DOCSLIB.ORG

Basic Concepts in Medicinal Chemistry, 2Nd Edition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Basic Concepts in Medicinal Chemistry, 2Nd Edition APP ANSWERS TO CHAPTER QUESTIONS CHAPTER 2 STRUCTURE ANALYSIS CHECKPOINT Checkpoint Drug 1: Venetoclax 1. Answers provided in table below. Functional Group Name Contribution to Water and/or Lipid Solubility A Halogen (chlorine atom) Lipid Solubility B Alicyclic ring, alkyl ring, cycloalkane Lipid Solubility C Tertiary amine (piperazine) Water Solubility D Heterocyclic ring system (pyrrolopyridine) Hydrocarbons: Lipid Solubility Nitrogen atoms: Water Solubility E Aromatic ring; phenyl ring; aromatic hydrocarbon Lipid Solubility F Sulfonamide Water Solubility G Secondary aromatic amine/aniline Water Solubility H Ether Hydrocarbons: Lipid Solubility Oxygen atom: Water Solubility 2. The sulfonamide and tertiary amine will be primarily ionized in most physiological environments and can participate in ion-dipole interactions (as the ion) with water. In the event that they are unionized, they could participate in hydrogen bonding interactions with water. The nitrogen atoms of the heterocyclic ring system, as well as the secondary aromatic amine, and the oxygen atom of the ether will not be appreciably ionized, but can participate in hydrogen bonding interactions with water. Thus, all of these functional groups contribute to the water solubility of venetoclax. The halogen as well as the hydrocarbon chains and rings are not able to ionize or form hydrogen bonds with water and thus contribute to the lipid solubility of venetoclax. 477 Unauthenticated | Downloaded 09/26/21 08:19 PM UTC 478 BASIC CONCEPTS IN MEDICINAL CHEMISTRY 3. Answers provided in table below. Electron Donating or Withdrawing Resonance or Induction A Electron Withdrawing Induction B Both Donates electrons into the aromatic ring through resonance. Withdraws electrons from adjacent methylene groups through induction. C Electron Donating Resonance D Electron Withdrawing Induction (from aromatic ring) Resonance (from ionized sulfonamide) E Electron Withdrawing Resonance Checkpoint Drug 2: Elamipretide 1. Answers provided in the grid below. Character: Function: Name of Functional Group Hydrophobic, Hydrophilic, or both Contribute to Solubility or Absorption A Guanidine Hydrophobic (R) Absorption (R) Hydrophilic (H2NCNHNH) Solubility (H2NCNHNH) B Primary amine Hydrophobic (R) Absorption (R) Hydrophilic (NH2) Solubility (NH2) C Amide Hydrophobic (R) Absorption (R) Hydrophilic (C=ONH2) Solubility (C=ONH2) D Aromatic hydrocarbon; Hydrophobic (R) Absorption (R) aromatic ring; phenyl ring E Phenol Hydrophobic (R) Absorption (R) Hydrophilic (OH) Solubility (OH) R = carbon scaffolding 2. Part A: Every amino acid has an amine (basic), a unique side chain, and a carboxylic acid (acidic). As building blocks of proteins, the amine and carboxylic acid of adjacent amino acids are linked to form an amide or peptide linkage (neutral). Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the amine and carboxylic acid of adjacent amino acids are linked to form a peptide bond (amide = neutral). The easiest way to read these kinds of molecules is to look for the pattern “amine-side chain-carbonyl” (representing one amino acid) and to completely ignore the fact that the amine and adjacent carboxylic acid are really an amide. In the diagram below, the “amine-side chain-carbonyl” pattern for the first two amino acids/amino acid derivatives is shown. Unauthenticated | Downloaded 09/26/21 08:19 PM UTC 32 New Structures: Pages 3, 4, 10, 12, 14, 21, 22 (2 instances), 45, 46, 47, 48 (2 instances), 75, 77, 78 (2 instances), 79, 82, 84, 85, 86 (2 instances), 87, 93 (2 instances), 94, 95, 96 (all structures of this page), 97, 107 (2 instances) 6 Revised Structures: Pages 6, 15, 51, 52, 58, 59 1 New/Replacement Structure: Page 91 Every structure in Chapter 10 (Pages 108-151) is new. Answers to Chapter Questions CHAPTER 2 Checkpoint Drug 2: Elamipretide APPENDIX: ANSWERS TO CHAPTER QUESTIONS 479 Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the amine and H2N NH NH2 N H carbonyl side chain amine O O H H N N H N N NH 2 H 2 side chainO amine O carbonyl H3C CH3 OH Using this pattern, the first amino acid in the sequence is the amino acid arginine, the second amino acid is a derivative of tyrosine, the third amino acid is lysine, and the fourth amino acid is phenylalanine. Pa rt CPart: The C: portions The portions of the of moleculethe molecule that that represent represent arginine, arginine, lysine, lysine, and and phenylalanine have phenylalanine have been boxed. arginine lysine phenylalanine Part D: The second amino acid is a derivative of tyrosine. REVIEW QUESTIONS 3. Part A: Functional groups are identified in the structure shown below. amidine thioether guanidine H UnauthenticatedN | Downloaded 09/26/21 08:19 PM UTC NH2 N S H N H N N 2 S SO2NH2 aromatic heterocycle (1.3 thiazole) 480 BASIC CONCEPTS IN MEDICINAL CHEMISTRY 3. Answers provided in the grid below. Amino Acid Side Chain Amino Acid Side Evaluation: Amino Acid Side Chain Chain Evaluation: Name of Amino Acid or Hydrophobic, Hydrophilic, Evaluation: Nucleophilic, Amino Acid Derivative or Both Acidic, Basic, Neutral Electrophilic, NA 1 Arginine Hydrophilic (NHC=NHNH2) Basic NA Hydrophobic (R) 2 Tyrosine derivative Hydrophilic (OH) Acidic Nucleophilic Hydrophobic (R) 3 Lysine Hydrophilic (NH2) Basic Nucleophilic Hydrophobic (R) 4 Phenylalanine Hydrophobic Neutral NA R = carbon scaffolding. REVIEW QUESTIONS 1. Answers provided in the grid below. Box Functional Group Name A Guanidine B Secondary amine C Cycloalkane (cyclopropane) D Carboxylic acid E Amide F Sulfonamide G Aromatic hydrocarbon (or aromatic ring) 2. Answers provided in the grid below. Box Functional Group Name A Ketone B Cycloalkene (cyclohexadiene) C Secondary alcohol D Aliphatic halogen E Ester F Cycloalkane Unauthenticated | Downloaded 09/26/21 08:19 PM UTC Part C: The portions of the molecule that represent arginine, lysine, and phenylalanine have arginine lysine phenylalanine REVIEW QUESTIONS APPENDIX: ANSWERS TO CHAPTER QUESTIONS 481 3. Part A: Functional groups are identified in the structure shown below. 3. Part A: Functional groups are identified in the structure shown below. amidine thioether guanidine H N NH2 N S H N H N N 2 S SO2NH2 aromatic heterocycle (1.3 thiazole) Part B: The aromatic heterocycle (1,3 thiazole) and the sulfonamide are both electron withdrawing groups and will significantly decrease the magnitude of the pK values for both the guanidine and amidine. The experimentally measured pK a a values for the guanidine and the amidine are in the range of 6.7–6.9. Part C: The amidine is not protonated at physiological pH because the sulfonamide is an electron withdrawing group and will pull (or withdraw) electrons from the amidine through induction. This will decrease the ability of the amidine to attract protons (H+); therefore, its basicity will decrease. The experimentally measured pKa values for famotidine are all in the range of 6.7 and 6.9. The amidine, guanidine, and aromatic heterocycle are all basic in character. At pH = 7.4, the pH > pKa for these functional groups and, therefore, the basic functional groups are predominantly unionized in this pH environment. 