg/kg), insufficient feed was consumed to even supply maintenance protein and energy demands. No adaptation to concentrations of gramine was observed throughout the 6-week study. No effects on nitrogen, energy or phosphorus digestibility were seen at the 500 mg/kg inclusion concentration of gramine relative to the reference diet, although the inclusion of the yellow lupin kernel meals (both Wodjil and Teo varieties) in the diet did improve the digestibility of phosphorus. Growth, as assessed using a range of parameters including weight gain, growth rate, nutrient and energy retention of fish fed the experiment treatments was largely consistent with feed intake. Survival of fish was significantly reduced at gramine inclusion levels above 1000 mg/kg. Feed conversion ratio (FCR) and feed conversion efficiency (FCE) were also reflective of feed intake and growth levels observed of each treatment. The concentrations of the plasma thyroid hormones tri-iodothyronine (T 3) and thyroxine (T 4) of fish from each of the treatments were consistent with feed intake (including the controls) suggesting that the concentrations of these hormones are in response to feed intake, not specifically the gramine levels in the diets. However, the inclusion of the Lupinus luteus kernel meals resulted in a significant change in T 4 levels, with a degree of independence of the feed intake, suggesting that there may be another mechanism by which these meals are influencing the concentrations of this hormone. In this study, there was an increase in the density of melano-macrophage centres (MMC) with high dietary levels of gramine. However, in the absence of any histological evidence for a toxic effect, it is likely that the increased MMC densities observed in the fish fed high concentrations of gramine are associated with starvation. This study demonstrated that the lupin alkaloid gramine, can have a strong anti-nutritional effect on fish at inclusion concentrations greater than 100 mg/kg, but that its mode of action is primarily through an anti-palatability effect. It is therefore considered unlikely that alkaloid effects would be observed in diets even with 50% inclusion of kernel meals from Australian commercial L. luteus varieties.

On the structure and spectroscopic properties of two 13-hydroxylupanine epimers

The crystal structures of 13α- and 13β-hydroxylupanines present a rare case of unexpected configuration and conformation of bis-quinolizidine alkaloid free bases. The configuration of A/B and C/D ring junctions is trans– cis and quasi trans– cis in α and β epimers, respectively. Ring C adopts a distorted chair form in both of them which is unusual for lupin alkaloids free bases. Such a drastic rearrangement of electronic configuration at N16 is caused by intermolecular hydrogen bonds formation between the OH and C O groups. In spite of different orientations of the OH groups - an axial or an equatorial in α and β epimers, respectively, the hydrogen bond geometry is the same in both crystal structures. This causes different distortions in all four rings of bis-quinolizidine skeletons. The Duax-Norton approach has been used to analyze them. In solution, both epimers occur in conformational equilibrium with considerable domination of the C-boat conformer (85–90%). This conformation is stabilized by the other type of intermolecular hydrogen bonds in comparison with that operating in the solid. Intermolecular deuterium bonds between 13α- and/or 13β-hydroxylupanine molecules and the solvent CDCl 3 molecules as well as the N16⋯H–O association have been found to play a crucial role.

How do slugs cope with toxic alkaloids?

Arion lusitanicus and other slugs are able to feed on a variety of plants, even those containing toxic secondary metabolites, such as alkaloids. Alkaloids, like sparteine, lupanine, quinidine and atropine are avoided in no-choice feeding experiments only when they are present in concentrations above 1 mg/g food pellet. Alkaloids (sparteine, lupanine, cytisine, quinidine, atropine, senecionine, eserine, and harmaline) are toxic to Arion lusitanicus when injected. LD50 values are 10 to 20 fold higher than in vertebrates indicating that slugs have a high tolerance towards food toxins. The tolerance is higher in young animals than in adult slugs. Injected alkaloids are rapidly detoxified within 72 h. Tolerance and detoxification can be induced by feeding slugs on non-lethal doses of lupin alkaloids. Using isolated microsomal preparations from the digestive gland, active detoxification was observed in vitro. Evidence is presented that cytochrome p450 plays an important role in detoxification of the applied alkaloids. A powerful and inducible detoxification systems appears to be the main mechanism that allows slugs to feed on plants rich in secondary metabolites (when no other food is available), that are usually avoided by other herbivores.

