Phytotherapy and Natural Products Chemistry (1) Lectures - PDF

22/01/1446 Phytotherapy and natural products chemistry (1) Dr. Yahia Tabaza 1 Phytotherapy and natural products chemistry (1) Lect...

22/01/1446 Phytotherapy and natural products chemistry (1) Dr. Yahia Tabaza 1 Phytotherapy and natural products chemistry (1) Lecture 1 2 1 22/01/1446 Introduction 3 Chemistry of Natural Products  What are natural products?  Natural products are chemical compounds produced by a living organism.  What is Phytochemistry?  Why are natural products important?  Importance: food, perfumes, colouring agents, therapeutic agents. 4 2 22/01/1446 Drug Discovery  Why is the process of drug discovery and drug development continuous?  Because of: 1. The emergence of new life threatening infections, cancers and diseases. 2. Drug resistance.  What else do you think? 5 Drug Discovery 1. Rational drug design: tailoring.  A drug is tailored to fit its suggested target. 6 3 22/01/1446 Drug Discovery 2. Combinatorial chemistry.  Combinatorial chemistry: a huge number of compounds is prepared in silico to form a combinatorial library, which, in turn, is tested against the suggested target to determine the most potent and active 7 compounds. Drug Discovery 3. Natural Products. 8 4 22/01/1446 Classification of Natural Products Natural Products Primary Secondary metabolites metabolites 9 Primary Metabolites  Primary metabolites are compounds produced by a living organism that are essential for its life and growth.  They are derived from sugars via primary metabolic pathways and include: sugars, lipids, amino acids, peptides and proteins. 10 5 22/01/1446 Primary Metabolites Primary metabolic pathway of Carbon Primary metabolic CO2 photosynthesis products sugars carbohydrates Erythrose glycolysis PO4 phosphoenolpyruvate shikimic acid aromatic amino acids proteins pyruvate aliphatic amino acids acetyl-CoA Malonyl-CoA Fatty acids (lipids) tricarboxylic acid cycle CO2 isoprene 11 squalene Primary Metabolites starch cellulose 12 phospholipid 6 22/01/1446 Secondary Metabolites  Secondary metabolites are low molecular weight compounds that are not required for the growth of an organism, but are produced for adaptation for its specific functions in nature and are considered a phenotype of the organism.  They are derived from primary metabolites via secondary metabolic pathways.  They are more important than primary metabolites as a therapeutic agents. 13 Secondary Metabolites Primary metabolic Primary metabolic Secondary metabolic pathway of Carbon products products CO2 photosynthesis Glycosides carbohydrates Complex polysaccharides sugars Aminoglycosides antibiotics Erythrose glycolysis PO4 Phenyl propanoids phosphoenolpyruvate shikimic acid Alkaloids aromatic amino acids Peptides proteins pyruvate aliphatic amino acids Penicillins cephalosporins acetyl-CoA Malonyl-CoA Fatty acids (lipids) Erythromycins Tetracyclins tricarboxylic acid cycle anthraquinones Terpenoids CO2 isoprene 14 steroids squalene 7 22/01/1446 Secondary Metabolites digoxin morphine aspirin penicillin 15 Secondary Metabolites  Digoxin: cardiotonic, from foxglove (Digitalis lanata).  Morphine: pain killer, from opium (Papaver somniferum). This is generally believed to be the first isolation of an active ingredient from a plant.  Aspirin: painkiller and anti-infalmmatory, from willow (Salix spp).  Penicillin: antibiotic, from (Penicillium spp). 16 8 22/01/1446 The importance of NPs in drug discovery  Misconceptions about natural products: 1. Natural products are old fashioned and incompatible with the latest technologies that are utilised in drug discovery and those that are based on high-throughput screening directed at molecular targets. 2. The overestimation of the difficulties of isolating and purifying natural products from their origin. 17 The importance of NPs in drug discovery 18 9 22/01/1446 The importance of NPs in drug discovery  B Biological macromolecule.  N Unaltered natural product.  NB Botanical drug (defined mixture).  ND Natural product derivative.  S Synthetic drug.  S* Synthetic drug (NP pharmacophore).  V Vaccine.  /NM Mimic of natural product. 19 The importance of NPs in drug discovery 20 10 22/01/1446 The importance of NPs in drug discovery  1. Natural products possess structural diversity that makes them suitable for lots of targets and receptors as well as appropriate models for drug design. penicillin 21 The importance of NPs in drug discovery  2. NPs have a wide range of pharmacophores and a vastness of stereochemistry, which enable them to provide hits against screening targets, even for the more difficult protein-protein interactions 22 11 22/01/1446 The importance of NPs in drug discovery  3. NPs have the advantage of being good substrates for many cellular transporter systems which give them the ability to act intracellularly.  4. NPs cover parts of the chemical space that are not represented by synthetic compounds.  5. On average, NPs are more readily absorbed from the gastrointestinal tract than synthetic drugs when they conform to the Lipinski's rule of five. 23 Lipinski’s rule of five  An orally active drug should has no more than one violation of the following criteria: 1. No more than 5 hydrogen bond donors. 