Macrocyclic Pyrrolizidine Alkaloids Research Articles

Macrocyclic Pyrrolizidine Alkaloids and Silphiperfolanol Angelate Esters from Solanecio mannii

AbstractThree new compounds, the silphiperfolanol angelate ester umutagarananol (1), the macrocyclic pyrrolizidine alkaloids umutagarinine A and B (2–3), and five known secondary metabolites (4–8) were isolated from the CH2Cl2−MeOH (1 : 1) extract of the roots and the stem bark of Solanecio mannii (Hook. f.) (Asteraceae). The isolated compounds were characterized by NMR and IR spectroscopic, and mass spectrometric analyses, whereas the relative stereochemistry of 4 was established by NAMFIS‐based combined computational and solution NMR analysis. Synthetic modification of 5 provided two new compounds, 2‐angeloyloxy‐4,8‐epoxypresilphiperfolane (9) and 2‐angeloyloxy‐4,8‐epoxypresilphi‐perfolane (10). The crude extracts and the isolated constituents showed weak antibacterial activities (EC50 0.7–13.3 mM) against the Gram‐negative Escherichia coli and the Gram‐positive Bacillus subtilis. Compounds 2, 3 and 4 exhibited strong cytotoxicity against MCF‐7 human breast cancer cells, with EC50 values of 35.6, 21.7 and 12.5 μM, respectively.

A new pyrrolizidine alkaloid and other constituents from the roots of Ligularia achyrotricha (Diels) Ling

Ligularia achyrotricha (Diels) Ling has been used as a traditional Tibetan herbal medicine. Ligulachyroine A (1), a new twelve-membered macrocyclic pyrrolizidine alkaloid with a ketonic group located at C-3 and an hydroxy group linked at C-8, was isolated from the roots of L. achyrotricha. It is particularly noteworthy that the structure of 1 rarely appears in any other naturally occurring twelve-membered macrocyclic pyrrolizidine alkaloid reported to date. Three known lignans (2–4) and eight known coniferyl and sinapyl alcohol derivatives (5–12) were also obtained in this species. Their structures were elucidated through a careful analysis of their IR, MS, and NMR spectra. Compound 1 exhibited moderate activity against HL-60 and SMMC-7721 cells.

Ceroplastes albolineatus, the first scale insect shown to sequester pyrrolizidine alkaloids from its host-plant Pittocaulon praecox

The occurrence of pyrrolizidine alkaloids (PAs) in Pittocaulon (ex Senecio) praecox (Asteraceae) a species endemic to Mexico was established. The aboveground plant organs contain the 1,2-saturated monoester 7-angeloyl-dihydroxyheliotridane together with a small proportion of its 9-angeloyl isomer as major alkaloid. The monoesters are accompanied by the macrocyclic otonecine derivative senkirkine. Roots contain only related macrocyclic PAs with senecionine, senkirkine and platyphylline as major components; monoesters are absent. The broom-like succulent stems of P. praecox are infested by the scale insect Ceroplastes albolineatus conspicuously visible by its huge wax cover. All life-history stages, i.e. females, eggs, first instar nymphs (crawlers) and the wax cover were found associated with PAs. The measured PA concentrations clearly indicate sequestration. The highest PA concentrations (mg / g dry weight) reached are: mature females, 0.44; eggs, 0.58; crawlers, 0.37; wax cover, 0.08. The host plant as well as in the infesting scale insect contain the PAs exclusively as free bases. As a phloem-feeder C. albolineatus must acquire the PAs with the ingested phloem sap. This appears plausible since in Senecio species PA are transmitted and circulated through the phloem path. It is suggested that PAs may protect particularly the crawlers as the most endangered stage in the life-cycle of the scale insect.

Are insect-synthesized retronecine esters (creatonotines) the precursors of the male courtship pheromone in the arctiid moth Estigmene acrea?

The pyrrolizidine alkaloid (PA) profiles were determined for adults of the polyphagous arctiid Estigmene acrea, which as larvae had fed on artificial diet supplemented with Crotalaria-pumila powder with known concentrations of PAs. The larvae always had a free choice between alkaloid-containing and plain diets. The alkaloid profiles of adults revealed a striking sexual dimorphism. Both sexes contained macrocyclic PAs of the monocrotaline type sequestered from the diet and, in addition, a substantial proportion of supinidine and retronecine esters synthesized by the insects from necine bases derived from the dietary alkaloids and necic acids of insect origin. These insect alkaloids accounted for 35% and 55% of total PAs in males and females, respectively. The difference was that in females the retronecine esters (creatonotines) made up 58 microg (43% of total PAs), while males contained a fivefold lower proportion, 12 microg (13%). Four of the ten male individuals analyzed were found devoid of creatonotines. Based on the experimental data in combination with evidence from the literature, it is suggested that the creatonotines are direct pheromone precursors in E. acrea. It is hypothesized that this may represent a general mechanism of hydroxydanaidal formation from diverse macrocyclic PAs in arctiids.

