2024 Carbohydrate Drugs PDF

Carbohydrate Drugs Carbohydrates in Pharmacy Karol S. Bruzik October 21-25, 2024 ◆ Carbohydrates: chemistry, structure, function and pharmaceutical applications (3h) ◆ Nucleic Acids as Drug Targets (1h) ◆ Enzymes as Drug Targets (1h) ◆ Membranes and Proteins (1h) ◆ Recep...

Carbohydrate Drugs Carbohydrates in Pharmacy Karol S. Bruzik October 21-25, 2024 ◆ Carbohydrates: chemistry, structure, function and pharmaceutical applications (3h) ◆ Nucleic Acids as Drug Targets (1h) ◆ Enzymes as Drug Targets (1h) ◆ Membranes and Proteins (1h) ◆ Receptors Thermodynamics (4h) “Carbohydrates” associate with what pharmacy application, feature or property? 60  Where Do You Find Carbohydrates in Biology? Energy homeostasis – cellular storage and metabolism monosaccharides – glucose & fructose -linked polysaccharides – glycogen and starch Structural elements of cells and organisms -linked poly-glucose and glycosaminoglycans (cellulose, chitin) Post-translational modification of proteins glycoproteins: O-linked (serine and threonine) protection from proteolysis, solubilization recognition of binding partners Proteoglycans: N-linked (asparagine) specialized functions in tissues Metabolism of xenobiotics Glucuronidation in phase II metabolism Spontaneous protein glycation hemoglobin A1C  Mono- and Oligosaccharides in Pharmacy – I. Topics ◆ Reduced monosaccharides and their applications: osmotic diuretics, laxatives, humectants and thickeners, tweens and spans. ◆  vs  Glycosides: properties and metabolic implications. ◆ Fructose: a sweet reward or a villain. ◆ Artificial sweeteners: the sweeter and the bitter. ◆ Pharmaceutical applications of oligosaccharides: drugs, nutraceuticals and texturizing agents. ◆ Carbohydrate-based drugs: antivirals, antibacterials, adjuvants, vaccines and a “wolf in sheep clothing”.  New Carbohydrate Drugs During 2000-21, 54 carbohydrate drugs were approved for use worldwide including antivirals (10), antibacterials-antihelmintics (9), antidiabetics (8) and anticancer agents (8). By chemistry, the largest group are nucleoside analogs. In the natural products-derived compounds, carbohydrate residues are frequently not directly interacting with the drug target but serve to increase solubility and modify other pharmacokinetic properties, as well as use the natural transmembrane transport mechanisms. Cao et al. Acta Pharm Sin 2022, 10, 3783-821. Physical properties of carbohydrates are derived from their chemical structures Carbohydrates are polar molecules: large number of hydroxyl groups – make HBs with water. Have high solubility in aqueous media, insoluble in organics. Aqueous solutions have high viscosity: suitable for thickeners, and in formulations as syrups and suspensions. Viscosity increases with the number of carbohydrate residues in the molecule but is not strictly additive: raffinose > sucrose > glucose. Viscosity is related to the number of HB the molecule makes with the solvent. Due to high solvation with water, carbohydrates are suitable as humectants and laxatives.  Physical Properties Related to Syrups and Suspending Agents disaccharides Keywords: Molecular size – Solvent accessible area – Hydrodynamic radius – Diffusion coefficient – Viscosity Solvation energy The solvent accessible area and the number of HBs depend on carbohydrate molecular size. Larger carbohydrates are more strongly solvated. Increase in molecular size increases hydrodynamic radius and disaccharides reduces diffusion coefficient. Increase of molecular size increases viscosity. Vviscosity monosaccharides Increase of concentration increases viscosity. Solutions of higher MW carbohydrates have stronger viscosity – concentration dependence. urea Longer-chain carbohydrate oligomers are very viscous, form colloidal dispersions, or become insoluble.  