2. No more than 10 hydrogen bond acceptors. 24 12 22/01/1446 Lipinski’s rule of five 25 Lipinski’s rule of five  An orally active drug should has no more than one violation of the following criteria: 1. No more than 5 hydrogen bond donors. 2. No more than 10 hydrogen bond acceptors. 3. A molecular mass less than 500 daltons. 4. An octanol-water partition coefficient (log P) not greater than 5. 26 13 22/01/1446 Lipinski’s rule of five 27 In this course  We studied primary metabolites in biochemistry, that included: carbohydrates, lipids, peptides.  In Phytotherapy and natural products chemistry (1) and (2), secondary metabolites will be covered. They include the products of: 1. Acetate pathway. 2. Shikimate pathway. 3. Mevalonate and methylerythritol phosphate pathway. 4. Alkaloids. 5. Non-ribosomal peptides and some ribosomal peptides. 28 14 22/01/1446 In this course 29 Phytotherapy and natural products chemistry (1) Lecture 2 30 15 22/01/1446 The Building Blocks and Construction Mechanisms 31 The Building Blocks and Construction Mechanisms The Building Blocks 32 16 22/01/1446 The Building Blocks 33 The Building Blocks 34 17 22/01/1446 Remember: Photosynthesis: Dark reactions 3 C’s 15 C’s ribulose 1,5 bisphosphate 6 x 3 = 18 C’s 3-phosphoglyceric acid RuBisCO: Ribulose- 1,5-bisphosphate 6 x 3 = 18 C’s carboxylase/oxygen glyceraldehyde 3-phosphate 35 ase. Remember: Aerobic respiration: Krebs cycle 36 18 22/01/1446 The Building Blocks 37 The Building Blocks 38 19 22/01/1446 The Building Blocks 39 The Building Blocks 40 20 22/01/1446 The Building Blocks 41 The Building Blocks 42 21 22/01/1446 The Building Blocks and Construction Mechanisms Acidity 43 Acidity 44 22 22/01/1446 The Building Blocks and Construction Mechanisms Alkylation Reactions: Nucleophilic Substitution 45 Remember 46 23 22/01/1446 Remember 47 Remember 3 3 1 4 1 2 4 2 S R Nucleophilic substitution type 2: SN2 48 24 22/01/1446 Remember 49 Remember 4 4 1 1 2 3 2 3 R R Nucleophilic substitution type 1: SN1 50 25 22/01/1446 Alkylation Reactions: Nucleophilic Substitution  Formation of SAM: 51 Alkylation Reactions: Nucleophilic Substitution 52 26 22/01/1446 The Building Blocks and Construction Mechanisms Wagner-Meerwein Rearrangements 53 Wagner-Meerwein Rearrangements 54 27 22/01/1446 The Building Blocks and Construction Mechanisms Water solubility 55 Water solubility 𝛿- 𝛿- 𝛿+ 𝛿+ 𝛿+ 𝛿+ 𝛿+ 𝛿- 𝛿+ 𝛿- 𝛿+ 𝛿+ 𝛿- 𝛿+ 𝛿- 56 28 22/01/1446 Phytotherapy and natural products chemistry (1) Lecture 3 57 The Building Blocks and Construction Mechanisms Acetals and ketals formation 58 29 22/01/1446 Hemiacetal formation 59 Hemiacetal formation 60 30 22/01/1446 Hemiaketal formation 61 Hemiaketal formation 62 31 22/01/1446 The Building Blocks and Construction Mechanisms Imine Formation 63 Imine Formation 64 32 22/01/1446 The Building Blocks and Construction Mechanisms Transamination 65 Transamination 66 33 22/01/1446 Transamination 67 Transamination 68 34 22/01/1446 Transamination 69 The Building Blocks and Construction Mechanisms Oxidation and Reduction Reactions 70 35 22/01/1446 Oxidation and Reduction Reactions  What is oxidation?  What is reduction?  What do we mean by saying “oxidising agent” or “reducing agent”? 71 Oxidation and Reduction Reactions 72 36 22/01/1446 Oxidation and Reduction Reactions  Cofactors/Coenzymes: 1. NAD+: Nicotineamide adenine dinucleotide. 2. NADP+: Nicotineamide adenine dinucleotide phosphate. 3. FAD: Flavin adenine dinucleotide. 73 Oxidation and Reduction Reactions 74 37 22/01/1446 The Building Blocks and Construction Mechanisms Ester formation 75 Ester formation 76 38 22/01/1446 The Building Blocks and Construction Mechanisms Amide formation 77 Amide formation 78 39 22/01/1446 Phytotherapy and natural products chemistry (1) Lecture 4 79 The Acetate Pathway Aldol and Claisen Reactions 80 40 22/01/1446 Aldol and Claisen Reactions 81 Aldol and Claisen Reactions 82 41 22/01/1446 Aldol and Claisen Reactions 83 Aldol and Claisen Reactions 84 42 22/01/1446 Aldol and Claisen Reactions O S O O O S 85 Aldol and Claisen Reactions 86 43 22/01/1446 Aldol and Claisen Reactions 87 Aldol and Claisen Reactions 88 44 22/01/1446 Aldol and Claisen Reactions 89 Aldol and Claisen Reactions 90 45 22/01/1446 Aldol and Claisen Reactions 91 Aldol and Claisen Reactions Theo-ester Poly-B-keto-theo-ester Poly-B-keto-ester Polyketide 92 46 22/01/1446 Aldol and Claisen Reactions Polyketide synthase: polyketides 93 Aldol and Claisen Reactions 94 47 22/01/1446 Phytotherapy and natural products chemistry (1) Lecture 5 95 The Acetate Pathway Macrolides 96 48 22/01/1446 Macrolides Introduction 97 The Acetate Pathway Polyketide synthase: polyketides 98 49 22/01/1446 Macrolides  What are they? 1. A large family of compounds. 2. Characterised by a macrocyclic lactone (sometimes lactam) ring. 3. Rings are usually 12-, 14, or 16- membered. 4. Many of them have antibiotic activity. 5. Extensive branching. Why? 6. Glycosides (6-deoxysugars, aminosugars). 99 Macrolides Erythromycins 100 50 22/01/1446 Eryhtromycins  They were first isolated from Saccharopolyspora erythraea (formly known as Streptomyces erythraeus). 