Metabolism of pyrrolizidine alkaloids by Peptostreptococcus heliotrinreducens and a mixed culture derived from ovine ruminal fluid

A mixed culture of ovine ruminal microbes metabolizes the macrocyclic pyrrolizidine alkaloids present in the plant Senecio jacobaea, including jacobine and seneciphylline. Previous attempts to identify metabolites of these alkaloids have not been successful. The objective of this study was to compare the metabolism of pyrrolizidine alkaloids by a mixed culture of ovine ruminal microbes to the metabolism of pyrrolizidine alkaloids by the known organism Peptostreptococcus heliotrinreducens. P. heliotrinreducens metabolizes the pyrrolizidine alkaloids heliotrine and lasiocarpine to 7α-hydroxy-1-methylene-8α-pyrrolizidine and 7α-angelyl-1-methylene-8α-pyrrolizidine, respectively. This organism does not metabolize the pyrrolizidine alkaloids jacobine or seneciphylline. A mixed culture of ovine ruminal microbes also metabolized heliotrine and lasiocarpine to identical methylene compounds. This mixed culture also metabolized jacobine and seneciphylline, with the production of very low levels of the corresponding 1-methylene compounds. Samples were analyzed by TLC and GC/MS.

Storage and metabolism of radioactively labeled pyrrolizidine alkaloids by butterflies and larvae of Mechanitis polymnia (Lepidoptera: Nymphalidae, Ithomiinae)

Tracer feeding studies with radioactively labeled pyrrolizidine alkaloids (PAs) were performed to attain experimental information about the specificity and mechanisms of uptake, metabolism and storage of PAs in the alkaloid sequestering ithomiine butterfly Mechanitis polymnia. Adult butterflies easily ingest the tracers offered dissolved in a saturated sugar solution. Feeding of [14C]rinderine (free base) confirmed that M. polymnia is well adapted to sequester and maintain PAs of the lycopsamine type. Approximately 80% of the ingested radioactivity can be recovered in methanol extracts of the butterflies over a period of at least 6 hours. Labeled rinderine is efficiently N-oxidized and transformed into a metabolite of still unknown structure. These two metabolites are formed in almost equal amounts and account for more than 90% of total radioactivity. After four hours the toxic free base is only detectable in traces. Radioactively labeled senecioylretronecine (free base), a PA that often accompanies PAs of the lycopsamine type in plants, is metabolized in a different manner. The toxic free base disappeared as fast as the tertiary rinderine, but the final products which accumulated in a stable ratio after 12 hours were mainly two polar metabolites of unknown structure; senecioylretronecine N-oxide accounts for less than 10% of total PAs. Labeled senecionine a macrocyclic PA, which never has been found in wild caught M. polymnia is only slowly N-oxidized. In females ca 50% of the ingested senecionine is still present as free base after 24 hours, whereas under the same conditions in males this percentage is only ca 20%. This difference in N-oxidation was the only significant sex-specific difference observed in various experiments. Larvae of M. polymnia which feed on Solanum tabacifolium, a plant that does not contain PAs, are able to sequester and partly N-oxidize labeled senecioylretronecine and senecionine. However, the storage is not very efficient; with the two tracers less than 5% of radioactivity remained in the bodies after 24 hours.

Pyrrolizidine Alkaloids from Senecio roseus and Senecio helodes

Two new 13-membered macrocyclic pyrrolizidine alkaloids, (13R)-13-hydroxyretroisosenine (2b) and (12S)-12-hydroxyretroisosenine (2c), have been isolated from Senecio roseus and Senecio helodes. Their structures were established from spectral and chemical studies including 2D NMR. The hydrochloride of retroisosenine (2a·HCl) was also isolated, and its absolute configuration was determined by X-ray diffraction analysis.