Mono- and some di-saccharides are not suitable as drug formulation excipients due to rapid glycolysis. Pyruvate + 2 NADH + 2 ATP The reason for the rapid metabolic turnover is the presence of the carbonyl group (in the open chain form). To increase their metabolic stability, H2/Pd monosaccharides can be chemically or enzymatically converted into carbohydrate polyols. The product is sugar alcohol (alditol, a polyol). glucose What is the most important functional group present in a monosaccharide that distinguishes it from another “carbohydrate” myo-inositol? OH HO OH O HO OH OH -glucose HO HO OH myo-inositol OH OH C6H12O6 C6H12O6 A. Primary hydroxyl group B. All equatorial hydroxyl groups C. Ether group D. Aldehyde group E. Hemiacetal group  Important Messages Carbohydrates serve important roles in pharmacy. Physical and chemical properties of carbohydrates depend on their chemical structures. Applications of carbohydrate depend on their properties such as molecular weight, stereochemistry of glycoside linkages and rates of metabolism. Carbohydrate can serve as drug formulation excipients: binders, sweeteners, syrups, suspension agents, emulsifiers, texturizers, disintegrators, enteric coatings, formulation modifiers. Carbohydrates can also serve as pharmacologically active ingredients such as laxatives, diuretics, antiviral, antibacterial and anticancer agents, antidiabetics, vaccine adjuvants. Carbohydrate Polyols Derived From Monosaccharides ◆ Glucose (dextrose) forms sorbitol (glucitol) ◆ Mannose forms mannitol ◆ Fructose forms a mixture of mannitol and sorbitol ◆ Xylose forms xylitol ◆ Glyceraldehyde forms glycerol  Sugar Polyols as Drugs and Adjuvants ◆ Mannitol and isosorbide are used as osmotic diuretics. ◆ Glycerol is used as a humectant and thickener, can be nitrated to nitroglycerin. ◆ Sorbitol (glucitol), is used as a laxative, can also be dehydrated to tetrahydrofuran compounds (sorbitans). ◆ Sorbitans are converted to detergents known as spans and tweens (used in drugs formulated as emulsions). ◆ 1,4,3,6-Dianhydro-D-sorbitol (isosorbide) formed by dehydration of sorbitol can be nitrated into isosorbide dinitrate and isosorbide mononitrate (both used in treatment of angina).  Osmotic Diuretics mannitol sorbitol isosorbide ◆ Osmotic diuretics… Prevent reabsorption of water and sodium. Sequester water molecules for hydration. Upon intravenous administration increase osmolarity of blood and draw water from the interstitial spaces. Acts by expanding plasma volume, eventually leading to increase in urine volume. Are slowly metabolized or non-metabolized carbohydrate derivatives. ◆ Osmotic diuretics are mostly used to decrease intracranial (hydrocephalus) and intraocular (glaucoma) pressure. ◆ Mannitol, sorbitol and isosorbide are typical osmotic diuretics (polar, mostly impermeable to cell membranes, not readily metabolized).  Spans and Tweens ◆ Tweens and Spans are hydrophobic isosorbide 1,4-sorbitan derivatives. Product of glucose reduction ◆ Spans and tweens are mild detergents used in biochemical and O pharmaceutical preparations. O O R O R O O w ◆ Used in eye drops and vaccines. OHO O (OC2H4)xOH Polysorbate 80 is an excipient used to HO OH HO(C2H4O)z (OC2H4)yOH stabilize drug formulations for SPANS (form WiO emulsions) TWEENS (form OiW emulsions) parenteral administration. R = aliphatic hydrocarbon ◆ Polysorbate 80 (TWEEN) is also used x + y + z + w = 20 Polysorbate 80 as food emulsifier, eg. ice-creams contain 0.5% of polysorbate 80 (0.1 g consumption per day in US).  large head W/O and O/W Surfactants Hydrophobic tail Polar head Span 80 Polysorbate 80 = Tween 80 Hydrophobic tail Polar head Lipophilic, low HLB Hydrophilic, high HLB small head O/W Tween Oil W/O Water Span Water Oil W/O emulsion  Important Messages The reduced monosaccharides, polyols, are osmotic diuretics if administered intravenously – laxatives is administered orally. The reduced polyols do not undergo rapid metabolism, have low glycemic value and, as diuretics, work by increasing the blood volume through increased blood osmolality. The products of polyol dehydration, sorbitans, after modification with polyethylene glycol and hydrophobic fatty acids, are mild detergents capable of forming oil-in-water and water-in-oil emulsions. The type of emulsion depend on the ratio hydrophilic/lipophilic balance (HLB) – those with the large ratio form oil-in-water emulsions (Tweens), those with small HLB (Spans) form water-in-oil emulsions.  