4. Part A: Answers provided in the grid below. Contribution to Water Name of Three Oxygen Hydrophilic Solubility Containing Functional and/or and/or Hydrogen Bond Acceptor, Groups Hydrophobic Lipid Solubility Donor, Both, or Neither Primary alcohol Hydrophilic (OH) Water solubility (OH) Hydrogen bond acceptor Hydrophobic (R) Lipid solubility (R) and donor Secondary alcohol Hydrophilic (OH) Water solubility (OH) Hydrogen bond acceptor Hydrophobic (R) Lipid solubility (R) and donor Ether Hydrophilic (O) Water solubility (O) Hydrogen bond acceptor Hydrophobic (R) Lipid solubility (R) R = carbon scaffolding. Part B: The primary and secondary alcohols, as well as the ethers, all have hydrophilic character. The alcohols (primary and secondary) are able to interact with water as both hydrogen bond acceptor and donors, which means that they make a sizable contribution to the water solubility of lactulose. The ethers are able to interact with water as a hydrogen bond acceptor only and, therefore, make somewhat less of a contribution to water solubility as compared to the alcohols. Unauthenticated | Downloaded 09/26/21 08:19 PM UTC &'UXJZDWHULQWHUDFWLRQVGLSROHGLSROHLQWHUDFWLRQ 1RWH:KHQDSSURSULDWHEHVXUHWRGUDZLQWKHFRUUHFWDUURZDQGSDUWLDOFKDUJHV + 2 2 482 BASIC CONCEPTS IN MEDICINAL CHEMISTRY + 2 + 2 2+ 2 Part C: The primary and secondary alcohols,+ 2 as2 well as the ethers all have hydrophilic character. The alcohols (primary 2+and secondary) are able to interact with water as both hydrogen bond acceptors and donors, which means that they will be able to attract and interact with water. The2+ ethers are able to interact with water as a hydrogen bond acceptor only and, therefore,2+ make somewhat less of a contribution to the drug’s ability to attract and interact with water. /DFWXORVH One mechanism to relieve constipation is to (Q increaseXORVH the water content of the stool so as to make it easier to eliminate. Lactulose achieves this by attracting and interacting with water with its seven OH groups and two ethers. $QVZHU Part D: Answer provided in figure below. :DWHU +\GURJHQERQG GRQRU 'UXJ +\GURJHQERQG DFFHSWRU δ+ δ− :DWHU +\GURJHQERQG DFFHSWRU 'LSROHGLSROH − δ 'UXJ +\GURJHQERQG δ+ GRQRU 5. Part A: Answers provided in the grid below. Contribution to Water Solubility and/or Name of Functional Group Hydrophilic and/or Hydrophobic Lipid Solubility Aromatic
Load more

Recommended publications
  • Aldehydes and Ketones
    12 Aldehydes and Ketones Ethanol from alcoholic beverages is first metabolized to acetaldehyde before being broken down further in the body. The reactivity of the carbonyl group of acetaldehyde allows it to bind to proteins in the body, the products of which lead to tissue damage and organ disease. Inset: A model of acetaldehyde. (Novastock/ Stock Connection/Glow Images) KEY QUESTIONS 12.1 What Are Aldehydes and Ketones? 12.8 What Is Keto–Enol Tautomerism? 12.2 How Are Aldehydes and Ketones Named? 12.9 How Are Aldehydes and Ketones Oxidized? 12.3 What Are the Physical Properties of Aldehydes 12.10 How Are Aldehydes and Ketones Reduced? and Ketones? 12.4 What Is the Most Common Reaction Theme of HOW TO Aldehydes and Ketones? 12.1 How to Predict the Product of a Grignard Reaction 12.5 What Are Grignard Reagents, and How Do They 12.2 How to Determine the Reactants Used to React with Aldehydes and Ketones? Synthesize a Hemiacetal or Acetal 12.6 What Are Hemiacetals and Acetals? 12.7 How Do Aldehydes and Ketones React with CHEMICAL CONNECTIONS Ammonia and Amines? 12A A Green Synthesis of Adipic Acid IN THIS AND several of the following chapters, we study the physical and chemical properties of compounds containing the carbonyl group, C O. Because this group is the functional group of aldehydes, ketones, and carboxylic acids and their derivatives, it is one of the most important functional groups in organic chemistry and in the chemistry of biological systems. The chemical properties of the carbonyl group are straightforward, and an understanding of its characteristic reaction themes leads very quickly to an understanding of a wide variety of organic reactions.
