2.3 Sesquiterpenes PDF

2. Isoprenoids - Terpenes and Terpenoids 2.3 Sesquiterpenes 1. Basic Concepts 2. Isoprenoids 3. Phenolics 4. Essential Oils 5. Alkaloids 6. Polysacharides D-CHAB Institute of Pharmaceutical Sciences Lecture in Pharmaceutical Biology HS 2024 Isoprenoid cla...

2. Isoprenoids - Terpenes and Terpenoids 2.3 Sesquiterpenes 1. Basic Concepts 2. Isoprenoids 3. Phenolics 4. Essential Oils 5. Alkaloids 6. Polysacharides D-CHAB Institute of Pharmaceutical Sciences Lecture in Pharmaceutical Biology HS 2024 Isoprenoid classification The classification of isoprenoids is based on the number of carbon Polyprene atoms that make them up, starting from a C10 unit as the basic component: Hemiprene- C5 substituted O- O- O- O- plant materials O O O O H-T P P - P P - O O O O O O OPP C10 OPP IPP Geranyldiphosphate (GPP) Mono- terpenes H-T 2x Triterpene T-T C15 OPP OPP OPP Sesqui- Steroid IPP Farnesyldiphosphate (FPP) H-T terpenes GPP 2x T-T C20 Carotenoid OPP OPP OPP Diterpenes FPP IPP Geranylgeranyldiphosphate (GGPP) HO Installation in Tocopherols hydroquinones O ⍺-Tocopherol Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 2 Isoprenoid classification The classification of isoprenoids is based on the number of carbon Polyprene atoms that make them up, starting from a C10 unit as the basic component: Hemiprene- C5 substituted O- O- O- O- plant materials O O O O H-T P P - P P - O O O O O O OPP C10 OPP IPP Geranyldiphosphate (GPP) Mono- terpenes H-T 2x Triterpene T-T C15 OPP OPP OPP Steroid IPP Farnesyldiphosphate (FPP) Sesquiterpenes GPP Sesquiterpenes - “Sesqui” in Latin means one and a half. So one basic C10 unit + C5 unit. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 3 General characteristics of Sesquiterpenes Sesquiterpenes have a carbon skeleton consisting of 15 carbon atoms, which can be broken down into 3 isoprene units (regularly built sesquiterpenes). o In many cases, the structures of sesquiterpenes no longer have a regular structure due to the migration of methyl groups or secondary ring cleavage (irregularly built sesquiterpenes). Sesquiterpenes form the largest group of terpenes: o >12,000 representatives o Over 100 different ring skeletons Practically ubiquitous distribution in the Asteraceae family o Also found in liverworts, basidiomycetes, algae and marine organisms Within the group of sesquiterpenes, it is mainly the sesquiterpene lactones that are of pharmaceutical interest: o Approx. 5000 naturally occurring representatives Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 4 The biosynthesis of sesquiterpenes Farnesyldiphosphate acts as a key intermediate in the biosynthesis of sesquiterpenes, either directly (as the 2E, 6E- or 2Z, 6E-isomer) or after rearrangement to the isomeric nerolidyldiphosphate. Nerolidyldiphosphate 2E, 6E-Farnesyldiphosphate Conversion into cyclic terpenes via cationic intermediate stages conversion (→ sesquiterpenes of the Bisabolane, Caryophyllane, Germacrane, Eudesmane, Cadinane, Guaiane, Pseudoguaiane- type) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 5 Conversion of nerolidyl diphosphate into sesquiterpenes of the germacran and eudesmane type Eudesmane-Type Germacrane-Type Conversion into cyclic terpenes via cationic intermediate stages conversion (→ sesquiterpenes of the bisabolane, caryophyllane, germacrane, eudesmane, cadinane, guaiane, pseudoguaiane type) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 6 The conversion of nerolidyl diphosphate to sesquiterpenes of the guaiane type Nerolidyldiphosphate Germacrene A Guaiane-Type Conversion into cyclic terpenes via cationic intermediate stages conversion (→ sesquiterpenes of the bisabolane, caryophyllane, germacrane, eudesmane, cadinane, guaiane, pseudoguaiane type) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 7 Oxidized variants of sesquiterpenes: Sesquiterpene lactones Migration of the C4-methyl group Germacrane-Type Eudesmane-Type Guaiane-Type Pseudoguaiane-Type Germacranolide Eudesmanolide Guaianolide Pseudoguaianolide Biologically active compounds (bitter or pungent taste, local skin irritation, allergic potential, relatively high toxicity after systemic administration) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 8 Structure and biological properties of sesquiterpene lactones The characteristic structural feature of all sesquiterpene lactones is a 𝛾-lactone ring: An important subgroup of sesquiterpene lactones carries a reactive methylene group at the ⍺- position of the lactone ring carbonyl group (possibility of 1,4-addition): o In addition, further reactive structural elements may be present (additional ⍺,β-unsaturated carbonyl groups, epoxides). o Sesquiterpene lactones with an ⍺-methylene-𝛾-lactone structure are widespread among the Asteraceae (over 200 species described in the literature). Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 9 Structure and biological properties of sesquiterpene lactones Many sesquiterpene lactones have cytotoxic, antitumor, antibacterial, parasiticidal, anthelminthic, antiphlogistic, antihyperlipidemic and cardiotonic properties. o The cytotoxic, antitumor and antibacterial effects of sesquiterpene lactones are generally attributed to the presence of ⍺-methylene-𝛾-lactone group and the associated alkylating properties: o Inactivation of target proteins, e.g. by alkylation of exposed SH groups Sesquiterpene lactones are the main group of plant substances that are referred to as phytoeczematogens: o Chemically defined low-molecular substances (100–1000 Da) that trigger an allergic contact dermatitis (type IV allergy = cell-mediated or delayed-type allergy; the allergic reaction occurs only after a long delay). o eczema reaction primarily at the point of contact with the allergen (plant material, topical application of medication) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 10 Raw materials / extracts with sesquiterpenes and therapeutically used pure substances. Raw materials (Arzneidroge) Sesquiterpene type − Alant Eudesmanolide − Arnikablüten (Arnica flowers) Pseudoguajanolide (Helenalide) − Beifusskraut Eudesmanolide, 4,5-Secopseudoguajanolide − Kamillenblüten (→ Kap. Ätherische Öle) Guaianolide − Benediktenkraut Germacranolide − Lorbeerfrüchte Guaian olide − Löwenzahn (Dandylion) Eudesmanolide, Germacranolide − Mutterkraut Germacranolide, Eudesmanolide, Guajanolide − Rainfarnkraut Eudesmanolide, Germacranolide − Römische Kamille (→ Kap. Ätherische Öle) Germacranolide (Helianolide), Guaianolide. (German and Roman Chamomile) − Schafgarbenkraut (Yarrow) Germacranolide, Eudesmanolide, Guaianolide, Longipinenderivate − Wermutkraut Germacranolide, Eudesmanolide, Guaianolide (Wormwood − Pure substances (Reinstoff) / Extracts Anwendung − Artemisinin Malariamittel − Petasites Extract Krämpfe im GI-, Urogenitaltrakt u.a. Colt’s foot Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 11 Sesquiterpene-containing raw materials (Arzneidrogen) Anicae flos, Arnikablüten (Arnica flowers) Parent plant: Arnica montana L. (Arnika) Family: Asteracae Plant raw material (Droge): Dried flower buds (inflorescence) of Arnica montana L. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 12 Sesquiterpene-containing raw materials (Arzneidrogen) Anicae flos, Arnikablüten (Arnica flowers) Components: Sesquiterpene lactones of the pseudoguaianolide type [A. montana 0.3 - 1.0%; PhEur = at least 0.4%. A. chamissonis ssp. foliosa 0.07 - 1.4%], especially esters of helenalin and dihydrohelenalin, also arnifoline, chamissonolide (only A.chamissonis !) Essential oil (0.2 - > 0.3%), 50% fatty acids and alkanes Flavonoids (0.4 - 0.6%), including isoquercitrin, astragalin, luteolin-7-glucoside Phenolic carboxylic acids Coumarins Flower pigments of the carotenoid type (xanthophylls) Traces of non-toxic pyrrolizidine alkaloids Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 13 Sesquiterpene-containing raw materials (Arzneidrogen) Anicae flos, Arnikablüten (Arnica flowers) Effects and mechanism of action: Arnica preparations have an antiphlogistic, analgesic, and antiseptic effect when applied topically The main active ingredients are probably the sesquiterpene lactones, with anti-inflammatory effects o Helenalin generally shows greater efficacy than dihydrohelenalin. o Helenalin and other sesquiterpene lactones of the 10 ⍺-methyl- pseudoguaianolide type cause inhibition of the transcription factors NF-κB and NF-AT in the micromolar concentration range in vitro. o Simultaneous inhibition of the expression of different types of inflammatory mediators (cytokines such as IL-1β, TNF-⍺, adhesion molecules) or of enzymes of eicosanoid metabolism. Widen, JC, ACS Chem. Biol. (2016). The inhibitory effect of sesq. lactones on NF-κB is based on the covalent modification of SH groups by the ⍺-methylene-𝛾-lactone. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 14 Sesquiterpene-containing raw materials (Arzneidrogen) Anicae flos, Arnikablüten (Arnica flowers) Applications: Arnica preparations are a component of a large number of phytopharmaceuticals. As an infusion, tincture and component of ointments for external use in the aftermath of injuries and accidents (e.g. haematomas, bruises etc.), for rheumatic muscle and joint complaints, inflammation of the mucous membranes of the mouth and throat, for insect bites. Do not administer orally due to possible side effects Side effects: Arnica is one of the most important contact allergy-inducing species within the Asteraceae family. High sensitization potential. Cross-allergies with other Asteraceae Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 15 Sesquiterpene-containing raw materials (Arzneidrogen) Taraxaci herba cum radice, Löwenzahn (Dandylion) Parent plant: Taraxacum officinale L. (Löwenzahn) Family: Asteracae Plant raw material: (Droge): herba cum radice, The above- and below-ground dried plant parts harvested before flowering. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 16 Sesquiterpene-containing raw materials (Arzneidrogen) Taraxaci herba cum radice, Löwenzahn (Dandylion) Components: Sesquiterpene lactones, especially sesquiterpene carboxylic acids with ester bond to β-D-glucose (taraxic acid, dihydrotaraxic acid glucoside, aisnlioside); glucosides of taraxacolide and tetrahydrooridentin B. Taraxic acid glucoside Taraxcolide glucoside (Germacrane-Type) (Eudesmane-Type) Triterpenes Phenolic compounds (dihydroconiferin, syringin, dihydrosyringin, taraxacoside, phenolic carboxylic acids, flavonoids, coumarins) Carbohydrates (inulin: up to 40% in spring, approx. 2% in fall; fructose) Minerals with a high content of potassium salts Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 17 Sesquiterpene-containing raw materials (Arzneidrogen) Taraxaci herba cum radice, Löwenzahn (Dandylion) Applications: As a cut drug for the production of infusions Dandelion plant juice from fresh plants On the basis of extracts, production of finished drugs (Fertigarzneimitteln) (combination preparations, Kombinationspräparate) of the indication group Cholagoga and Urologica o Use in dyspeptic disorders and mild biliary tract disorders, loss of appetite o The diuretic effect is probably due to the high content of potassium ions. o No clinical data available Taraxic acid glucoside is a potent contact allergen; skin eczema only occurs after very intensive contact with dandelion sap, not with finished medicinal products (Fertigarzneimitteln) o High instability of the allergen Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 18 Sesquiterpene-containing raw materials (Arzneidrogen) Millefolii herba, Schafgarbenkraut (Yarrow) Parent plant: Achillea millefolium L. (Schafgarbe) – Polymorphe Sammelart Family: Asteracae Plant raw material: (Droge): herba, The dried flowering tops of Achillea millefolium L. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 19 Sesquiterpene-containing raw materials (Arzneidrogen) Millefolii herba, Schafgarbenkraut (Yarrow) Components: Essential oil (0.1 - > 1%; PhEur = at least 2 ml/kg) Sesquiterpene lactones (PhEur = at least 0.02% proazulene), especially guaianolides (e.g. achillicin, achillin, leucodin, 3-oxa-achillicin); germacranolides, eudesmanolides, longipinene derivatives Polyacetylenes flavonoids, especially 7-O-glycosides and 7-O-malonyl glycosides of apigenin and luteolin, C-glycosyl flavones, lipophilic flavonoid aglycones phenolic carboxylic acids Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 20 Sesquiterpenes as proazulene: Example Matricin Vapor destillation (Component of (Blue) chamomile blossoms) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 21 Sesquiterpenes as proazulene: Example Matricin Vapor destillation (Component of (Blue) chamomile blossoms) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 22  Sesquiterpenes as proazulene: Example Matricin Vapor destillation Pseudoguaianolide (Component of (Blue) chamomile blossoms) How would the matricin compound look in the Pseudoguaianolide form? Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 23  Sesquiterpenes as proazulene: Example Matricin Vapor destillation Pseudoguaianolide (Component of (Blue) chamomile blossoms) O HO O O O Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 24 Sesquiterpene-containing raw materials (Arzneidrogen) Millefolii herba, Schafgarbenkraut (Yarrow) Effects and uses: Pharmacological effects of yarrow: o anti-inflammatory (sesquiterpene lactones, proazulene) ⍺-peroxyachifolid o spasmolytic (essential oil, flavonoids) o slightly antimicrobial, antifungal (essential oil, sesquiterpene lactones, polyacetylenes) o choleretic (combination of different substances) Yarrow is a common ingredient in industrial tea blends and (in the form of extracts) of finished drugs: o The main areas of application are (similar to chamomile): loss of appetite and dyspeptic disorders (bitter effect of sesquiterpene lactones), mild spasmodic disorders of the gastrointestinal tract o In folk medicine, used externally for wound healing and the treatment of inflammatory skin diseases Yarrow is one of the plants with medium allergenic potency (potential for allergies of the delayed type; due to ⍺-peroxyachifolid and similar substances): Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 25 Sesquiterpene-containing raw materials (Arzneidrogen) Millefolii herba, Schafgarbenkraut (Yarrow) Effects and uses: Pharmacological effects of yarrow: o anti-inflammatory (sesquiterpene lactones, proazulene) ⍺-peroxyachifolid o spasmolytic (essential oil, flavonoids) o slightly antimicrobial, antifungal (essential oil, sesquiterpene lactones, polyacetylenes) o choleretic (combination of different substances) Yarrow is a common ingredient in industrial tea blends and (in the form of extracts) of finished drugs: o The main areas of application are (similar to chamomile): loss of appetite and dyspeptic disorders (bitter effect of sesquiterpene lactones), mild spasmodic disorders of the gastrointestinal tract o In folk medicine, used externally for wound healing and the treatment of inflammatory skin diseases Yarrow is one of the plants with medium allergenic potency (potential for allergies of the delayed type; due to ⍺-peroxyachifolid and similar substances): Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 26 Sesquiterpene-containing raw materials (Arzneidrogen) Millefolii herba, Schafgarbenkraut (Yarrow) Effects and uses: Pharmacological effects of yarrow: o anti-inflammatory (sesquiterpene lactones, proazulene) ⍺-peroxyachifolid o spasmolytic (essential oil, flavonoids) o slightly antimicrobial, antifungal (essential oil, sesquiterpene lactones, polyacetylenes) o choleretic (combination of different substances) Yarrow is a common ingredient in industrial tea blends and (in the form of extracts) of finished drugs: o The main areas of application are (similar to chamomile): loss of appetite and dyspeptic disorders (bitter effect of sesquiterpene lactones), mild spasmodic disorders of the gastrointestinal tract o In folk medicine, used externally for wound healing and the treatment of inflammatory skin diseases Yarrow is one of the plants with medium allergenic potency (potential for allergies of the delayed type; due to ⍺-peroxyachifolid and similar substances): Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 27 Sesquiterpene-containing raw materials (Arzneidrogen) Absinthii herba, Wermutkraut (Wormwood) Parent plant: Artemisia absinthium L. (Wermut) Family: Asteracae Plant raw material: (Droge): herba, The dried basal leaves or the upper parts of the shoots and leaves collected during the flowering period of Artemisia absinthium L. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 28 Sesquiterpene-containing raw materials (Arzneidrogen) Absinthii herba, Wermutkraut (Wormwood) Components Essential oil (0.2–1.5 %; PhEur = at least 2 ml/kg), mainly composed of mono- and sesquiterpenes, the composition varying depending on the chemical type (β-thujone, trans-sabinene acetate, cis-epoxyocimene or chrysantenyl acetate can account for up to 40% of the essential oil in each case). O H O O O H O H β-Thujone trans-sabinene acetate cis-epoxyocimene Chrysantenyl acetate Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 29 Sesquiterpene-containing raw materials (Arzneidrogen) Absinthii herba, Wermutkraut (Wormwood) Components Essential oil (0.2–1.5 %; PhEur = at least 2 ml/kg), mainly composed of mono- and sesquiterpenes, the composition varying depending on the chemical type (β-thujone, trans-sabinene acetate, cis-epoxyocimene or chrysantenyl acetate can account for up to 40% of the essential oil in each case). H (Bitter-tasting) sesquiterpene lactones (0.15–0.4%), primarily the guaianolides absinthin, artabsin O Artabsin Absinthin β-Thujone Flavonoids, lipophilic flavonoid aglycones Phenolic carboxylic acids, coumarins, sesamin-type lignans Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 30 Terms for the systematic description of the intraspecific variability of the composition of plant constituents The chemical characteristics of medicinal plants can vary intraspecifically (within a species) both qualitatively and quantitatively. o The qualitative trait formation in higher plants is usually genetically controlled. o The quantitative differentiation is either genetically or modificatively determined. The variability of chemical characteristics can occur in different forms: o Polymorphismus = (Genetically fixed) variability within local populations: - Chemotype (Chemovar) o Polytypism = Geographical and ecological racialization (populations with their own range): - Chemodem (Chemical breed) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 31 Sesquiterpene-containing raw materials (Arzneidrogen) Absinthii herba, Wermutkraut (Wormwood) Effects and uses As Amarum aromaticum (reflectory stimulation of gastric and bile secretion); for loss of appetite and dyspeptic complaints − As an herbal tea blend for infusions (teas), an ingredient in tea blends − Phytopharmaceuticals with powdered wormwood herb (mono- or combination preparations (e.g. Gastritol®)) − Ready-to-use preparations based on various types of wormwood herb extracts (usually not declared as such) No recent pharmacological data available. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 32 La fée verte - Absinth Oscar Wilde Vincent van Gogh (1854 - 1900) (1853 - 1890) "After the first glass, you see things as you wish they were. After the second, you see things as they are not. Finally, you see things as they really are, which is the most horrible thing in the world." Cafétisch mit Absinth, 1887 Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 33 La fée verte - Absinth H O β-Thujone (Sesquiterpene) GABAA receptor antagonist, Oscar Wilde Vincent van Gogh stimulatory, mood altering. (1854 - 1900) (1853 - 1890) Present in very low amounts. "After the first glass, you see things as you HO wish they were. After H H HO the second, you see H H H things as they are not. Finally, you see things O HH β-Thujone O H as they really are, which O is the most horrible O thing in the world." Absinthin (2x Guaianolide precursors) Cafétisch mit Absinth, 1887 Anti-inflammatory activity. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 34 Sesquiterpene-containing raw materials (Arzneidrogen) Petasitidis rhizome et follium, Pestwurz and Pestwurzblätter Parent plant: Petasites hydribicus L. GAERTN., MEY. et SCHERB. (Pestwurz) Family: Asteracae Plant raw material: (Droge): rhizome and foliage Manufacture of finished drugs (Fertigarzneimitteln) based on CO2 extracts or 90% ethanol extracts, which are freed from pyrrolizidine alkaloids (PA) by cation exchange. CO2 extracts are free of PA. The drug itself (Petasitidis rhizoma or Petasitidis folium) may no longer be used as a tea due to its PA content. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 35 Extraction with supercritical gases (Supercritical Fluid Extraction, SFE) A supercritical fluid (SCF) is defined as a substance that is (simultaneously) above its critical pressure and critical temperature. The critical point (CP) represents the highest temperature and pressure at which a substance can exist in equilibrium between the gaseous and liquid states (see phase diagram of carbon dioxide). Phase diagram of CO2 73.8 31.3 ℃ Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 36 Extraction with supercritical gases (Supercritical Fluid Extraction, SFE) Of practical importance for drug extractions is only supercritical CO2, which is available cheaply in large quantities and high purity, and is considered harmless to health. o Critical temperature = 31.3 °C → gentle extraction of thermolabile substances possible Supercritical CO2 is a purely lipophilic, relatively weak solvent. o → The most extractable compounds are lipophilic organic compounds of medium polarity. o Adjustment of solution capacity and selectivity by varying the gas density (only possible in the supercritical range!) o Increase of polarity by adding EtOH as an entrainer (additives > 5% not recommended) Use of supercritical CO2 for the extraction of solid plant drugs and for the purification and fractionation of primary extracts. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 37 Extraction with supercritical gases: Applications Industrial applications in the food and cosmetics industries o Decaffeination of coffee and tea o Production of spice extracts (Gewürzextrakten) o Extraction of (fatty) vegetable oils. o Extraction of essential oils Production of Drogenextrakten o Analytical and preparative applications for example: - Valepotriate-rich Valerian extract (Baldrian-Extrakt) - St. John’s wort extract (Johanniskraut-Extrakt) o Commercial applications Sentyca Nutridermaceuticals - Hop extracts - Selective removal of unwanted ingredients (e.g. removal of the thujone-containing essential oil from wormwood herb before further processing of the material) Isolation of thermolabile natural products (e.g. fragrances and proazulenes from chamomile flowers; artabsin from wormwood) Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 38 Sesquiterpene-containing raw materials (Arzneidrogen) Petasitidis rhizome et follium, Pestwurz and Pestwurzblätter Ingredients: Occurrence of two Chemotypes o Petasin chemotype (derivatives of petasol, neopetasol and isopetasol) and furanopetasin chemotype Eudesmane Type Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 39 Sesquiterpene-containing raw materials (Arzneidrogen) Petasitidis rhizome et follium, Pestwurz and Pestwurzblätter Petasites extracts have anti-inflammatory and spasmolytic effects. The active ingredients (Wirksamkeitsbestimmende) are, in particular, Petasines o Petasites extracts inhibit the synthesis of leukotrienes (LTB4; cysteinyl leukotrienes LTC4, LTD4 and LTE4 (inflammatory mediators)). Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 40 The formation of leukotrienes from arachidonic acid and the role of 5-lipoxygenase Arachidonic Acid 5-Lipoxygenase (5-LO) OOH COOH 5-Hydroperoxyeicosatraenoate (5-HPETE) OH O COOH COOH OH Leukotrien A4 Leukotriene B4 H2N COOH Cysteine-Res. S COOH Andere Leukotriene, OH Fraley | Pharmaceutical Biology Lecture | 2024 z. B. LTE4 10.10.2024 41 Sesquiterpene-containing raw materials (Arzneidrogen) Petasitidis rhizome et follium, Pestwurz and Pestwurzblätter Petasites extracts have anti-inflammatory and spasmolytic effects. The main active ingredients are petasins o Petasites extracts inhibit the synthesis of leukotrienes (LTB4; cysteinyl leukotrienes LTC4, LTD4 and LTE4 (inflammatory mediators)). - Petasin inhibits PAF- (and C5⍺-) induced release of intracellular Ca2+ from mitochondria, which is required for activation of 5-lipoxygenase (5-LO) in leukocytes. - The molecular mechanisms of inhibition of LT synthesis by iso- and neopetasins are not clear. o Petasites extracts as well as a mixture of petasins inhibit the release of the pro-inflammatory cytokine IL-8 from polyIC-stimulated human nasal epithelial cells (HNEC) in vitro. - No inhibition by single petasins ! o Petasites extracts inhibit the release of pro-inflammatory cytokines and chemokines from IL-4, IL-6, or TNF-g stimulated HNEC by blocking the STAT signaling pathway. o The mechanism of the spasmolytic effect has not been clarified. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 42 Sesquiterpene-containing raw materials (Arzneidrogen) Petasitidis rhizome et follium, Pestwurz and Pestwurzblätter Applications: Petasites root extract for migraine prophylaxis, for tension headaches, urogenital and digestive tract spasms Petasites leaf extract for asthma and allergic rhinitis - Clinical data are available on the efficacy of butterbur root extract preparations in the treatment of migraine and allergic rhinitis. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 43 The therapeutic use of sesquiterpenes as pure substances: Artemisinin Artemisinin (Qinghaosu) is one of the ingredients of an ancient Chinese medicinal drug, the herb of Artemisia annua L. (Family: Asteraceae) Content in wild plants approx. 0.1 – 0.5%. Cadinan-type sesquiterpene Cadinan basic scaffold Artemisinin Artemisia annua L. Artemisinin is an active substance in the nM concentration range against Malaria parasites. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 44 The life cycle of the malaria parasite Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 45 The therapeutic use of sesquiterpenes as pure substances: Artemisinin Artemisinin (Qinghaosu) is one of the ingredients of an ancient Chinese medicinal drug, the herb of Artemisia annua L. (Family: Asteraceae) Content in wild plants approx. 0.1 – 0.5%. Cadinan-type sesquiterpene Cadinan basic scaffold Artemisinin Artemether Artemisinin is an active substance in the nM concentration range against Malaria parasites. o Its therapeutic use is based on the selective uptake of the substance by infected erythrocytes. Artemisinin is only toxic to human and animal cells in mM concentrations. Extra-erythrocytic schizonts (e.g. in the liver) remain unaffected. Artemisinin is also effective against gametocytes that are ingested by the biting mosquito from the blood of infected persons. Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 46  Tu Youyou’s research report 1971 – 1978 Emphasizes the importance of preparation methods o Tu and her team initially prepared the wormwood extracts via boiling and saw no activity. o They next tried boiling in an ether-based solvent which boils at a lower temperature and obtained an active extract. o They ultimately isolated the pure compound Artemisinin Fraley | Pharmaceutical Biology Lecture | 2024 https://www.nobelprize.org/womenwhochangedscience/stories/tu-youyou 10.10.2024 47 Mechanism Mechanistically, the toxic effect of artemisinin is based on the formation of free radicals and is linked to the presence of the endoperoxide structure: Artemisininoids Activation by Fe(III) Free radical or (Endoperoxide) (Heme-bound or free) Electrophilic intermediate “Malaria- Target proteins” Alkylated “Malaria- Target proteins” Artemisinin and its analogs, such as artemether, are used worldwide for malaria therapy in areas where drug-resistant parasites occur. o Do not use as monotherapy due to high recurrence rate, but only in combination with long-acting antimalarials Do not use in prophylaxis to avoid accelerating the development of resistant strains! Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 48 Summary of the key messages Sesquiterpenes are C15-terpenes; different basic scaffolds: sesquiterpenes of the Bisabolan-, Germacran-, Eudesman-, Cadinan-, Guaian-, and Pseudoguaian-type. The pharmaceutically most important subgroup of sesquiterpenes are the sesquiterpene lactones; sesquiterpene lactones with an ⍺-methylene-𝛾-lactone ring are potentially reactive (alkylating) compounds and phytoeczematogenic. Important sesquiterpene (lactone) active materials are: o Arnica flowers (Arnikablüten) → Helenaline o Yarrow herb (Schafgarbenkraut) → Guaianolides such as Achillicin o Wormwood herb (Wermutkraut) → Guaianolides such as Artabsin o Butterbur (Pestwurz) → rearranged sesquiterpenes of the Eudesman type); use of the active materials (e.g. for tea preparations) not permitted Sesquiterpene lactones as individual substances o Artemisinin → Ring-extended sesquiterpene lactone of the Cadinan type; antimalarial agent Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 49 Examination-relevant structural formulas Farnesyl diphosphate, Nerolidyl diphosphate Biosynthetic intermediates from geranyl diphosphate to farnesyl diphosphate / nerolidyl diphosphate Basic structures: Germacrane / Germacranolide, Eudesmane / Eudesmanolide, Guaiane / Guaianolide, Pseudoguaiane / Pseudoguaianolide Structure of an ⍺-methylene-𝛾-lactone ring Helenin Fraley | Pharmaceutical Biology Lecture | 2024 10.10.2024 50