101 Eryhtromycins Propionyl CoA Methylmalonyl CoA Lactonisation 102 51 22/01/1446 6-deoxysugars: Usually restricted to macrolide antibiotics 103 Eryhtromycins  The commercial erythromycin is mixture of erythromycins A, B and C. 104 52 22/01/1446 Eryhtromycins  What are the applications of erythromycin? 1. It is active against Gram-positive bacteria. 2. Mainly prescribed for penicillin- allergic patients. 3. It is used against penicillin-resistant Staphylococcus strains. 4. It is used systemically for skin conditions such as acne. 5. It is the antibiotic of choice for infections of Legionella pneumophila, the cause of legionnaire’s disease: 105 (‫مى الفَيلَق‬ ُ ‫داء الفيالقة أو‬: severe ّ ‫ح‬ form of pneumonia) Eryhtromycins  What is the mechanism of action of erythromycins?  It binds reversibly to the larger 50S subunit of bacterial ribosomes and blocks the translocation step in which the growing peptidyl-tRNA moves from the aminoacyl acceptor site to the peptidyl donor site on the 106 ribosome. 53 22/01/1446 Eryhtromycins Unstable in acid conditions Responsible for GI side effects Thus, it is usually formulated as 107coated tablets or insoluble enteric esters (ethyl succinate esters). Has no significant antibacterial activity Eryhtromycins 108 54 22/01/1446 Eryhtromycins  Semi-synthetic derivatives of erythromycin: 1. Clarithromycin. 2. Azithromycin. 109 Eryhtromycins A ring expanded aza-macrolide 110 55 22/01/1446 Eryhtromycins  What are the mechanism of bacterial resistance to erythromycins? 1. Change in permeability of the bacterial cell wall.  Why are erythromycins inactive against Gram-negative bacteria? 2. Modifying the chemical nature of the binding site on the ribosome. 3. Metabolising the macrolide ring to yield inactive products. 111 Eryhtromycins  Ketolides (semi-synthetics) are developed to overcome the bacterial resistance of erythromycins. Carbamic acid 112 56 22/01/1446 Eryhtromycins 113 Phytotherapy and natural products chemistry (1) Lecture 6 114 57 22/01/1446 The Acetate Pathway Macrolides 115 Macrolides Polyene Antifungals 116 58 22/01/1446 Polyene Antifungals  The macrolide ring size ranges from 26 to 38 atoms.  They are characterised by a conjugated polyene of up to seven E double bonds.  They are classified according to the longest conjugated chain present: heptaene, tetraene,.. etc. 117 Polyene Antifungals  The polyenes are relatively unstable, undergoing light-catalysed decomposition. Why?  They are also effectively insoluble in water. Why?  This insolubility actually protects the antibiotic from gastric decomposition, allowing oral treatment of infections in the intestinal tract. 118 59 22/01/1446 Polyene Antifungals  Amphotericin B is isolated from Streptomyces nodosus.  Nystatin A1 from Streptomyces noursei. 119 Polyene Antifungals Acetyl CoA Malonyl CoA Methylmalonyl CoA Relatively few methyl groups are attached to the ring, and thus malonyl-CoA is utilised more frequently than methylmalonyl-CoA as chain extender. Glycosylation Glycosylation 120 Nystatin 60 22/01/1446 Polyene Antifungals  What is the mechanism of action of polyene antifungals?  Their activity is a result of binding to sterols in the eukaryotic cell membrane.  This binding modifies the cell wall permeability and leads to formation of transmembrane pores that allow K+, Na+, Ca2+ ions, sugars, and proteins to be lost from the microorganism. 121 Polyene Antifungals  Why are they inactive against bacteria?  Because bacterial cells do not contain sterol components.  Since they bind to sterols in the eukaryotic cell membrane, how could they be used clinically?  Fungal cells are attacked rather than mammalian cells because the antibiotics bind about 10-fold more strongly to ergosterol, the major fungal sterol, than to cholesterol, the main animal sterol component.  Though binding to cholesterol is less than to ergosterol, it is responsible for the observed toxic side-effects of these agents on humans. 122 61 22/01/1446 Polyene Antifungals  Amphotericin is an antifungal polyene produced by cultures of Streptomyces nodosus and contains principally the heptaene amphotericin B together with structurally related compounds, e.g. the tetraene amphotericin A (about 10%).  Amphotericin A is much less active than amphotericin B. 123 Polyene Antifungals  Amphotericin is active against most fungi and yeasts.  However, it is not absorbed from the gut.  Thus, so oral administration is restricted to the treatment of intestinal candidiasis. 124 62 22/01/1446 Polyene Antifungals  It is administered intravenously for treating potentially life- threatening systemic fungal infections.  However, it then becomes highly protein bound.  This results in poor penetration and slow elimination from the body.  After parenteral administration, toxic side-effects, including nephrotoxicity, are relatively common and close supervision is neccessary.  Lipid formulations of amphotericin are much less toxic and have proven a significant advance.  Candida infections in the mouth or on the skin may be treated with appropriate formulations.  More recently, amphotericin has been shown to be among the few125 agents that can slow the course of prion disease in animal models. Polyene Antifungals  Nystatin A1 is the principal component in the commercial form of nystatin that also contains nystatin A2 and A3 that have additional glycoside residues.  