2.1+2.2 Terpenes + Monoterpenes PDF

2. Isoprenoids - Terpenes and Terpenoids 2.1 Structure, classification, and biosynthesis of the basic building blocks 1. Basic Concepts 2. Isoprenoids 3. Phenolics 4. Essential Oils 5. Alkaloids 6. Polysacharides D-CHAB Institute of Pharmaceutical Sciences Lecture...

2. Isoprenoids - Terpenes and Terpenoids 2.1 Structure, classification, and biosynthesis of the basic building blocks 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 Basic structural characteristics of isoprenoids Isoprenoids – (terpenes, terpenoids) are a structurally heterogeneous group of natural substances that are biosynthetically derived from two simple C5 compounds, namely isopentenyl diphosphate (IPP) and its isomer, dimethylallyl diphosphate (DMAPP): Isoprene IPP DMAPP Isoprene – 2-methyl-1,3-butadiene, cannot be isolated o Prevalent in both plants and animals − Produced directly by many plants, especially Dictamnus albus L.; Diptam; Family: Rutaceae. − The most abundant hydrocarbon in the exhaled air of humans (17 mg/d at 70kg human weight) Dictamnus albus L. - Gas plant can be set on fire on hot days. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 2  Isoprene Rule Terpenes can be formally broken down into isoprene building blocks (if necessary after prior schematic ring opening), i.e. the branching of the carbon chain created in the IPP or DMAPP is still reflected in the end products of biosynthesis (⟹ methyl groups on C4-residues). Head Tail Otto Wallach 1847 – 1931 Leopold Ružička Nobel Prize in 1887 – 1976 Chemisty (1910) Nobel Prize in Chemistry (1939) Early work on mono- terpene isolation and Terpenes are composed of a characterization. Showed common building block, that terpenes can easily Abietic acid skeleton, built up isoprene. Succeeded in the be altereed and changed of 4 isoprene units. From L. production of higher terpenoids into each other. Ružička Nobel Lecture (1945) from each other. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 3  Biosynthesis of isoprenoids: Biogenic Isoprene Rule Structure and nomenclature of the basic building blocks O- O- O O P P - OH O O O Isopentene Isopentenol Isopentenyldiphosphate (IPP) OH Propene Allylalcohol O- O- O O OH P P - O O O 2-methyl-1,3-butadiene Dimethylallylalcohol Dimethylallyldiphosphate (DMAPP) (2-methyl-but-2-ene) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 4  Biosynthesis of isoprenoids: Biogenic Isoprene Rule Connections 1 3 4 1 3 4 1,4 – Linkage (Asymmetrical) 2 2 During biosynthesis, the 1,4 - Head-Tail methyl-substituted unit can be linked via either 3 3 the C1-C4 or C4-C4 1 2 4 4 2 1 4,4 – Linkage (Symmetrical) 4,4 - Tail-Tail Examples 4,4-link Myrcene Limonene β-Carotene (Irregular terpene) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 5 Occurrence and biological significance of isoprenoids Isoprenoids are present in all organisms, and particularly prevalent in plant materials. o Approx. 40,000 naturally occurring representatives. o Individual isoprenoids or their presence in combinations are often characteristic of certain plant species and can therefore be used as a “fingerprint” for identification via Chemotaxonomy. OH Biological functions of isoprenoids: 4,4-link o Carotenoids → Photosynthesis o Gibberellins → Plant hormones HO o Cholesterol → Steroid hormones in animals Lutein O OH H O Gibberellin A1 4,4-link H H OH H O H H Cholesterol HO Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 6  Occurrence and biological significance of isoprenoids In pharmacy, isoprenoids play an important role as efficacy-determining (and co-determining) ingredients of a number of drugs Generalizations regarding the importance of isoprenoids for pharmacy and medicine are not possible due to the very different chemical and physical properties of the compounds More lipophilic representatives are mainly found as components of essential oils. Limonene Citronelle ⍺-Pinene Camphene Eremophilane Germacrene D Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 