Pyrrolizidine Alkaloids Mediate Host–Plant Recognition by Ovipositing Females of an Old World Danaid Butterfly, Idea leuconoe

A giant danaid butterfly, Idea leuconoe, specializes on apocynaceous plants such as Parsonsia laevigata, which has been reported to contain pyrrolizidine alkaloids. Females of I. leuconoe deposited eggs in response to methanolic extract of P. laevigata, and subsequent bioassay-guided fractionation of the extract revealed that phytochemicals crucial for host recognition by ovipositing females are Parsonsia-specific macrocyclic pyrrolizidine alkaloids including parsonsianine, parsonsianidine, and 17-methylparsonsianidine. Parsonine, another P. laevigata pyrrolizidine component with a keto-dihydropyrrolizine moiety that is closely related in structure to male pheromones of the butterfly, and several nonhost pyrrolizidine alkaloids were entirely inactive. We interpret these data as strong evidence for an ancestral association through herbivory between danaid butterflies and pyrrolizidine alkaloids.

Pyrrolizidine alkaloid composition in six brazilian Senecio species

Four macrocyclic pyrrolizidine alkaloids (PA) could be identified and quantified in extracts of the Brazilian Senecio oxiphyllus by means of proton- and inverse-gated decoupling 13C NMR spectroscopy. Seasonal and local differences were found in PA composition. Reinvestigation of five other Senecio species by the same method led to the identification of various retronecine- and otonecine-based PA, exceeding prior results in both qualitative and quantitative respects. In the extract of S. selloi, a new alkaloid was found, which was identified as 18-hydroxyjaconine (20-chloro-15,20-dihydro-12,15,18-trihydroxysenecionan-11,16-dione) according to NMR and GC-mass spectrometry data.

Retrorsine: Correct Assignment of Quaternary Carbons

Via COLOC NMR spectroscopy it was possible to assign the13C chemical shifts of C-1 and C-15 of retrorsine. The results are in agreement with those for other retronecine-type macrocyclic pyrrolizidine alkaloids.

Analysis of pyrrolizidine alkaloids: a competitive enzyme-linked immunoassay (ELISA) for the quantitative determination of some toxic pyrrolizidine alkaloids.

A highly sensitive and specific competitive enzyme-linked immunoassay (ELISA) for the determination of retrorsine, senecionine, and integerrimine in the nanogram range has been developed. Pyrrolizidine alkaloids were detected in Senecio rupestris. No cross-reactivity was seen with either retrosine N-oxide, otonecine alkaloids, or other macrocyclic pyrrolizidine alkaloids.

Enantioselective Synthesis of the Macrocyclic Pyrrolizidine Alkaloid Yamataimine

Abstract Described is a short-step synthesis of optically active yamataimine, a 12-membered pyrrolizidine alkaloid of retronecine type. Methyl (1S,5R)-5-methyl-2-oxocyclopentanecarboxylate derived from (R)-(+)-pulegone was converted into the necic acid component required for the synthesis of yamataimine, in a nine-step sequence. Regioselective coupling of (+)-retronecine with the necic acid component via tin-mediated regioselective acylation followed by macrolactonization led to the first synthesis of (+)-yamataimine.

A Synthesis of Senecionine, a Representative of Hepatotoxic, Macrocyclic Pyrrolizidine Alkaloids of Retronecine Type

Abstract Described is a synthesis of (−)-senecionine, the best-known hepatotoxic, 12-membered pyrrolizidine alkaloid of retronecine type. Integerrinecic acid lactone methyl ester was converted into protected senecic acid, which was regioselectively coupled with (+)-retronecine, achieving the first synthesis of (−)-senecionine.

Mechanisms and pathology of monocrotaline pulmonary toxicity.

Monocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatotoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolite of MCT is the dehydrogenation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.

Cynoglossum officinale toxicity in calves

Six calves were given dried, ground Cynoglossum officinale daily in a dose which provided 15 (two calves) or 60 (four calves) mg per kg per day of total pyrrolizidine alkaloids. Those calves given 60 mg per kg of total pyrrolizidine alkaloids per day died following a single dose of plant material. These calves had a marked elevation of serum gamma-glutamyltransferase (GGT) and aspartate transaminase (AST) activities and serum bile acid and total bilirubin (TBili) concentrations. These four calves all had massive hepatocellular necrosis and haemorrhage of the liver. Of the two calves that were given 15 mg per kg of total pyrrolizidine alkaloids per day, one died on day 34 and the other survived until day 35 when it was painlessly killed. There were significant elevations in serum AST and GGT activities in these calves. The histological lesions of the calf surviving until 35 days were compatible with pyrrolizidine alkaloid toxicity, that is megalocytosis, karyomegaly and necrosis of hepatocytes with karyomegaly of biliary epithelium. The pyrrolizidine base present in Cynoglossum officinale (heliotridine) and its esters have a similar type of toxicity to the highly toxic and more familiar macrocyclic diester pyrrolizidine alkaloids of the pyrrolizidine base (retronecine), present in Senecio or Crotolaria species.