Nystatin is too toxic for intravenous use.  It has value for oral treatment of intestinal candidiasis, as lozenges for oral infections, and as creams for topical control of Candida species. 126 63 22/01/1446 Macrolides Ascomycin and Tacrolimus 127 Ascomycin and Tacrolimus  These compounds contain a 23-membered macrolactone that also incorporates an N-heterocyclic ring.  They are identical apart from the substituent at C-21. 128 64 22/01/1446 Ascomycin and Tacrolimus 129 Ascomycin and Tacrolimus 130 65 22/01/1446 Ascomycin and Tacrolimus  Ascomycin is obtained by fermenting Streptomyces hygroscopicus.  It has strong immunosuppressant properties.  It has been researched for the treatment of autoimmune diseases, skin diseases, and to prevent organ rejection after organ transplant surgeries. 131 Ascomycin and Tacrolimus  Tacrolimus is obtained by fermenting Streptomyces tsukubaensis. 132 66 22/01/1446 Ascomycin and Tacrolimus  Tacrolimus is used in liver and kidney transplant surgery.  Both tacrolimus and cyclosporine A share the same mode of action. 133 Ascomycin and Tacrolimus  Both tacrolimus and cyclosporine A inhibit T-cell activation in the immunosuppressive mechanism by binding first to a receptor protein, giving a complex which then inhibits a phosphatase enzyme called calcineurin.  The resultant aberrant phosphorylation reactions prevent appropriate gene transcription and subsequent T-cell activation. 134 67 22/01/1446 Ascomycin and Tacrolimus  However, tacrolimus is 100 times more potent than cyclosporine A.  Both drugs produce similar side-effects, including neurotoxicity and nephrotoxicity.  Tacrolimus is also used topically to treat moderate to severe atopic eczema.  The ascomycin derivative pimecrolimus is also used for mild to moderate conditions. 135 Phytotherapy and natural products chemistry (1) Lecture 7 136 68 22/01/1446 The Acetate Pathway Macrolides 137 Macrolides Sirolimus 138 69 22/01/1446 Sirolimus  Sirolimus is also called rapamycin. 139 Sirolimus 140 70 22/01/1446 Sirolimus  Like ascomycin, sirolimus is obtained by fermenting Streptomyces hygroscopicus. 141 Sirolimus 142 71 22/01/1446 Sirolimus  Like tacrolimus and cyclosporine A, sirolimus is an immunosuppressant drug and it is used for organ transplant surgeries.  However, it doesn’t share their mechanism of action.  Everolimus is a semi-synthetic derivative of sirolimus with better oral bioavailability now available for kidney and heart transplants. 143 Sirolimus  Another semi-synthetic derivative is zotarolimus.  It inhibits cell proliferation, preventing scar tissue formation following cardiovascular surgery; this agent is delivered via a coronary stent.  Temsirolimus is another semi-synthetic derivative that is now approved for treatment of renal cell carcinoma.  Deforolimus is in advanced clinical trials against a variety of cancers. 144 72 22/01/1446 Macrolides Rifamycins 145 Rifamycins  The rifamycins are ansamycin antibiotics produced by cultures of Amycolatopsis mediterranei (formerly Nocardia mediterranei or Streptomyces mediterranei).  Ansa macrolides: these have non-adjacent positions on an aromatic ring bridged by a long aliphatic chain (Latin: ansa = handle). 146 73 22/01/1446 Rifamycins deoxy-d-arabino-heptulosonic acid 7-phosphate 147 Rifamycins  Rifamycin B has essentially no antibacterial activity, but may be converted chemically, enzymically, or by biotransformation into rifamycin SV, a highly active antibacterial agent, and the first rifamycin to be used clinically.  Further chemical modifications of rifamycin SV have produced better clinically useful drugs. 148 74 22/01/1446 Rifamycins  Rifampicin:  The most widely used rifamycin and a semi-synthetic derivative.  It inhibits the bacterial RNA synthesis. 149 Rifamycins  Rifampicin has a wide antibacterial spectrum, with high activity towards Gram-positive bacteria and a lower activity towards Gram- negative organisms.  Its most valuable activity is towards Mycobacterium tuberculosis, and rifampicin is a key agent in the treatment of tuberculosis, usually in combination with at least one other drug to reduce the chances for development of resistant bacterial strains.  It is also useful in control of meningococcal meningitis and leprosy )‫(الجذام‬. 150 75 22/01/1446 Rifamycins  Rifabutin has good activity against the Mycobacterium avium complex frequently encountered in patients with AIDS.  Rifapentine has a longer duration of action than the other anti-tubercular rifamycins. 151 Phytotherapy and natural products chemistry (1) Lecture 8 152 76 22/01/1446 The Acetate Pathway Linear Polyketides and Polyethers 153 Linear Polyketides and Polyethers Statins 154 77 22/01/1446 Statins  What are statins?  Statins are a class of drugs that help lower cholesterol levels in the blood. 155  How do they work? Statins  Lovastatin is produced by Monascus ruber and Aspergillus terreus. 156 78 22/01/1446 Statins  Lovastatin was the first statin to be marketed, but has since been superseded by more active agents. 157 Statins 158 79 22/01/1446 Statins 159 Statins  Simvastatin is obtained from lovastatin by ester hydrolysis and then re- esterification.  