Natural Sweeteners: Fructose vs Glucose ◆ Traditionally, bee honey has been used as a natural sweetener: a mixture of fructose (38%), glucose (31%) and maltose (7%). ◆ An unnatural sweetener, high-fructose corn syrup (HFCS) is made from maize (corn starch) by degradation with glycosidases. High fructose corn syrup has the ratio of fructose to glucose similar to honey and is very inexpensive. ◆ In USA, HFCS is commonly used in soda and sports drinks, baking industry, etc. In US, 10% of the diet calorie intake come from HFCS. ◆ A connection between the consumption of fructose and obesity has been recently documented. A 2013 paper in JAMA 1 explains a connection between fructose and obesity: an increased sensation of fullness and satiety after glucose, but not fructose, consumption. ◆ These findings support the following concept: when the human brain is exposed to fructose, neurobiological pathways involved in appetite regulation are unmodulated, thereby allowing excessive food intake.  Sweetness – Sensing Mechanism ◆ Carbohydrates and artificial sweeteners bind to the same T1R receptors. ◆ T1R2 and T1R3 are G protein-coupled receptors that are linked to guanylate cyclase. They are involved in sweet and umami taste sensing. ◆ Certain sweeteners (e.g. saccharin) can also bind to other receptors (nociceptors) imparting a bitter aftertaste. Dose-response curves of T1R3 with a number of sweeteners.  Artificial Sweeteners – Sucralose ◆ Also know as Splenda®, a halogenated disaccharide, binds to sweet-sensing GPCR-type receptors T1R2/3 with greater affinity than sucrose. ◆ 600 times sweeter than sucrose. ◆ Only sparingly absorbed in the GI tract and not metabolized; more stable chemically than Aspartame® – very slowly degrades in Nature. ◆ The individual Splenda® packet has ~3.4 cal ( 200,000) ▪ white amorphous products (glassy) ▪ not sweet! ▪ not reducing; do not test positive in the typical aldose or ketose detection reactions ▪ Not water soluble; some form colloidal solutions or suspensions  Polysaccharides: Structure Amylopectin of starch homopolymer Cellulose heteropolymer Amylose Amylopectin Chondroitin Peptidoglycan Chitin  Cellulose ◆ Most abundant of all organic compounds ◆ Wood: ~ 50% cellulose ◆ Cotton flax: 97-99% cellulose ◆ Polymer of D-glucose attached by (1,4) linkages A sequoia ◆ Only digested and utilized by ruminants (cow, deer, horse) ◆ Structural polysaccharide ◆ Yields glucose upon complete hydrolysis ◆ Partial hydrolysis produces cellobiose [glucosyl--(1-4)-glucose] ◆ Gives no color with iodine ◆ Held together with lignin in woody plant tissues  Cellulose: Intra- and Inter-Chain Hydrogen Bonds ◆ The rigidity of a single fiber is enhanced by intramolecular hydrogen bonds: 2-OH to 6-O and 5-O to 3-OH. ◆ The neighboring chains interact via hydrogen bonds cause formation of strong associations (sheets). ◆ The very tight packing of chains make cellulose resistant to most glycosidases, eg. mammals cannot digest cellulose. ◆ Ruminants can feed on cellulose only because their gut contains bacteria that makes cellulase enzyme. Cellulose fibers in the cell wall of the alga Chaetomorpha melagonium  Cellulose: Glycosidic Bond Conformation ◆ Rotation about the C1-O and O-C4 bonds (dihedral angles /) determines the overall 3D structure of polysaccharides. ◆ In cellulose both angles are small and of opposite rotation, giving it a linear chain conformation. Ramachandran plot  Products Obtained from Cellulose ◆ Microcrystalline cellulose: binder-disintegrant in tablets ◆ Methyl cellulose: suspending agent and bulk R = H or CH3 laxative (Citrucel) ◆ Sodium