7  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 03.10.2024 8  Biosynthesis of isoprenoids starting from hemiterpenes The common precursors of all isoprenoids are isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). o IPP and DMAPP are by far the most important hemiterpenes o Two known biosynthetic pathways 1. Acetate / Mevalonate Route 2. Glyceraldehyde / Pyruvate Route (Triose / pyruvate, xylulose-5-phosphate) Occurs in the cytosol of fungi, seed plants, and Observed in eubacteria, in the cytosol and plastids mammals of algae and in the plastids of seed plants. Presumably the relevant pathway for the provision Presumably the relevant pathway for the provision of IPP and cytosolically synthesized isoprenoids in of IPP for the synthesis of isoprenoids in plastids animals, fungi, and higher plants (sesquiterpenes, (isoprene, monoterpenes, diterpenes, and triterpenes, steroids, and polyterpenes) tetraterpenes) Starting compound: Acetyl-CoA Starting compounds: Pyruvate and glyceraldehyde phosphate Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 9  The biosynthesis of IPP and DMAPP via the acetate-mevalonate pathway 4. MVA Kinase 1. 2. 3. 5. Acetoacetyl-CoA Thiolase HMG-CoA Synthase HMG-CoA Reductase MVAP Kinase MVAPP Decarboxylase O O NADPH NADP+ ATP ADP SCoA SCoA H2O ATP O O O O 2x 2x OH O O OH O O OH OH O OH SCoA SCoA CoAS SCoA HO SCoA HO HO O P P O P P HSCoA Acetoacetyl-CoA HSCoA 3-Hydroxy-3-Methylglutaryl-CoA Mevalonate Diphosphomevalonate (MVAPP) CO2 Isopentenyldiphosphate (HMG-CoA) (MVA) H2O (IPP) (Mevalonsäure) Isopentenyl-PP 6. Isomerase O P P Dimethylallyldiphosphate (DMAPP) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 10  The biosynthesis of IPP and DMAPP via the acetate-mevalonate pathway 4. MVA Kinase 1. 2. 3. 5. Acetoacetyl-CoA Thiolase HMG-CoA Synthase HMG-CoA Reductase MVAP Kinase MVAPP Decarboxylase O O NADPH NADP+ ATP ADP SCoA SCoA H2O ATP O O O O 2x 2x OH O O OH O O OH OH O OH SCoA SCoA CoAS SCoA HO SCoA HO HO O P P O P P HSCoA Acetoacetyl-CoA HSCoA 3-Hydroxy-3-Methylglutaryl-CoA Mevalonate Diphosphomevalonate (MVAPP) CO2 Isopentenyldiphosphate (HMG-CoA) (MVA) H2O (IPP) (Mevalonsäure) Isopentenyl-PP 6. Isomerase O HO OH O O O P P P. citrinum A. terreus HO HO OH Dimethylallyldiphosphate OH OH (DMAPP) HO O HO O OH OH F N F O O O O F N O O O H H O N NH Lipitor from Warner / Lambert, previously Pfizer, was the world’s top selling Compactin Mevinolin Atorvastatin Fluvastatin Cerivastatin drug in 2009 ($13.2 bil turnover) (IC50 = 23 nM) (Lovastatin) (Lipitor) (IC50 = 28 nM) (IC50 = 10 nM) For a review of the history of statins: Chemie in Unsere Zeit. 44, 344 (2010) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 11  The biosynthesis of IPP and DMAPP via the acetate-mevalonate pathway 4. MVA Kinase 1. 2. 3. 5. Acetoacetyl-CoA Thiolase HMG-CoA Synthase HMG-CoA Reductase MVAP Kinase MVAPP Decarboxylase O O NADPH NADP+ ATP ADP SCoA SCoA H2O ATP O O O O 2x 2x OH O O OH O O OH OH O OH SCoA SCoA CoAS SCoA HO SCoA HO HO O P P O P P HSCoA Acetoacetyl-CoA HSCoA 3-Hydroxy-3-Methylglutaryl-CoA Mevalonate Diphosphomevalonate (MVAPP) CO2 Isopentenyldiphosphate (HMG-CoA) (MVA) H2O (IPP) (Mevalonsäure) Isopentenyl-PP Historical Discovery 6. Isomerase Mevalonate isolated from concentrated yeast extracts at the end of a beer brewing process. O P P Dimethylallyldiphosphate (DMAPP) H O H H OH HO Danielsson, H., and Bloch, K., J. Am. Chem. Soc., 79, 500 (1957). Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 12  The biosynthesis of IPP and DMAPP via the glyceraldehyde-pyruvate route 4. MVA Kinase 1. 2. 3. 