It is two to three times as potent as lovastatin.  Lovastatin and simvastatin are both lactones, but at physiological pHs they exist in equilibrium with the open-ring hydroxy acids; only160the open-ring form is biologically active. 80 22/01/1446 Statins  Pravastatin is prepared from mevastatin (isolated from Penicillium citrinum and Penicillium brevicompactum) by microbiological hydroxylation using Streptomyces carbophilus.  It is consequently more hydrophilic than the other drugs, with an activity similar to lovastatin. 161 Statins  Other agents currently in use are synthetic.  Though, they feature the same 3,5-dihydroxycarboxylic acid side- chain as in pravastatin.  Atorvastatin, fluvastatin, and rosuvastatin have all been introduced recently, and others are in development. 162 81 22/01/1446 Statins 163 Statins  What is the mechanism of action of statins? 164 82 22/01/1446 Statins β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) 165 Statins 166 83 22/01/1446 Statins  Statin drugs work by blocking the action of the liver enzyme HMG-CoA reductase that is responsible for producing cholesterol.  High blood cholesterol levels contribute to the incidence of coronary heart disease, so statins are of potential value in treating high-risk coronary patients, and several agents are already in use.  As the liver synthesises less cholesterol, this in turn stimulates the production of high-affinity LDL receptors on the surface of liver cells.  Consequently, the liver removes more LDL from the blood, leading to the reduction of blood levels of both LDL and cholesterol. 167 Statins 168 84 22/01/1446 Statins 169 Phytotherapy and natural products chemistry (1) Lecture 9 170 85 22/01/1446 The Acetate Pathway Aromatic Polyketides 171 Aromatic Polyketides Introduction 172 86 22/01/1446 In the absence of any reduction processes, Aromatic Polyketides the growing poly-β-keto chain needs to be stabilised on the enzyme surface until the chain length is appropriate, at which point cyclisation or other reactions can occur. 173 Aromatic Polyketides  A poly-β-keto ester is very reactive, and there are various possibilities for undergoing intramolecular Claisen or aldol reactions, dictated of course by the nature of the enzyme and how the substrate is folded.  Methylenes flanked by two carbonyls are activated, allowing formation of carbanions/enolates and subsequent reaction with ketone or ester carbonyl groups, with a natural tendency to form strain-free six- membered rings. 174 87 22/01/1446 Aromatic Polyketides δ- δ- δ- δ- δ- - - - - δ+ δ+ δ+ δ+ δ+ 175 176 88 22/01/1446 Aromatic Polyketides  A distinctive feature of an aromatic ring system derived through the acetate pathway is that several of the carbonyl oxygens of the poly-β- keto system are retained in the final product.  These end up on alternate carbon atoms around the ring system: a meta oxygenation pattern.  This meta oxygenation pattern contrasts with that seen on aromatic rings formed via the shikimate pathway. 177 Aromatic Polyketides Anthraquinones 178 89 22/01/1446 Anthraquinones  What are anthraquinones? 179 180 90 22/01/1446 Anthraquinones  Emodin is a metabolite of Penicillium species and also found in higher plants like Rhamnus )‫ (النبق‬and Rumex )‫ (الحميض‬species.  It is used as laxative. 181 Anthraquinones  Aloe-emodin is found in Aloe vera, Rhamnus spp., Senna and rhubarb.  It is also used as laxative. 182 91 22/01/1446 Anthraquinones  A semi-synthetic compound.  It is also used as laxative. However, its use is limited these days. 183 Anthraquinones  A semi-synthetic compound.  An antineoplastic, used in the treatment of cancer. 184 92 22/01/1446 Anthraquinones  The free anthraquinones themselves have little therapeutic activity and need to be in the form of water-soluble glycosides to exert their action.  Although simple anthraquinone O-glycosides are present in the drugs, the major purgative action arises from compounds such as sennosides. 185 Anthraquinones 186 93 22/01/1446 Anthraquinones 187 Anthraquinones 188 94 22/01/1446 Anthraquinones  The active constituents in both )‫ (السنا‬senna (Cassia Leguminosae, Cassia angustifolia, Cassia acutifolia, Cassia Alexandria) leaf and fruit are dianthrone glycosides, principally sennosides A and B. 189 Anthraquinones  After oral administration, the sennosides are transformed by intestinal flora into rhein anthrone which appears to be the ultimate purgative principle.  The glycoside residues in the active constituents are necessary for water solubility and subsequent transportation to the site of action. 190 95 22/01/1446 Anthraquinones Hyp-1 191 Anthraquinones  Components of St John’s Wort: )‫ عرن مثقوب‬،‫ )نبتة القديس يوحنا‬Hypericum perforatum.  It have been used for many years for its antiseptic and wound healing properties.  It is now widely used as antidepressant: Inhibitor of amine reuptake (such as serotonin). 192  However, it interacts with many drugs. 96 22/01/1446 Anthraquinones 193 194 97 22/01/1446 Phytotherapy and natural products chemistry (1) Lecture 10 195 The Acetate Pathway Aromatic Polyketides 196 98 22/01/1446 Aromatic Polyketides Tetracyclines 197 Tetracyclines  The tetracyclines are a group of broad-spectrum antibiotics produced by species of Streptomyces.  