carboxymethyl cellulose: lubricant in artificial tear drops, laxative, toothpaste, thickening agent, component of laundry R = H or CH2COOH detergents ◆ Cellulose acetate: rayon, photographic film, plastics, surgical threads ◆ Cellulose acetate phthalate: stable to low pH, used as enteric coating for solid pharmaceuticals to be released in small intestine ◆ Nitrocellulose: explosives, collodion (pyroxylin)  Cellulose Derivatives R = H, cellulose OR R = Me, methyl cellulose RO R = CH2CO2H, carboxymethyl cellulose O O R = CH2CH(OH)CH3, hydroxypropyl cellulose R = acetate or phthalate, cellulose acetate phthalate OR n R = ONO2, nitrocellulose Degrees of OH substitution and MW vary Ionization (solubility) depends on pH insoluble at low pH (stomach), soluble at neutral and higher pH (small intestine) O COO-  Important Messages Cellulose is a polymer of -glucose that forms large rigid structures maintained by a network of intra- and inter-chain hydrogen bond interactions. Cellulose in not metabolized by higher organisms, but can be broken down by the bacteria of ruminant mammals. Cellulose digestion by ruminants is a source of greenhouse gas, methane. Cellulose and cellulose derivatives find broad applications as pharmaceutical excipients: disintegrants and enteric coats Cellulose derivatives with modified hydroxyl groups are soluble and non- digestible and serve as lubricants and laxatives.  Starch: Amylose and Amylopectin ◆ most common storage polysaccharide in plants ◆ composed of 10 – 30% -amylose and 70-90% amylopectin depending on the source ◆ amylopectin is a highly branched structure, with branches occurring every 12 to 30 residues This regularly repeating ◆ the chains have varying length and molecular weights from polymer forms a left- several thousands to half a million handed helix.  Starch: Sources and Applications ◆ Main sources of starch are rice, corn, wheat and potatoes. ◆ A storage polysaccharide and biological fuel. ◆ Used as an excipient – a binder in drug compounding to aid the formation of tablets. ◆ Industrially, it has many applications such as in adhesives, paper manufacturing, biofuels. Starch detection: suspensions of amylose in water makes it adopt a helical conformation Iodine (I2) can insert in the middle of the amylose helix to give a blue color that is characteristic and diagnostic for starch.  Glycogen ◆ also known as animal starch ◆ stored in muscle and liver (mostly) ◆ present in cells as granules (high MW) ◆ contains both (1,4) links and (1,6) branches at every 8-12 glucose unit (more frequent than in starch) ◆ complete hydrolysis yields glucose ◆ glycogen and iodine gives a red-violet color ◆ hydrolyzed by both - and -amylases* and by glycogen phosphorylase  Chitin ◆ Chitin is the second most abundant carbohydrate polymer (1 billion ton/year). ◆ Linear (1,4)-linked polymer of N-acetyl glucosamine. ◆ Like cellulose, chitin is a structural polymer. ◆ Present in the cell wall of fungi and in the exoskeletons of crustaceans, insects and spiders. ◆ Deacetylated chitin, chitosan, binds iron atoms in meat and slows the rancidity process (degradation of unsaturated fats by oxygen). ◆ Chitosan, a deacetylated chitin, is used in food preservation.  Glycosaminoglycans ◆ Polysaccharide chains of proteoglycans. ◆ Linked to the protein core via a serine or threonine (O-linked). ◆ Chains are linear (unbranched). ◆ Glycosaminoglycan chains are very long (over 100 monosaccharides). ◆ Composed of repeating disaccharides. ◆ Glycosaminoglycans contain acidic functionalities (carboxylate and/or sulfates)..  