Do Naïve Ruminants Degrade Alkaloids in the Rumen?

Three different methods for the culture of rumen microorganisms (Hungate's technique, the Hohenheim in vitro gas production method, and the semicontinuous rumen simulation technique) were employed to study the influence of various alkaloids (sparteine, lupanine, cytisine, atropine, quinidine, lobeline, harmaline, arecoline, nicotine, caffeine, pilocarpine, gramine, senecionine, and monocrotaline) on rumen microorganisms. Rumen micro-organisms from naive ruminants (sheep, cattle) that had not been exposed to the alkaloids before were generally not able to degrade most of the alkaloids. Only the alkaloids pilocarpine, gramine, and monocrotaline appeared to be degradable. Rumen microorganisms from a sheep preconditioned to lupin alkaloids tolerated lupanine much better than nonadapted microorganisms, but no degradation occurred. The findings indicate that the main site of detoxification in naive ruminants is not the rumen but more likely the liver and kidneys as in nonruminants.

Indolizidine and Quinolizidine Alkaloids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Short Synthesis of (.+‐.)‐Cytisine.

The synthesis of racemic cytisine 1 has been completed using (i)N-selective alkylation of 6-bromopyridone with bromide 6 and (ii) Pd(0) mediated intramolecular α-arylation of lactam 8 as key steps to achieve rapid assembly of the tricyclic core skeleton of the lupin alkaloids.

The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus pursh) in sheep.

Several species of lupine (Lupinus spp.) are poisonous to livestock, producing death in sheep and "crooked calf disease" in cattle. Range livestock cope with poisonous plants through learned foraging strategies or mechanisms affecting toxicant disposition. When a toxic plant is eaten, toxicant clearance may be influenced by the animal's nutritional and/or physiological status. This research was conducted to determine whether differences in body condition or short-term nutritional supplementation of sheep altered the disposition of lupine alkaloids given as a single oral dose of ground silvery lupine (Lupinus argenteus) seed. Ewes in average body condition (ABC, n = 9) and low body condition (LBC, n = 10) received a single dose of ground lupine seeds including pods (8.5 g/kg BW) via gavage on the first day of the experiment, and were then randomly assigned to one of two nutritional supplement treatments. Blood samples were taken 0 to 60 h after dosing to compare blood alkaloid concentration and to evaluate alkaloid absorption and elimination profiles. Concentrations of total alkaloid and anagyrine, 5,6 dehydrolupanine, lupanine, and alkaloid E were measured in serum. These four alkaloids constituted 78 and 75% of the total alkaloid concentration in serum for LBC vs. ABC groups, respectively. Initial analysis indicated that short-term supplementation had no effect on alkaloid disposition, and supplementation was removed from the statistical model. The highest concentration of total alkaloids was observed 2 h after dosing. Overall, serum total alkaloid and anagyrine levels (area under the curve) were higher (P < 0.01) for sheep in the LBC group. Serum peak concentrations of total alkaloid and anagyrine were higher in LBC vs. ABC groups (P < 0.05). Serum elimination of anagyrine, unknown alkaloid E, and lupanine was decreased in LBC vs. ABC treatments (P < 0.05). These results demonstrate that body condition is important in the disposition of lupine alkaloids; however, further research is needed to determine the potential benefit, if any, that short-term nutritional supplementation might have on alkaloid disposition.

A Stereoselective Entry to Tetrasubstituted Quinolizidines and the Puzzling Structural Assignment of the Lupin Alkaloid Plumerinine

A thermodynamically controlled stereoselective synthesis of quinolizidinone (+/-)-13 via α-amidoalkylation of an intermediate N-acyliminium ion derived from α-ethoxy piperidine 9, followed by intramolecular Michael addition is described. Based on their NMR data, quinolizidine alcohols 14 and 15 were ruled out as possible structures of the lupin alkaloid plumerinine.

A short synthesis of (+/-)-cytisine.