They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA. 198 99 22/01/1446 Tetracyclines 199 Tetracyclines 200 100 22/01/1446 201 Tetracyclines  Tetracyclines have both amino and phenolic functions, and are thus amphoteric compounds.  They are more stable in acid than under alkaline conditions.  They are thus suitable for oral administration and are absorbed satisfactorily.  However, because of the sequence of phenol and carbonyl substituents in the structures, they act as chelators and complex with metal ions, especially calcium, aluminum, iron, and magnesium. 202 101 22/01/1446 Tetracyclines  Chelation of tetracyclines with calcium also precludes their use in children developing their adult teeth, and in pregnant women, since the tetracyclines become deposited in growing teeth and bone.  In children, this would cause unsightly and permanent staining of teeth with the chelated yellow tetracycline. 203 Tetracyclines  Their antimicrobial activity arises by inhibition of protein synthesis.  This is achieved by interfering with the binding of aminoacyl-tRNA to acceptor sites on the ribosome by disrupting the codon–anticodon interaction. 204 102 22/01/1446 Tetracyclines  Only minor alterations can be made to the basic tetracycline structure to modify the antibiotic activity, and these are at positions 5, 6, and 7.  Other functionalities in the molecule are all essential to retain activity. 205 Tetracyclines  Tetracyclines are the antibiotics of choice for infections caused by Chlamydia, Mycoplasma, Brucella, and Rickettsia, and are valuable in chronic bronchitis due to activity against Haemophilus influenzae.  They are also used systemically to treat severe cases of acne, helping to reduce the frequency of lesions by their effect on skin flora.  Tetracycline and oxytetracycline are probably the most commonly prescribed agents, whilst chlortetracycline and methacycline have both been superseded. 206 103 22/01/1446 Tetracyclines  There is little significant difference in the antimicrobial properties of the various agents, except for minocycline.  Minocycline which has a broader spectrum of activity and, being active against Neisseria meningitides, is useful for prophylaxis of meningitis. 207 Tetracyclines  Doxycycline is the agent of choice for treating Lyme disease (caused by the spirochaete Borellia burgdorferi), and also finds use as a prophylactic against malaria in areas where there is widespread resistance to chloroquine and mefloquine. 208 104 22/01/1446 Tetracyclines  Although the tetracycline antibiotics have a broad spectrum of activity spanning Gram-negative and Gram-positive bacteria, their value has decreased as bacterial resistance has developed in pathogens such as Pneumococcus, Staphylococcus, Streptococcus, and E. coli.  These organisms appear to have evolved two main mechanisms of resistance: 1. Bacterial efflux: a membrane-embedded transport protein exports the tetracycline out of the cell before it can exert its effect. 2. Ribosome protection: it releases tetracyclines from the ribosome. 209 Tetracyclines  A new generation of tetracyclines known as glycylcyclines has been developed to counter resistance and provide higher antibiotic activity.  The first of these in general use is tigecycline, a semi-synthetic derivative of minocycline. 210 105 22/01/1446 Aromatic Polyketides Anthracyclines 211 Anthracyclines  Like tetracyclines, anthracyclines are produced by species of Streptomyces.  A number of anthracyclines have structurally similar tetracyclic skeletons.  Thus, they would appear to be related to the tetracyclines.  However, anthraquinone derivatives are intermediates in anthracycline biosynthesis, and the fourth ring is constructed later. 212 106 22/01/1446 Anthracyclines  Many Anthracyclines have antitumor porperties.  How do they work?  The planar anthracycline molecule intercalates between base pairs on the DNA helix.  The sugar unit provides further binding strength and also plays a major role in sequence recognition for the binding.  Thus, they inhibit the enzyme topoisomerase II, which is responsible for cleaving and resealing of double-stranded DNA during replication. 213 Anthracyclines 214 107 22/01/1446 Anthracyclines 215 Anthracyclines 216 108 22/01/1446 Anthracyclines  Doxorubicin (adriamycin) is produced by cultures of Streptomyces peucetius var caesius.  It is one of the most successful and widely used antitumour drugs.  It has one of the largest spectrum of antitumour activity shown by antitumour drugs and is used to treat acute leukaemias, lymphomas, and a variety of solid tumours.  Common toxic effects include nausea and vomiting, bone marrow suppression, hair loss, and local tissue necrosis, with cardiotoxicity at higher dosage as a result of inhibiting cardiac Na+, K+ ATPase. 217 Anthracyclines  Daunorubicin is produced by Streptomyces coeruleorubidus and Streptomyces peucetius.  It is similar to doxorubicin in its biological and chemical properties.  However, it is no longer used therapeutically to any extent.  It has a much less favourable therapeutic index than doxorubicin.  