Glycosaminoglycans Hyaluronan, 50,0000 repeats Chondroitin sulfate, 20-60 repeats Keratan sulfate, ~25 repeats Heparin, 15-90 repeats  Hyaluronic acid ◆ Nonsulfated, very high molecular weight (>10 6 Da) (1,3)-linked (inside dimer) and (1,4)- linked (between dimers) copolymer of glucuronic acid and N-acetyl glucosamine. ◆ HA forms a protective viscoelastic coating of an inner surface of a joint. It also shield local pain receptors from noxious stimuli. ◆ Because of its viscosity and water absorption it is used by the body as a lubricant. hyaluronan Protective layer of HA Collagen Pain receptor Chondrocyte Proteoglycan monomer Hyaluronan backbone Cartilage Synovium  Hyaluronic Acid: Macromolecular Assembly X-Ray structure of Ca2+ hyaluronan fiber  Hyaluronic Acid: Viscoelastic Properties During strong – short During slow gradual sheer Viscoelastic properties are duration impact, HA serves stress of longer duration, more pronounced in high as a cushion exhibiting the polymer chain stretch, MW polymers, but the MW is elastic properties – a shock align and exhibit viscous reduced with age. absorber. properties act as lubricant.  The volume occupied by HA is much greater in solution than in the dehydrated solid. Why is the hydrated volume so much greater? The polymer chain in chondroitin sulfate contains a large number of negative charges which repel one another via Coulombic interactions. These interactions are relieved when the polysaccharide strains are separated by solvating water molecules that increase the molecular volume. This process is very efficient in reducing the energy of such interaction due to high dielectric constant of aqueous medium.  Hyaluronic Acid: Pharmaceuticals ◆ Used in the management of osteoarthritis symptoms (Hyalgan and Synvisc). ◆ As eye drops, ophthalmic surgical adjuncts in cataract extractions, intraocular lens implantation, corneal transplant and retinal attachment surgery (Healon, Amvisc, AMO Vitrax). ◆ It is also used in facial and plastic surgery augmentation. ◆ A common ingredient of cosmetics.  Important Messages Glycosaminoglycans are usually -linked polymers of a monosaccharide and N-acetyl glucosamine. Most glycosaminoglycans have high molecular weight, contain dense negative charge due to the presence of glucuronic acid or sulfate residues, are highly hygroscopic and water soluble (or dispersible), and form high viscosity solutions. Due to their unique viscoelastic properties they are widely used in nature as surfaces of cartilage tissues, lubricants and shock-absorbing synovial fluids of bone joints. Hyaluronic acid finds broad application augmenting agent in cosmetic surgery.  Heparin and Heparan Sulfate ◆ Heparin is an acidic carbohydrate with anticoagulant properties. It is used in blood banks to prevent clotting, and in the prevention of blood clots in patients recovering from serious injury, surgery, ischemic heart attack or stroke, or treatment of DVT and pulmonary embolism. ◆ Contains sulfated glucosamine and sulfated glucuronic (iduronic) acid dimers. ◆ While high MW heparin is a natural GAG, a short synthetic pentasaccharide fragment (Fondaparinux) is also used therapeutically.  Blood Coagulation Cascade The point of heparin intervention  Heparin: Mechanism of action Fondaparinux: Synthetic pentasaccharide sulfate A conformational change induced in antithrombin (AT) upon binding to specific pentasaccharide S domain of heparin allows sequestration of Factor Xa - a blood clotting factor - preventing blood coagulation. The synthetic pentasaccharide marketed under name Fondaparinux is used in treatment of pulmonary embolism and deep vein thrombosis.  Important Messages Heparin is a highly sulfated glycosaminoglycan bearing patches (S domain) of dense negative charge. In the blood clotting cascade, a protease thrombin, converts a soluble blood protein fibrinogen into an insoluble fibrin, thereby causing a blood clot. Active thrombin is formed only during a bleeding event by a protease Factor Xa cleaving prothrombin into thrombin. Factor Xa usually exists as an inactive complex with antithrombin. Negatively charged domain S of heparin binds to the positively charge surface of antithrombin causing its conformational change and preventing it from inactivating Factor Xa. Sequence of events: Heparin bind to antithrombin activates Xa  makes thrombin makes fibrin.