The synthesis of racemic cytisine has been completed using (i)N-selective alkylation of 6-bromopyridone with bromide and (ii) Pd(0) mediated intramolecular alpha-arylation of lactam as key steps to achieve rapid assembly of the tricyclic core skeleton of the lupin alkaloids.

On the structure and spectroscopic properties of sparteine and its diastereoisomers

Abstract The equilibrium structures of the lupine alkaloid sparteine, its diastereoisomers (α-sparteine and β-sparteine), and two related tricyclic diamines were investigated with the density functional theory ansatz B3LYP and HF-MP2 method. With the exception of β-sparteine, these free molecules are structurally simple, since one conformer predominates both in the gas phase and in solution. The mono-protonated forms of all these molecules are characterized by intramolecular asymmetric hydrogen bonds. The di-protonated species have the same structural preferences as the parent free bases. All the theoretical structural predictions are consistent with the available experimental results. The NMR chemical shifts, calculated by the continuous set of gauge transformations formalism with the DFT/B3LYP method, are fairly consistent with NMR observation. The He(I) photoelectron spectra were measured and assigned by means of ab initio outer valence Green’s function calculations. The overwhelming predominance of the lowest-energy conformer of all compounds is confirmed by various spectroscopic results. However, the structure of β-sparteine is very special. The 13 C NMR spectra in solution at room temperature are indicative of an effective C 2 molecular symmetry. From the analysis of the NMR spectra from +20 to −85 °C it is inferred that the most stable C 1 conformer of β-sparteine is almost exclusively present in solution. At room temperature, it rapidly interconverts between two enantiomeric forms to produce the NMR spectrum of a time-averaged C 2 conformer.

Indolizidine and Quinolizidine Alkaloids: Structure and Bioactivity

Abstract A review of the structural identification and bioactivity of simple indolizidine and quinolizidine alkaloids isolated from amphibians, ants,fungi, plants and marine sources, covering the period from 1994 to 1999,is herein presented. Some of the new alkaloids do not have complete structural assignments due to the minute amounts that were isolated and the proposed structures rely on GC-MS and GC-FTIR analyses. Some previously known structures were corrected and others now have complete spectral assignments. The configurational and conformational analysis of new alkaloids is discussed and the alkaloids whose structures were established by X-ray analysis are also presented. Indolizidine and quinolizidine alkaloids from amphibians and ants have been described as noxious compounds and are believed to play an important role in the self defence system of these animals. Their biological activity is likely to arise from interference with ion channels in nerve and muscles cells. Polyhydroxylated indolizidines form an important group of bioactive alkaloids. Different structures are referred as potent inhibitors of glycosidases, as immunosuppressants, as anticancer agents and others are described as anti-HIV agents. Lupine alkaloids (quinolizidine alkaloids from Lupinus species) are associated with plant ecological equilibrium because they are important protectors of plants against herbivores, microorganisms and competing species. They are responsible for the toxic and teratogenic effects observed in livestock and theiraction can be associated with their affinity for nicotinic and muscarinic receptors. Important bioactivity of specific alkaloids is outlined.

Indolizidine and quinolizidine alkaloids.

This review covers the isolation, structure determination, synthesis, chemical transformations and biological activity of indolizidine and quinolizidine alkaloids from microbial, plant and animal sources. Included in the review are slaframine; the hydroxylated indolizidines lentiginosine, swainsonine, castanospermine and their analogues; alkaloids from amphibians and marine sources; plumerinine; ipalbidine, phenanthroindolizidines and related alkaloids; lasubine-II: and lupin alkaloids. The literature from July 2001 to June 2002 is reviewed, and 142 references are cited.

Indolizidine and quinolizidine alkaloids.

This review covers the isolation, structure determination, synthesis and biological activity of indolizidine and quinolizidine alkaloids from microbial, plant and animal sources. Included in the review are slaframine; hydroxylated indolizidines and their analogues; alkaloids from ants and amphibians; metabolites of the genera Prosopis, Streptomyces and Nuphar and the Lythraceae; phenanthroindolizidines and related alkaloids; lupin alkaloids; and alkaloids from sponges. tunicates and coccinellid beetles. The literature from July 2000 to June 2001 is reviewed, and 172 references are cited.