Amino Acids (Medicinal Chemistry), Slides of Pharmaceutical Chemistry

Download Amino Acids (Medicinal Chemistry) and more Slides Pharmaceutical Chemistry in PDF only on Docsity! Medicinal Chemistry-I Course: Pharm 333 Chapter: Amino Acids Dr. Md. Aslam Hossain Professor Dept. of Pharmaceutical Chemistry Faculty of Pharmacy University of Dhaka AMINO ACIDS Amino acids are the organic compounds having one or more carboxyl group (organic acid) and one or more amino group (organic base) in the same molecule. Amino acids have primary amino group and a carboxylic acid bonded to same carbon. Amino acids share a general structure • An amino group (-NH2) which is basic • A carboxyl group (-COOH) which is acidic • An alpha carbon attached to a hydrogen • An R group consisting of a variable side chain • Protonation state at phyological pH 7 Classification of Amino acids Depending upon the variable side chains (R group), amino acids are classified Aliphatic amino acids Aromatic amino acids Sulfur containing amino acids Depending upon the acidity and basicity of amino acids, they are classified Neutral Acidic Basic Depending upon the polarity of side chains (R group), amino acids are classified Non polar Polar uncharged Polar charged Depending upon the in-vivo synthesis, amino acids are classified Essential Non-essential Aliphatic (alkane) Amino Acids Alanine Valine Leucine Isoleucine Aromatic Amino Acids Phenylalanine Tyrosine Tryptophan Sulfur Containing Amino Acids Methionine Cysteine Acidic Amino Acids: Amino acids have side chain that carboxyl group that is these amino acids contain one amino and two carboxyl groups. • Negatively charged at physiological pH • Carboxyl groups function as nucleophiles in some enzymatic reactions Basic Amino Acids: Amino acids containing side chains with amino groups that is they contain two amino and one carboxyl group • Hydrophillic nitrogenous bases • Positively charged at physiological pH ArginineLysine Histidine Aspartic acid Glutamic acid Neutral Amino Acids: These amino acids contain one amino group and one carboxyl group • Zwitterion at physiological pH AlanineGlycine Essential and non-essential amino acids Amino acids can be synthesized by all living organisms, plants and animals. Many higher animals, however, are deficient in their ability to synthesize all of the amino acids they need for their proteins. Thus, these higher animals require certain amino acids as a part of their diet. Where do organisms obtain their amino acids? Bacteria, yeast and plants make all of their own Animals make the “nonessential” but not the “essential” amino acids • Some amino acids are made by multi-step biosynthetic pathways • Some are made from metabolic intermediates of other amino acids – Tyrosine is made from phenylalanine – Alanine from pyruvate Essential amino acid • An essential amino acid or indispensable amino acid is an amino acid that cannot be synthesized internally by the human body, and therefore must be supplied in the diet. • Ten amino acids are generally regarded as essential for humans. They are: arginine, isoleucine, leucine, lysine, threonine, tryptophan, methionine, histidine, valine and phenylalanine. • Arginine is required for the juvenile but not for adults • A mnemonic used to remember these acids runs: I Like Light That Tries Making Home Very Pretty. • In addition, the amino acids arginine, cysteine, glycine, glutamine and tyrosine are considered conditionally essential, meaning they are not normally required in the diet, but must be supplied exogenously to specific populations that do not synthesize it in adequate amounts. • An example would be with the disease Phenylketonuria (PKU). Individuals living with PKU must keep their intake of phenylalanine extremely low to prevent mental retardation and other metabolic complications. However, phenylalanine is the precursor for tyrosine synthesis. Without phenylalanine, tyrosine cannot be madeand so tyrosine becomes essential in the diet of PKU patients. • Which amino acids are essential varies from species to species, as different metabolisms are able to synthesize different substances. Phenylketonuria • Phenylketonuria is a disease that is occurred due to inborn errors of metabolism of phenylalanine caused by inherited mutations leads to a defect in an enzyme required for a metabolic pathway of phenylalanine to tyrosine. • Phenylalanine is metabolized to tyrosine by phenylalanine hydroxylase. Individuals with phenylketonuria (PKU) lack the enzyme • Instead of being hydroxylated to tyrosine, phenylalanine is transaminated to