Macrocyclic pyrrolizidine alkaloids from Parsonsia laevigata

Parsonsianidine, a new minor macrocyclic pyrrolizidine alkaloid having two ethyl side-chains at C-11 and C-20, was isolated along with parsonsianine from the leaves of Parsonsia laevigata. Its structure was determined by spectral analyses. 17-Methylparsonsianidine, having the same plane structure as spiranine, was also identified.

Excretion and blood radioactivity levels following [ 14C]senecionine administration in the rat

Macrocyclic pyrrolizidine alkaloids (PAs) are a mixed group of phytotoxins with similar chemical structures and varying biological effects. A commonly studied member of this group is senecionine (SEN) which causes hepatotoxicity. We have undertaken metabolism and excretion studies of SEN in rats to provide data for comparison between PAs and to evaluate the potential role of metabolism and excretion in toxicity. Following intravenous administration of [ 14C]SEN (60 mg/kg, 10 μCi/kg), bile, urine and blood were collected over a 7-h period. Of the total administered radioactivity, 44% and 43% were excreted in the bile and urine, respectively. Using mass spectroscopy, senecionine N-oxide (SENNOX) was identified as the major metabolite in the bile (52% of 44%) and urine (30% of 43%). For the total 7 h, less than 5% in bile and 18% in urine was excreted as parent alkaloid. The plasma concentration of Senecionine-equivalents/g (SEN-EQ/g) decreased from 107 to 12 nmol, while red blood cell (RBC) concentrations declined from 109 to 26 nmol/g. Without bile collection, the plasma levels of SEN-EQ were similar, while the final RBC level was almost double (47 vs. 26 nmol/ g) and total radioactivity excreted in the urine was increased (59% vs. 43%). Biliary pyrrolic metabolites were estimated to be 1.43 mg, using a dehydroretronecine standard.

Alkaloids as taxonomic characters in the tribe Crotalarieae (Fabaceae)

Recent studies of alkaloids have led to a better understanding of the intricate taxonomic relationships in the tribe Crotalarieae. Data from alkaloidal metabolites are largely congruent with morphological data, but allow refinement of the understanding of the phylogeny. A well-supported and almost fully resolved cladogram is presented, which shows that the genera can be grouped into four main clades: (1) an unspecialized group without α-pyridone alkaloids and without esters of alkaloids ( Aspalathus, Lebeckia, Rafnia, Wiborgia and perhaps Spartidiurn); (2) a group specializing in lupanine-type esters ( Pearsonia and Rothia); (3) a group with macrocyclic pyrrolizidine alkaloids ( Crotalaria and Lotononis); and (4) a specialized group with α-pyridone alkaloids ( Argyrolobium, Dichilus, Melolobium and Polhillia).

Parsonsianine, a macrocyclic pyrrolizidine alkaloid from the leaves of Parsonsia laevigata(Studies on Parsonsia. III).

Parsonsianine, a 14-membered macrocyclic pyrrolizidine alkaloid, composed of retronecine, (2S, 3R)-2, 3-dihydroxy-2-ethylbutanoic acid and (2R, 3S)-2, 3-dihydroxy-2-isopropylbutanedioic acid, was isolated from the leaves of Parsonsia laevigata and the structure was determined by means of nuclear magnetic resonance and X-ray analysis.

ChemInform Abstract: Total Synthesis of Polyfunctionalized, Biologically Active Natural Products. Synthesis of Macrocyclic Pyrrolizidine Alkaloids

ChemInformVolume 20, Issue 1 Reviews ChemInform Abstract: Total Synthesis of Polyfunctionalized, Biologically Active Natural Products. Synthesis of Macrocyclic Pyrrolizidine Alkaloids H. NIWA, H. NIWA Dep. Chem., Fac. Sci., Nagoya Univ., Chikusa, Nagoya 464, JapanSearch for more papers by this author H. NIWA, H. NIWA Dep. Chem., Fac. Sci., Nagoya Univ., Chikusa, Nagoya 464, JapanSearch for more papers by this author First published: January 3, 1989 https://doi.org/10.1002/chin.198901332Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume20, Issue1January 3, 1989 RelatedInformation