Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications
Abstract
:1. Introduction
2. Chemical Structure and General Characteristics of PAs
3. Plants as a Source of PAs
4. Environmental and Food Safety
5. Functions of Microbial PAs in the Environment and Their Significance for Humans
Type of Microorganism | Name of Species/Origin | PA | Refs. |
---|---|---|---|
Endophytic fungi | Epichloe sp. (Ascomycota: Clavicipitaceae), endophytes of grasses | lolines (saturated 1 -aminopyrrolizidines) | [8,44] |
Penicillium sp. GD6, endophyte of Bruguiera gymnorhiza | penibruguieramine A | [43] | |
Fungi | Pochonia suchlasporia var. suchlasporia TAMA 87 from soil | pochonicine | [55] |
Aspergillus sclerotiicarbonarius (IBT 28362) | sclerolizine (oxidized pyrrolizidine) | [66] | |
Bacteria | Actinosporangium sp. C36,145 (ATCC 31127) | bohemamine | [56] |
Streptomyces UMA-044 from sediment collected in a catfish pond, Stoneville, Mississippi, USA | bohemamine 3 NP25302 | [57] | |
Streptomyces sp. CNQ-583 from marine sediment | bohemamines 4, B, C 5-chlorobohemamine NP25302 | [58] | |
Streptomyces spinoverrucosus from marine sediment | bohemamine A, B | [59] | |
Streptomyces spinoverrucosus SNB-032 | bohemamines N; 1; 5-Cl; 5-Br dibohemamines A–C | [60] | |
Streptomyces sp. CPCC 200497 | dibohamamine A, D–F | [61] | |
Streptomyces sp. CB02009 | bohemamines 1–4 | [26] | |
Streptomyces MF990-BF4 | clazamycins A, B | [64] | |
Streptomyces puniceus subsp. doliceus NRRL 11160 | clazamycin B | [67] | |
Streptomyces sp. MA37 from Ghanaian soil | legonmycins A, B | [7] | |
Streptomyces sp. HK10297 | jenamidines A–C | [68] | |
Streptomyces spinoverrucosus | spithioneines A, B | [59] | |
Pseudomonas fluorescens HK 10770 from forest soil in Germany | pyreudiones A–D | [69] |
6. Various Susceptibility to PAs
7. Hepatotoxicity
8. Pyrrolizidine Alkaloids and Their Positive Activities
8.1. Anticancer Properties
Compound | Plant Source | Cell Line | Dose | Effect | Ref. |
---|---|---|---|---|---|
In Vitro | |||||
Indicine-N-oxide | Heliotropium indicum | B16 (mouse melanoma), walker 256 (carcinosarcoma in rats), P388, and L1210 (murine leukemia) | 46–100 μM | Inhibition of cell proliferation | [111] |
7-angeloyl heliotrine | Heliotropium subulatum | Chinese hamster V79 cells | 100, 50, 30, 20, 10, 5, 3 and 1 µg/mL for 5 days | Cytotoxic effect at IC50 concentrations of 10 and 5 mg/mL | [115] |
Ligulachyroine A | Ligularia achyrotricha | human leukemia cell (HL-60) and human hepatoma cell (SMMC-7721) | The cells were treated with various concentrations for 48 h | A moderate cytotoxic effect at IC50 values of 12.17 µg/mL and 11.88 µg/mL, respectively | [116] |
In Vivo | |||||
Pyrroline bis(carbamate) | synthetic analogue of indicine-N-oxide | P388 lymphocytic leukemia | 100, 50, 25, and 12.5 mg/kg by injection of a solution in distilled water. 5× daily doses were administered beginning 24 h after tumor inoculation | Antileukemic effect of 225% T/C at 100 mg/kg (the most active among 5 other analogues of indicine-N-oxide) | [110] |
7-angeloyl heliotrine | Heliotropium subulatum | ICR albino mice implanted with Sarcoma 180 (1 × 10−6 cells/0.1 mL ascitic fluid) | Test group: 50–100 mg/kg/day of test crude extracts + 5–10 mg/kg/day of test compounds; control group: saline only | Maximum inhibition of 41.7% at 5 mg/kg/day (the highest inhibition among five other PAs) | [115] |
8.2. Antimicrobial Properties
8.3. Potential Applications of PAs and Future Perspectives
9. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Characteristics | Retronecine | Heliotridine | Otonecine | Platynecine |
---|---|---|---|---|
Ring | bicyclic | bicyclic | monocyclic | bicyclic |
Unsaturated 1,2-double bond | + | + | + | − |
Toxicity | + | + | + | − |
Combination of Necine Base and Necic Acid Forming Type of PA | Examples of PA | Examples of PA Structures |
---|---|---|
senecionine | senecionine, platyphylline, rosmarinine, nemorensine | |
triangularine | triangularine, sarracine, macrophylline | |
lycopsamine | lycopsamine, uplandicine | |
monocrotaline | monocrotaline, aucherine | |
phalaenopsine and ipanguline | nervosine VII, nervosine I, ipanguline B | |
triangularine and lycopsamine | echimidine, heliosupine, scorpioidine | |
simple | acetyllaburnine, 7-acetylretronecine | |
unusual | madurensine, labunamine, tussilagine |
Basic PAs | Additional PAs |
---|---|
intermedine/lycopsamine | indicine |
senecionine/senecivernine | echinatine |
seneciphylline | rinderine |
retrorsine | integerrimine |
echimidine | heliosupine |
lasiocarpine | spartioidine |
europine | usaramine |
heliotrine | with their N-oxide forms |
with their N-oxide forms | |
senkirkine |
Products | Max Level of PA [µg/kg] | Exceptions | Max Level of PA [µg/kg] |
---|---|---|---|
Tea, flavored tea, and herbal infusions (liquid product) for infants and young children | 1 | − | − |
Tea and flavored tea (dried product) | 150 | 75 | |
Herbal infusions (dried product) and ingredients used for herbal infusions (dried products) | 200 | ||
but of rooibos, anise, lemon balm, chamomile, thyme, peppermint, lemon verbena and mixtures exclusively composed of them | 400 | ||
Cumin | 400 | − | − |
Food supplements containing botanical preparation including extracts | 400 | Pollen-based food supplements Pollen and pollen products | 500 |
Dried herbs | 400 | Borage, lovage, marjoram, and oregano (dried product) and mixtures exclusively composed of them | 1000 |
PA | Microorganism Source | Cell Line | Assay Type | Effect | Ref. |
---|---|---|---|---|---|
derivatives of bohemamines: a quinoxalinone-bohemamine hybrid compound quinohemanine (1), 1-methyl-2(H)-quinoxalin-2-one (2) | Streptomyces sp. CPCC 200497, soil isolate from China | liver cancer cell line HepG2 | as in sulforhodamine B (SRB) method | moderate cytotoxicity against HepG2 with IC50 65.9 and 52.5 μM for (1) and (2), respectively) | [62] |
dibohemamine F | Streptomyces sp. CPCC 200497 | cancer cell lines of lungs A549 and liver HepG2 | as in SRB assay | cytotoxicity against cancer cell lines A549 and HepG2 with IC50 of 1.1 and 0.3 μM, respectively | [61] |
dibohemamines D and E | Streptomyces sp. CPCC 200497 | cancer cell lines A549 and HepG2 of lungs and liver, respectively | as in SRB assay | moderate cytotoxicity against both cancer cells; for dibohemamines D and E IC50 from 7.3 for HepG2 to 39.2 for A549, respectively | [61] |
dibohemamines B and C | Streptomyces spinoverrucosus marine-derived | non-small cell lung cancer cell line A549 | not mentioned | dibohemamines B and C extremely potent against A549 with IC50 values of 0.140 and 0.145 µm, respectively | [60] |
dibohemamine C | Streptomyces spinoverrucosus marine-derived | non-small cell lung cancer cell line HCC1171 | not mentioned | IC50 value of 1.2 µm | [60] |
Microorganism | PA | PA Dose | Observations | Antimicrobial Activity | Ref. |
---|---|---|---|---|---|
Bacteria | |||||
Bacillus anthracis | heliotric acid | 2 mg/mL | Zone of inhibition 14.61 ± 0.443 | High | [115] |