produce phenylpyruvate and other metabolites • Accumulation of these metabolites can lead to mental retardation • Individuals with PKU must restrict their dietary intake of peptides containing the amino acid, phenylalanine. Phenylalanine Tyrosine Phenylpyruvic acid Phenylalanine hydroxylase PKU D and L system for amino acids The optical isomers of amino acids do not provide any interpretable indication of the absolute configuration (spatial arrangement) of the chemical groups about a chiral center. D-L system has been used to specify the relative configuration at the asymmetric carbon. In this system, the configuration of the groups about the asymmetric center is related to that of glyceraldehyde, a molecule with one asymmetric center. According to Fischer convention, the dexoroatory (+) and the levorotatory (-) stereoisomers of glyceraldehydes are designated as D-glyceraldehyde and L-glyceraldehyde, respectively. The configuration of groups about a chiral center can be related to that of the gyceraldehyde by chemically converting these groups to those of glyceraldehyde using reaction of known stereochemistry. D-glyceraldehyde L-glyceraldehyde For α-amino acids, the arrangement of the amino, carboxyl, R and H groups about the alpha carbon atom is related to that of the hydroxyl, aldehyde, CH2OH and H groups, respectively. Generally, in the L form of glyceraldehyde the hydroxyl group is on the left side of the molecule, and in the D form it is on the right side so that in an amino acid, the position of the amino group on the left or right side of the alpha carbon determines the L or D designation. If the configuration at the asymmetric carbon atom of an amino acid can be related to D-configuration of glyceraldehyde, belongs to D-series and if it can to L-configuration of glyceraldehyde belongs to L- series D-glyceraldehyde L-glyceraldehyde D-alaline L-alaline D-phenylalanine L-phenylalanine All the amino acids obtained from proteins have the L-stereochemical configuration indicating that only the L- isomers are inserted into proteins using the normal protein synthesis machinery. Moreover, in synthetic amino acids, only belonging to L-series are biologically active. D-amino acids occur rarely • Some peptide antibiotics- D-phenylalaline occurs in the polypeptide antibiotic. Example: Germicidin-S • Bacterial cell walls Amino acids with two chiral centers were named by allotting a name to the first diastereoisomer then assigned the same name but with the prefix allo-. D-isoleucine L-isoleucine D-alloisoleucine L-alloisoleucine Adding an alkali to an amino acid solution: The pH of a solution of an amino acid is increased by adding hydroxide ions, the hydrogen ion is removed from the -NH3 + group. Adding an acid to an amino acid solution: The pH by is decreased by adding an acid to a solution of an amino acid, the –COO- part of the zwitterion picks up a hydrogen ion. In aqueous solution, an equilibrium exists between the dipolar ion and the anionic and cationic forms of an amino acid. The isoelectronic point is the pH at which the amino acid does not migrate in an electric field. This means it is the pH at which the amino acid is neutral, i.e. the zwitterion form is dominant. The pI is given by the average of the pKas that are involved for the formation of the zwitterion • The side chain "R" should be considered for the calculation of the isoelectronic point • Neutral side chains • These amino acids are characterised by two pKas : pKa1 and pKa2 for the carboxylic acid and the amine respectively. The isoelectronic point will be halfway between, or the average of these two pKas, i.e. pI = 1/2 (pKa1 + pKa2). • At very acidic pH (below pKa1) the amino acid will have an overall +vecharge • At very basic pH (above pKa2 ) the amino acid will have an overall -ve charge. Isoelectronic point, pI Glycine, pKa1= 2.34 and pKa2 = 9.6, pI = 5.97. 2.34 9.6 Acid-base titration of a neutral amino acid If alanine is dissolved in a strongly acidic solution (e.g., pH 0), it is present in mainly a net cationic form. In this state the amine group is protonated (+charge) and the carboxylic acid group is neutral (has no charge). As is typical of α -amino acids, the pKa for the carboxylic acid hydrogen of alanine is considerably lower (2.3). The protonated amine group of an α -amino acid is also acidic, but less so than the carboxylic acid group. The pKa of the aminium group in alanine is 9.7. The carboxylic acid proton is always lost before a proton from the aminium group in an α-amino acid. The isoelectric point (pI) of an amino acid such as alanine