Moreover, the markedly different effectiveness as an antitumour drug is not fully understood. 218 109 22/01/1446 Anthracyclines  Epirubicin is the semi-synthetic epimer of doxorubicin.  It is very effective in the treatment of breast cancer.  It produces lower side-effects than doxorubicin. 219 Anthracyclines  Aclarubicin (from Streptomyces galilaeus) and idarubicin (semi-synthetic) are structurally related to doxorubicin but can show increased activity with less cardiotoxicity.  They are used in the treatment of leukaemia. 220 110 22/01/1446 Anthracyclines  Mitoxantrone (mitozantrone) is a synthetic analogue of the anthracyclinones in which the non-aromatic ring and the aminosugar have both been replaced with aminoalkyl side-chains.  It has reduced toxicity compared with doxorubicin.  It is effective in the treatment of solid tumours and leukaemias.  In addition, it is currently proving useful in multiple sclerosis 221 treatment. Remember - Anthraquinones  A semi-synthetic compound.  An antineoplastic, used in the treatment of cancer. 222 111 22/01/1446 Anthracyclines  Synthetics, still in clinical trials. 223 Phytotherapy and natural products chemistry (1) Lecture 11 224 112 22/01/1446 The Shikimate Pathway Introduction 225 The Shikimate Pathway  Shikimic acid is isolated from plants of Illicium species (Japanese ‘shikimi’, Japanese star anise). 226 113 22/01/1446 Remember – The Building Blocks 227 3-deoxy-D-arabino-heptulosonic acid 7-phosphate 228 114 22/01/1446 The Shikimate Pathway Benzoic acids 229 The Shikimate Pathway – Benzoic acids 230 115 22/01/1446 116 22/01/1446 Benzoic Acids  It can arise in plants by two mechanisms: 1. It can be produced by hydroxylation of benzoic acid: 2. Or by side-chain cleavage of 2-coumaric acid, which itself is formed by an ortho-hydroxylation of cinnamic acid. 233 Benzoic Acids 234 117 22/01/1446 Benzoic Acids  Methyl salicylate is the principal component of oil of wintergreen from Gaultheria procumbens.  It was used for many years for pain relief. 235 Benzoic Acids  Salicin is found in many species of willow (Salix species).  It is responsible for the analgesic and antipyretic effects of willow barks, widely used for centuries. 236 118 22/01/1446 Benzoic Acids  Salicin provided the template for the synthesis of acetylsalicylic acid (aspirin).  Acetylsalicylic acid is more effective.  It is a widely used pain-killer. 237 Phytotherapy and natural products chemistry (1) Lecture 12 238 119 22/01/1446 The Shikimate Pathway Phenylpropanoids 239 Phenylpropanoids  The shikimate pathway provides an alternative route to aromatic compounds.  This includes particularly the aromatic amino acids phenylalanine, tyrosine, and tryptophan.  This pathway is employed by microorganisms and plants, but not by animals. 240 120 22/01/1446 Phenylpropanoids  Phenylalanine and tyrosine form the basis of C6C3 phenylpropane units found in many natural products, e.g. cinnamic acids, coumarins, lignans, and flavonoids, and along with tryptophan are precursors of a wide range of alkaloid structures. 241 Phenylpropanoids 242 121 22/01/1446 Phenylpropanoids  These compounds are volatile oils. 243 Phenylpropanoids  Fixed oils are non-volatile oils of animal or plant origin. Fixed oil Volatile oil Also called as a non-volatile oil Also called as an essential oil do not evaporate at room temperature evaporate at room temperature They require some specific techniques for extraction can be extracted easily by the distillation process Some type of spot (permanent stain) left after There is no spot (no permanent stain) left after evaporation evaporation Fixed oils can be easily sponified They are unable to undergo saponification Esters of higher fatty acids & glycerol (glycerin) are Are either terpenoids or phenylpropanoids called as fixed oils (products of acetate pathway) These are optically inactive These are optically active Their major source is seeds of the plant Their primary source is leaves, roots, petals and bark 244 122 22/01/1446 Phenylpropanoids 245 Phenylpropanoids 246 123 22/01/1446 Phenylpropanoids  Cinnamaldehyde is the principal component in the oil from the bark of cinnamon (Cinnamomum zeylanicum).  It is widely used as a spice and flavouring.  Fresh bark is known to contain high levels of the ester cinnamyl acetate.  Cinnamaldehyde is released from this by fermentation processes which are part of commercial preparation of the bark. 247 Phenylpropanoids  Eugenol is also the principal constituent in oil from cloves (Syzygium aromaticum).  It was used for many years as a dental anaesthetic as well as for flavouring. 248 124 22/01/1446 Phenylpropanoids 249 Phenylpropanoids  Myristicin from nutmeg (Myristica fragrans) is a further example of an allylphenol found in flavouring materials.  Myristicin also has a history of being employed as a mild hallucinogen via ingestion of ground nutmeg.  It is probably metabolised in the body via an amination reaction to give an amfetamine-like derivative. 250 125 22/01/1446 Phenylpropanoids  Anethole is the main component in oils from aniseed (anise, Pimpinella anisum), star anise (Illicium verum) and fennel (Foeniculum vulgare).  It is used as a flavouring agent, carminative and in aromatherapy. 