Bacillus subtilis | PA-1 | - | MIC: 0.0156 mg/mL | Moderate | [119] |
Enterobacter cloacae | lasiocarpine | 2 mg/mL | Zone of inhibition: 10.00 ± 0.41 mm | High | [120] |
Enterobacter cloacae | lasiocarpine-N-oxide | 2 mg/mL | Zone of inhibition: 9.00 ± 0.70 mm | High | [120] |
Escherichia coli | lasiocarpine | 2 mg/mL | Zone of inhibition: 12.00 ± 0.34 mm | High | [120] |
Escherichia coli | lasiocarpine-N-oxide | 2 mg/mL | Zone of inhibition: 9.00 ± 0.89 mm | High | [120] |
Escherichia coli | clazamycin | - | MIC: 0.1 mg/mL | Low | [121] |
Proteus vulgaris | PA-1 | - | MIC: 0.0313 mg/mL | Moderate | [119] |
Pseudomonas aeruginosa | PA-1 | - | MIC: 0.0313 mg/mL | Moderate | [119] |
Pseudomonas aeruginosa | clazamycin | - | MIC: 0.024–0.036 mg/mL | Low | [65] |
Staphylococcus aureus | PA-1 | - | MIC: 0.0039 mg/mL, 2*MIC within 8 h | Very High | [119] |
Staphylococcus epidermidis | usaramine | 1 mg/mL | Biofilm inhibition by 50% | Moderate | [122] |
Staphylococcus epidermidis | PA-1 | - | MIC: 0.0078 mg/mL | High | [119] |
Streptococcus pneumoniae | heliotric acid | 2 mg/mL | Zone of inhibition 13.64 ± 0.691 mm | High | [115] |
Streptococcus pneumoniae | 7-angeloyl heliotrine | 2 mg/mL | Zone of inhibition 12.69 ± 0.317 | High | [115] |
Fungi | |||||
Aspergillus fumigatus | heliotric acid | 2 mg/mL | Zone of inhibition 10.59 ± 0.221 | High | [115] |
Aspergillus niger | PA-1 | - | MIC: 0.125 mg/mL | Very low | [119] |
Candida albicans | PA-1 | - | MIC: 0.0625 mg/mL | Low | [119] |
Drechslera tetramera | heliotridine | 2 mg/mL | Zone of inhibition: 7.00 ± 0.51 mm | Moderate | [120] |
Fusarium moniliforme | asiocarpine-N-oxide | 2 mg/mL | Zone of inhibition: 7.00 ± 0.54 mm | High | [120] |
Penicillium chrysogenum | 7-angeloyl heliotrine | 2 mg/mL | Zone of inhibition 11.61 ± 0.268 | High | [115] |
Rhizoctonia phaseoli | heliotric acid | 2 mg/mL | Zone of inhibition 11.51 ± 0.187 | High | [115] |
PA | Potential Application | Refs. |
---|---|---|
Nervosin VII | human colorectal cancer cells | [106,107] |
N-oxides of monocrotaline and heliotrine | a potential treatment for hepatomas– if significant hepatotoxicity targeted against tumor cells specifically | [112] |
Indicine-N-oxide or its analogues | used as a microtubule-targeted anticancer drug | [111] |
Retrorsine | antifungal agent against phytopathogenic fungi | [123] |
Usaramine and monocrotaline | biomaterials surface coatings–usaramine antibiofilm activity and monocrotaline activity against Trichomonas vaginalis | [122] |
PA-1 | pro-drug against Gram-positive bacteria | [119] |
Synthetic DHP | potential anticancer treatment–targets cancer cells specifically | [117] |
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Jayawickreme, K.; Świstak, D.; Ozimek, E.; Reszczyńska, E.; Rysiak, A.; Makuch-Kocka, A.; Hanaka, A. Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications. Int. J. Mol. Sci. 2023, 24, 16972. https://doi.org/10.3390/ijms242316972
Jayawickreme K, Świstak D, Ozimek E, Reszczyńska E, Rysiak A, Makuch-Kocka A, Hanaka A. Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications. International Journal of Molecular Sciences. 2023; 24(23):16972. https://doi.org/10.3390/ijms242316972
Chicago/Turabian StyleJayawickreme, Kavindi, Dawid Świstak, Ewa Ozimek, Emilia Reszczyńska, Anna Rysiak, Anna Makuch-Kocka, and Agnieszka Hanaka. 2023. "Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications" International Journal of Molecular Sciences 24, no. 23: 16972. https://doi.org/10.3390/ijms242316972