5. Acetoacetyl-CoA Thiolase HMG-CoA Synthase HMG-CoA Reductase MVAP Kinase MVAPP Decarboxylase O O NADPH NADP+ ATP ADP SCoA SCoA H2O ATP O O O O 2x 2x OH O O OH O O OH OH O OH SCoA SCoA CoAS SCoA HO SCoA HO HO O P P O P P HSCoA Acetoacetyl-CoA HSCoA 3-Hydroxy-3-Methylglutaryl-CoA Mevalonate Diphosphomevalonate (MVAPP) CO2 Isopentenyldiphosphate (HMG-CoA) (MVA) H2O (IPP) (Mevalonsäure) Isopentenyl-PP 6. Isomerase O P P Dimethylallyldiphosphate (DMAPP) DXP-Reductoisomerase CDP-ME-Synthase CDP-ME Kinase ME-cPP Synthase HMBPP Synthase H2O OH H O P CTP P P ATP ADP PO2 O H+ H2O 2e- O O OH OH OH OH OH OH OH O 2e- O PO2 O P O P O P CMP O P CMP O O P P OH OH HO HO P O OH OH OH O CO2 CMP Pyruvate 1-Desoxy-D-Xylulose- Methylerythritol- CDP-Methyl-D-Erithritol CDP-ME-2-phosphate 2C-ME-2,4- Hydroxymethyl-butenyl-4 5-phosphate (DXP) phosphate (MEP) (CDP-ME) (CDP-MEP) cyclodiphosphate (ME-cPP) -diphosphate (HMBPP) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 13  The biosynthesis of IPP and DMAPP via the glyceraldehyde-pyruvate route 4. MVA Kinase 1. 2. 3. 5. Acetoacetyl-CoA Thiolase HMG-CoA Synthase HMG-CoA Reductase MVAP Kinase MVAPP Decarboxylase O O NADPH NADP+ ATP ADP SCoA SCoA H2O ATP O O O O 2x 2x OH O O OH O O OH OH O OH SCoA SCoA CoAS SCoA HO SCoA HO HO O P P O P P HSCoA Acetoacetyl-CoA HSCoA 3-Hydroxy-3-Methylglutaryl-CoA Mevalonate Diphosphomevalonate (MVAPP) CO2 Isopentenyldiphosphate (HMG-CoA) (MVA) H2O (IPP) (Mevalonsäure) Isopentenyl-PP 6. Isomerase O P P Dimethylallyldiphosphate (DMAPP) DXP-Reductoisomerase CDP-ME-Synthase CDP-ME Kinase ME-cPP Synthase HMBPP Synthase H2O OH H O P CTP P P ATP ADP PO2 O H+ H2O 2e- O O OH OH OH OH OH OH OH O 2e- O PO2 O P O P O P CMP O P CMP O O P P OH OH HO HO P O OH OH OH O CO2 CMP Pyruvate 1-Desoxy-D-Xylulose- Methylerythritol- CDP-Methyl-D-Erithritol CDP-ME-2-phosphate 2C-ME-2,4- Hydroxymethyl-butenyl-4 5-phosphate (DXP) phosphate (MEP) (CDP-ME) (CDP-MEP) cyclodiphosphate (ME-cPP) -diphosphate (HMBPP) Soliman, S. S. M.; et al. J. Nat. Prod., 74, 12 (2011). Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 14 2. Isoprenoids - Terpenes and Terpenoids 2.2 Monoterpenes 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 Structure and properties of monoterpenes Monoterpenes – Monoterpenes are formed by the 1,4-coupling (Head-to-tail) of two hemiterpenes. The simplest representative is Geraniol: Other linear compounds include linalool and citronellal Bicyclic representatives include Limonene, Menthol, Carvone, ⍺- and β-Pinene, Camphor These are lipophilic and relatively highly volatile Present almost exclusively in essential oils: (+)-Limonene (-)-Menthol 1,8-Cineol (Caraway oil) (Peppermint oil) (Eucalyptus oil) (Kümmelöl) (Pfefferminzöl) (Eucalyptusöl) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 16 The iridoids / secoiridoids form a special subgroup of monoterpenes Iridoids – Natural products with a cyclopentane-pyran backbone. The simplest representative in the Iridiole: Genuine occurrence in most cases as non-volatile glycosides (> 70%) Iridoid backbone Due to their polarity, there is no need to store the iridoid glycosides in special plant organs ⟹ Secoiridoids – formed by oxidative ring opening between C7 and Significantly greater prevalence C8 of the iridoid system, as in secologanin: than the lipophilic monoterpenes of essential oils Secoiridoid backbone Stereochemistry not relevant for exam Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 17 The iridoids / secoiridoids form a special subgroup of monoterpenes Iridoids – Natural products with a cyclopentane-pyran backbone. The simplest representative in the Iridiole: Iridoid backbone Menyanthidis trifoliatae folium (Bitter clover / Bitterkleeblätter) -Used for loss of appetite, stimulate secretion of gastric juice Secoiridoids – formed by oxidative ring opening between C7 and C8 of the iridoid system, as in secologanin: Secoiridoid backbone Lonicera japonica Thunb. (Honeysuckle / Geißblatt) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 18 Pharmaceutical Importance of iridoids / secoiridoids Iridoids are important lead compounds in analytical phytochemistry due to their widespread use in herbal medicine Their pattern is species specific (artspezifisch) and important for identity verification. They can be destroyed if the extract is not prepared properly (quality control is key). They are widespread as ingredients in many ancient