is the average of pKa1 and pKa2 Methods of Preparation of Amino Acids Amination of α-halo acids: Amino acids can be prepared by the amination of α-halo acids with excess of ammonia. Acids are converted to α-halo acids by the Hell-Volhard- Zelinsky reaction and α-halo acids are treated with excess ammonia to produce the amino acids Malonic ester synthesis COOCHs|~ COOC,H, Nat C;H;CH,Cl | KOH a CH Tr HC HCH ees Heat COOC>Hs COOC,Hs Sodiomalonic ester COOH COOH Bry | ——CHCsHs St ; __Heat COOH COOH Benzylmalonic acid Bromobenzylmalonic acid CsHsCH,CH-COOH NH3 CsH;sCH,CH-COOH oT Excess Br NH, Phenyl alanine Gabriel phthalimide synthesis: An ester of α-halo acid is treated with potassium phthalimide to form the corresponding substituted which on hydrolysis gives phthalic acid and amino acid Preparation of Metheonine i I | COOC3H; C COOC)Hs \ CICH,CH,SCH; N—6——Na Sse C COOC>H; i COOC)H; | 1,0 Oo Heat : 0 H COOH HOOC-CHCHCH)SCH. eee C)H;OH CO, NHa COOH Metheonine Phthalic acid Preparation of Aspartic acid i | | COOC.H; C COOC.H; CICH,COOC.Hs N—C—Na 9 —_ >» N—C—CH,COOC>H; i COOC3H, j COOC3H; H,O O Heat . o H COOH HOOC-CHCH,COOH 2 CoH;OH CO, NHp COOH Aspartic acid Phthalic acid Reactions of Amino Acids Amino acids contain two functional groups : amines and carboxylic acids. So amino acids undergo the reactions characteristic of those functional groups. Carboxylic Acid Esterification: Esterification of the carboxylic acid is usually conducted under acidic conditions. Under such conditions, amine functions are converted to their ammonium salts and carboxyic acids are not dissociated. The initial product is a stable ammonium salt. The amino ester formed by neutralization of this salt is unstable, due to acylation of the amine by the ester function. (1) Typical Fischer esterification involving methanol. (2) Benzylation of the two carboxylic acid functions of aspartic acid, using p-toluenesulfonic acid as an acid catalyst. (1) (2) Ninhydrin Reaction: In addition to these common reactions of amines and carboxylic acids, common alpha-amino acids, except proline, undergo a unique reaction with the triketohydrindene hydrate known as ninhydrin. Among the products of this unusual reaction is a purple colored imino derivative, which provides as a useful color test for these amino acids, most of which are colorless. • A common application of the ninhydrin test is the visualization of amino acids in paper chromatography. Metabolism of amino acids Metabolism of amino acids consists of three stages: • Deamination, the removal of amino group, whereby amino groups are converted either to ammonia or to the amino group of asparate. Both of these substances are derived from substrate, a product of most deamination reactions • Incorporation of ammonia and asparate nitrogen to produce urea for excretion • Conversion of amino acid carbon skeleton ( a-keto acids produced by deamination) to common metabolic intermediates. α-Keto acidsα-Amino acids Transamination α-Ketoglutarate L- Glutamate Oxidative deamination NH3 CO2 UreaUrea cycle Transamination Transamination (or aminotransfer) is the reaction between an amino acid and an alpha-keto acid. The amino group is transferred from the former to the latter; this results in the amino acid being converted to the corresponding α-keto acid, while the reactant α-keto acid is converted to the corresponding amino acid (if the amino group is removed from an amino acid, an α-keto acid is left behind). • Transamination is accomplished by enzymes called transaminases or aminotransferases. • Pyridoxal phosphate (coenzyme) acts as carriers for amino group Oxidative deamination, an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia and the amine functional group is replaced by the ketone group. The ammonia eventually goes into the urea cycle. • Oxidative deamination is accomplished by enzymes called Glutamate dehydrogenase, • In contrast to the transamination reactions which merely swop amino groups from one compound to another, Glutamate dehydrogenase catalyses a net loss of nitrogen from the amino acid pool, therefore the process is therefore termed "oxidative deamination". α-Ketoglutarate Oxidative deamination occurs primarily on glutamic acid because glutamic acid was the end product of many transamination reactions Transamination Reaction NH, 4 Il i 1 CHy-CH Coun Bis HO-C-CH,CH,-C-C-OH alanine alpha-ketoglutaric acid L J J NH, a3 i i ll ll CH;-C-C-OH uF HO-C-CH,CH;-CH-C-OH pyruvic acid glutamic acid C. Ophardt, ¢. 2003 Strecker synthesis: The strecker synthesis of amino acid involves two steps: Reaction