251 Phenylpropanoids 252 126 22/01/1446 Phenylpropanoids 253 Phenylpropanoids 254 127 22/01/1446 The Shikimate Pathway Aromatic polyketides 255 Aromatic Polyketides Introduction 256 128 22/01/1446 Aromatic Polyketides  Cinnamic acids, as their coenzyme A esters, may also function as starter units for chain extension with malonyl-CoA units via Polyketide synthases.  Thus, combining elements of the shikimate and acetate pathways.  Most commonly, three C2 units are added via malonate, giving rise to flavonoids and stilbenes. 257 Chalcones and Stilbenes  What are chalcones and stilbenes? 258 129 22/01/1446 6, 3nd extender 4, 2nd extender Carbonyl of cinnamoyl 2, 1st extender 3, 2nd extender 3, 2nd extender 5, 3rd extender 1, 1st extender 259 Chalcones and Stilbenes  Resveratrol is a polyphenol produced by many plants like grapes, blueberries, raspberries, mulberries, and peanuts.  It has antioxidant properties and has been identified as a pan- assay interference compound, which produces positive results in many different laboratory assays.  It’s gained a lot of attention for its reported anti-aging and disease-fighting powers. However, more research is needed to confirm this. 260 130 22/01/1446 Chalcones and Stilbenes  Resveratrol is now used as a dietary supplement for: 1. Heart disease: It’s thought to help reduce inflammation, lower LDL or "bad" cholesterol. 2. Cancer: It could limit the spread of cancer cells and start killing them. 3. Alzheimer's: It may protect nerve cells from damage and fight the plaque buildup that can lead to the disease. 4. Diabetes: It helps prevent insulin resistance.  Researchers believe that resveratrol activates the SIRT1 gene. That gene is believed to protect the body against the effects of obesity and the 261 diseases of aging. Aromatic Polyketides Styrylpyrones, Diarylheptanoids 262 131 22/01/1446 Styrylpyrones, Diarylheptanoids  Styrylpyrones are formed from a cinnamoyl-CoA and two malonyl- CoA extender units. 263 Styrylpyrones, Diarylheptanoids  Components of Piper methysticum (Kava kava).  It was used as intoxicating agent in folk medicine.  But now it is used for anxiety, nervous tension, agitation, and insomnia. 264 132 22/01/1446 265 Styrylpyrones, Diarylheptanoids  Curcumin is diarylheptanoid.  It is a constituent of turmeric (Curcuma longa).  It is now attracting considerable interest because of its anti- inflammatory, antiulcer, antitumour, and cancer- preventative properties. 266 133 22/01/1446 Styrylpyrones, Diarylheptanoids  6-Gingerol is a major pungent component in ginger root (Zingiber officinale).  It is widely employed as a flavouring and spice.  Shogaols are dehydrated analogues of gingerols, and tend to be the predominant pungent agents in dried root.  Ginger has useful anti-inflammatory activity due to the gingerols. 267 Aromatic Polyketides Flavonoids and Stilbenes 268 134 22/01/1446 Flavonoids and Stilbenes 269 270 135 22/01/1446 Flavonoids and Stilbenes  Chalcones act as precursors for a vast range of flavonoid derivatives found throughout the plant kingdom.  A high proportion of flavonoids occur naturally as water- soluble glycosides. 271 272 136 22/01/1446 Flavonoids and Stilbenes  Considerable quantities of flavonoids are consumed daily in our vegetable diet.  Some flavonoids are beneficial, acting as antioxidants and giving protection against cardiovascular diseases, certain forms of cancer, and, it is claimed, age-related degeneration of cell components.  Their polyphenolic nature enables them to scavenge injurious radicals such as superoxide and hydroxyl radicals. 273 Flavonoids and Stilbenes  Quercetin in particular is almost always present in substantial amounts in plant tissues.  It is a powerful antioxidant, chelating metals, scavenging radicals, and preventing oxidation of low density lipoprotein. 274 137 22/01/1446 Flavonoids and Stilbenes  Vitamin P:  Rutin: a flavonol glycoside from buckwheat (Fagopyrum esculentum) and rue (Ruta graveolens).  Hesperidin: a flavanone glycoside from Citrus.  Claimed to be of benefit in treating conditions characterised by capillary bleeding. 275 Flavonoids and Stilbenes  Isoflavonoids: 276 138 22/01/1446 Flavonoids and Stilbenes  Phyto-oestrogens:  Phyto-oestrogen is a term applied to non-steroidal plant materials displaying oestrogenic properties.  Preeminent amongst these are isoflavonoids.  These planar molecules mimic the shape and polarity of the steroid hormone estradiol.  They are able to bind to an oestrogen receptor, though their activity is much less than that of estradiol. 277 Flavonoids and Stilbenes  The main food source of isoflavonoids is the soya bean (Glycine max).  Foods rich in isoflavonoids are valuable in countering some of the side-effects of the menopause in women, such as hot flushes, tiredness, and mood swings.  They also help to prevent heart attacks and other cardiovascular diseases, protect against osteoporosis, lessen the risk of breast and uterine cancer, and display significant antioxidant activity which may reduce the risk of Alzheimer’s disease. 278 139 22/01/1446 Flavonoids and Stilbenes  Phenoxodiol:  Semi-synthetic from genistein.  In clinical trials as anti-cancer (against ovarian, prostate and cervical cancers). 279 140