medicines. Traditional use of such drugs in folk medicine (Volsmedizin) as bitter, sedative, painkiller, cough suppressant; for the treatment of wounds and high blood pressure. − Weak evidence for biological and medicinal effects Antimicrobial Antifungal Antiviral Anti-inflammatory Choleretic Purgative Hypoglycemic Antitumor Hepato-protection Immuno-modulating Effects attributed to the aglycones, which can be generated Cardiovascular Lipid Lowering via cleavage of the glycosidic bond by members of the human gut microbiome. Secoiridoids are also referred to as bitter agents (Bittermittel) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 19 Repetition (Org. Chemie) Reactions of aldehydes and ketones with amines Completely chemistry-based All reaction steps are, in principle, reversible. Imines and enamines can be hydrolized back to their core keto and Primary amine amine components. Secondary Amine Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 20 Repetition (Org. Chemie) Nucleophilic addition to conjugated double bonds (1,4 addition) Completely chemistry-based Y = Nucleophile (N, S, double bond) This type of reaction is not only with the carbonyl, but also with the imine (which is even stronger). Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 21 The biosynthesis of iridoids starts from Geraniol via iridoidial and epi- iridoidial as central intermediates 1. 2. Iridoid backbone 3. Reduction Hydrolysis Iridodial 8-C-Iridoide 8-C-Iridoide Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 22 The balance between monocyclic and bicyclic forms of iridoids. The transition of the iridodial from a monocyclic (pentane) structure (a dialdehyde) to a bicyclic (dihydropyrano-pentane) structure (a lactol) occurs via an enol as an intermediate. After glycosylation of the OH group at C-1 of the lactol, ring opening is no longer possible. Glycosylation occurs here Hemiacetal / Enol Enol / Ketone Equilibrium Equilibrium Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 23 Iridoid containing drugs Monk’s Pepper Fruit (Agni casti fructus, Mönchspfefferfrüchte) Parent plant: Vitex agnus castus L. (Mönchspfeffer, Keuschlamm) Family: Lamiaceae (früher Verbenaceae) Active substance: Fruit: Dried black spherical stone fruits Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 24 Iridoid containing drugs Monk’s Pepper Fruit (Agni casti fructus, Mönchspfefferfrüchte) Ingredients Iridoid glycosides (ca. 1%) aucubin, agnuside Lipophilic flavonoids (esp. Casticin, isoorientin) Essentiall oil (Ätherisches Öl) (0.7 – 1.8%) primarily mono-and sesquiterpenes Lipophilic diterpenes Fatty oil Tenth carbon missing due to loss of methylene during biosynthesis Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 25 Iridoid containing drugs Monk’s Pepper Fruit (Agni casti fructus, Mönchspfefferfrüchte) The biosynthesis of aucubin: loss of the C11 methyl group 1. 2. 3. 4. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 26 Iridoid containing drugs Monk’s Pepper Fruit (Agni casti fructus, Mönchspfefferfrüchte) Pharmacological effects and (possible) mechanism of action Inhibition of prolactin release in the lactotroph cells of the anterior pituitary → reduction of pathologically elevated prolactin levels Postulation of a dopaminergic effect (stimulation of dopamine type 2 receptors, which regulate prolactin release in the hypothalamic-pituitary-adrenal (HHN) axis) The observed effects cannot be attributed to specific individual active ingredients. One possible active ingredient is rotundifuran (a diterpene), which has a high binding affinity for the dopamine D2 receptor and inhibits prolactin release in vitro in a similar way to dopamine. Applied to: Exclusively for the production of aqueous-ethanolic extracts for processing in finished medicinal products Therapeutic use of the finished medicinal products for menstrual disorders, premenstrual symptoms (PMS), mastodynia Clinical efficacy proven for the indications mastodynia, PMS in placebo-controlled double-blind studies, for menstrual disorders in individual case reports Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 27 Iridoid containing drugs Rampion (Harpagophyti radix, Teufelskrallenwurzel) Parent plant: Harpagophytum procumbens (BURCH) (Teufelskralle) Family: Pedaliaceae Active substance: Radix, the cleansed and dried secondary storage roots. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 28 Iridoid containing drugs Rampion (Harpagophyti radix, Teufelskrallenwurzel) Ingredients Iridoid glycosides (1.1–3.6 %; PhEur min. 1.2 %), harpagide, harpagoside, 8- O-p-coumaroyl harpagide, procumbide, 6'-O-p-coumaroyl procumbide, procumboside. Phenylethanoid glycosides: verbacoside and isoacteoside Carbohydrates, especially stachyose, raffinose, sucrose, glucose Flavonoids, triterpenes, plant acids, among others Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 29 Iridoid containing drugs Rampion (Harpagophyti radix, Teufelskrallenwurzel) Pharmacological effects of Harpagophytum extracts Studies on the effect of Harpagophytum extracts in standard inflammation and pain models in vitro and in vivo: o The occurrence of an effect is highly dependent on the manufacturing process for the extract used and (in animal models) on the mode of application (i.v., p.o., i.p). In vitro, Harpagophytum extracts show concentration-dependent inhibition of the biosynthesis of thromboxane B2(TXB2) and cysteinyl leukotrienes (→ eicosanoid metabolism). Inhibition of the release of the pro-inflammatory cytokines TNF-a, IL-6, IL-1β and PGE2 from LPS-stimulated monocytes o Inhibition of the induction of pro-inflammatory gene expression mediated by the transcription factor AP-1 Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 30 Iridoid containing drugs Rampion (Harpagophyti radix, Teufelskrallenwurzel) Efficacy-determining ingredients The efficacy of Harpagophytum extracts cannot be attributed to specific individual ingredients. Significant contribution to pharmacological effect by harpagoside: o Extracts with higher harpagoside content show a stronger inhibitory effect on TXB2 and LT biosynthesis than those with lower harpagoside concentrations. o But: the effects of extracts are significantly more pronounced than those of pure harpagoside (→ presence of other ingredients that contribute to the effect). In humans, measurable plasma levels of harpagoside are achieved in a dose- dependent manner after oral administration of Harpagophytum whole extracts. Inhibition of the biosynthesis of TXB2/cysteinyl-LT after administration of Harpagophytum extracts has also been observed in humans, whereby the temporal course of the occurrence of these effects could indicate a metabolite that contributes to the efficacy. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 31 Iridoid containing drugs Rampion (Harpagophyti radix, Teufelskrallenwurzel) Utilization For the supportive therapy of wear and tear of the musculoskeletal system Efficacy in mild to moderate non-specific and inflammation-related back pain is clinically proven. (Only a small number of randomized, placebo-controlled double- blind studies available). Efficacy in inflammatory rheumatic diseases / osteoarthritis Loss of appetite, dyspeptic complaints ( bitter effect of iridoids) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 32 Iridoid containing drugs Gentian Root (Gentianae radix, Enzianwurzel) Parent plant: Gentiana lutea L. (Gelber Enzian) Family: Gentianaceae Active substance: Radix, the dried, crushed underground organs of Gentiana lutea L. Other gentian species can also be used as a source of the drug, but they do not play a major role in practice due to their significantly smaller root mass. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 33 Iridoid containing drugs Gentian Root (Gentianae radix, Enzianwurzel) Ingredients Secoiridoid glycosides (2–4 %; PhEur min. 1.2 %), main component gentiopicroside (ca. 2.5 %), little amarogentin Xanthone derivatives (ca. 0.25%) Sugars, including the weakly bitter-tasting trisaccharide gentianose (2.5–5%): when the drug dries, it splits into fructose and the more bitter-tasting gentiobioside Polysaccharides, phytosterols, triterpenes, mineral components (ca. 8%) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 34 Iridoid containing drugs Gentian Root (Gentianae radix, Enzianwurzel) The biogenetic origin of bitter iridoids The bitter principles of the Gentianaceae and Menyanthaceae are highly modified secoiridoids that can be traced biogenetically to secoiridoids of the loganine type. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 35 The conversion of iridoidial into secologanin O O OH H H H O O O H H H OH OH OH O O O O O OH H H H O HO O O O H H H O --D-Glc O --D-Glc O --D-Glc Secologanin Iridoid isoquinoline alkaloids Iridoid tryptophan alkaloids Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 36 Iridoid containing drugs Gentian Root (Gentianae radix, Enzianwurzel) Use of Gentian root As a tea infusion or tincture as an amarum to stimulate the secretion of gastric juices in cases of loss of appetite, dyspeptic complaints − Use is based on the bitter taste of the ingredients, with the bitter value of the drug being determined mainly by the amarogentin, which is only present in small amounts. − Bitter substances similar in structure to amarogentin are also found in other Gentianaceae drugs, e.g. centaury (Centaurii herba) (centapicrin, desacetylcentapicrin). Centaurii herba, Tausengüldenkraut Parent plant: Centaurium erythraea Rafn Family: Gentianacae Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 37 Iridoid containing drugs Gentian Root (Gentianae radix, Enzianwurzel) Use of Gentian root As a tea infusion or tincture as an Amarum to stimulate the secretion of gastric juices in cases of loss of appetite, dyspeptic complaints − Use is based on the bitter taste of the ingredients, with the bitter value of the drug being determined mainly by the amarogentin, which is only present in small amounts. − Bitter substances similar in structure to amarogentin are also found in other Gentianaceae drugs, e.g. centaury (Centaurii herba) (centapicrin, desacetylcentapicrin). In the mythology of the Quechua people of Equador, Amarum is a spirit in the shape of a water boa that brings the rain Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 38 Bitter substances and their value Bitter substances (Bitterstoffe) are substances with a bitter taste that trigger a reflex in the taste buds on the tongue, leading to increased secretion of saliva and gastric juices. The actual bitter substances must not have any pharmacological effect other than their bitter taste. The overall sensory evaluation of the usually heterogeneous substance mixtures that cause the bitter taste of bitter drugs is done by determining the bitterness value (Bitterkeitswertes): − The bitter value is the volume of water in mL that may at most be used to dissolve 1 g of substance or to extract 1 g of drug in order to obtain a solution that still tastes bitter. − Individual differences in taste perception must be compensated for by determining a personal correction factor (“sensitivity factor”). Reference substance: quinine hydrochloride, bitterness value = 200,000. Bitterness values of selected pure substances: Amarogentin: 58 000 000 Gentiopicrosid: 12 000 Amaroswerin: 58 000 000 Centapicrin: 4 000 000 Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 39 Iridoid containing drugs Valerian Root (Valerianae radix, Baldrianwurzel) Parent plant: Valeriana officinalis L. s.l., Baldrian Family: Valerianaceae Active substance: Radix, the dried, underground parts (rootstock and roots) of Valeriana officinalis L. s.l Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 40 Iridoid containing drugs Valerian Root (Valerianae radix, Baldrianwurzel) Ingredients Iridoids: ester iridoids [= valepotriate (0.8 – 1.7%)]: primarily valtrate and isovaltrate in a ratio of 1:1 – 1:4), valeroside (up to 1.5%) Valepotriate = valeriana-epoxy-triester: Essential oil (Ätherisches Öl) (0.5 – 2%; PhEur: at least 5 ml/kg for the whole and 3 ml/kg for the cut drug), primarily mono- and sesquiterpenes, as well as short-chain carboxylic acids (acetic, valeric, isovaleric, myristic acid and their esters with eugenol, isoeugenol, (-)-borneol, among others). Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 41 Iridoid containing drugs Valerian Root (Valerianae radix, Baldrianwurzel) Low-volatility sesquiterpene carboxylic acids (0.05 – 0.9%; PhEur: at least 0.17%, calculated as valerenic acid), primarily valerenic and acetoxyvalerenic acid. Mono- and diepoxylignans Free fatty acids Aromatic carboxylic acids (chlorogenic, caffeic, isoferulic acid) Amino acids (including GABA (g-aminobutyric acid)) Carbohydrates (high levels of glucose (1.5%), fructose (1%), sucrose (5%), raffinose (3%)) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 42 Iridoid containing drugs Valerian Root (Valerianae radix, Baldrianwurzel) Degradation of valepotriates in the production of aqueous-ethanolic extracts. Valtrate H+ Isovaltrate Acevaltrate Storage Polymerisate (Main conversion products) IVHD-Valtrate H+ Storage Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 43 Iridoid containing drugs Valerian Root (Valerianae radix, Baldrianwurzel) Valepotriate-rich valerian extracts Valepotriate-rich valerian extracts can be industrially produced from the roots of Valeriana mexicana DC (Mexican valerian) and Valeriana wallichii DC (Pakistani valerian). − Higher valepotriate content in the source drugs than in European species (V. mexicana: 5-8%; V. wallichii: 3-6%) − Extraction with lipophilic solvents → valepotriate content of the extracts: 20 – 80% − In the gastrointestinal tract, the valepotriates are converted to baldrinal and homobaldrinal, which in turn are subject to a high first-pass effect − Baldrinal and homobaldrinal (like the valepotriates themselves) are mutagenic substances − Metabolization in the liver leads to a no longer mutagenic glucuronide. − Use of the dry extracts in finished drugs for the treatment of anxiety and tension states, lack of concentration, mental and motor restlessness. The use of preparations with high valepotriate content is not recommended because of the unexplained side effect potential. Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 44 Chapters 2.1 and 2.2: Summary of the key messages Terpenes (isoprenoids): natural products that can be formally broken down into isoprene building blocks (occurrence of methyl groups at C4 residues). Biosynthesis starting from isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) (C5 building blocks); formation of IPP/DMAPP via the acetate/mevalonate or the triose/pyruvate pathway. Monoterpenes are formed by head-to-tail-coupling of DMAPP (→ geranyl diphosphate), possibly followed by cyclization reactions. Iridoids: Monoterpenes with a cyclopentanepyran backbone; oxidative opening of the cyclopentane ring leads to secoiridoids. Important iridoid and secoiridoid drugs are: − Teufelskrallenwurzel or Devil's claw root (→ harpagide, harpagoside) − Mönohspfefferfrüchte or Monk's pepper fruits (→ aucubin, agnuside) − Baldrianwurzel or Valerian root (→ valepotriates, valerian acid, valerian saponins) − Enzianwurzel or Gentian root (→ secoiridoids: amarogentin, gentiopicroside) Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 45 Exam-relevant structural formulas IPP, DMAPP Intermediates of the biosynthesis of IPP/DMAPP via the acetate-mevalonate pathway Geraniol/geranyl diphosphate Biosynthesis intermediates from IPP/DMAPP to geranyl diphosphate Basic structure iridoids/iridoid glycosides, secoiridoids/secoiridoid glycosides Aucubin Key steps in aucubin biosynthesis (starting from iridodial, according to the figure “The biosynthesis of Aucubin: loss of the C11 methyl group”) Harpagoside Amarogentin, gentiopicroside (secoiridoid glycosides without sugar residues) General structure of valepotriates Fraley | Pharmaceutical Biology Lecture | 2024 03.10.2024 46