    [Show full text]
  • 1 Reactive Methylene Compounds As Synthons for Various Bio Active
    Reactive methylene compounds as synthons for various bio active molecules Mohd. Shahnawaz khan1*, Saba Parveen Siddiqui2, Daya S. Seth3 1Department of Chemistry, JK. Lakshmipat University Jaipur (Raj) -302026, India 2Department of Chemistry Kendriya Vidhayalaya N0-1 Pratap Nagar, Udaipur (Raj) 313001, India 3Department of Chemistry, School of Chemical Sciences, St. John's College, Agra (UP)-282002, India *E-mail: [email protected] Abstract: Novel malonamic acid, hydrazide and amide were efficiently synthesized from the condensation of 3-NO2 aniline with diethyl malonate. Also the synthesis of coumarins, azo coumarins. benzocoumarins, cinnamamide, and α:β-unsaturated acid, were achieved by the reaction of above synthesized compounds in a single step reaction in good to excellent yields. And these eight compounds were tested for their antibacterial activities with two bacteria E. coli and S. aureus. Compounds are showing slightly to moderate antibacterial activities against same bacterias. Key words: Reactive methylene compounds, antibacterial activity. Introduction: Organic compounds containing the reactive methylene group provide excellent intermediates in synthetic organic chemistry. Such substances have been found to be useful as synthons for various bioactive agents. Using such type of compounds as starting material quiet a large number of heterocyclic and non-heterocyclic compounds can be prepared by condensing them with other substances. Heterocycles form by far the largest of classical divisions of organic chemistry. A broad spectrum of biological activity associated with heterocyclic compounds has attracted interest in drug discovery research. As evident from literature, both synthetic as well as natural oxygen and nitrogen containing heterocyclic molecules possesses significant antimicrobial activities and a large number have been made up to clinics for health care worldwide.
    [Show full text]
  • Aromaticity Sem- Ii
    AROMATICITY SEM- II In 1931, German chemist and physicist Sir Erich Hückel proposed a theory to help determine if a planar ring molecule would have aromatic properties .This is a very popular and useful rule to identify aromaticity in monocyclic conjugated compound. According to which a planar monocyclic conjugated system having ( 4n +2) delocalised (where, n = 0, 1, 2, .....) electrons are known as aromatic compound . For example: Benzene, Naphthalene, Furan, Pyrrole etc. Criteria for Aromaticity 1) The molecule is cyclic (a ring of atoms) 2) The molecule is planar (all atoms in the molecule lie in the same plane) 3) The molecule is fully conjugated (p orbitals at every atom in the ring) 4) The molecule has 4n+2 π electrons (n=0 or any positive integer Why 4n+2π Electrons? According to Hückel's Molecular Orbital Theory, a compound is particularly stable if all of its bonding molecular orbitals are filled with paired electrons. - This is true of aromatic compounds, meaning they are quite stable. - With aromatic compounds, 2 electrons fill the lowest energy molecular orbital, and 4 electrons fill each subsequent energy level (the number of subsequent energy levels is denoted by n), leaving all bonding orbitals filled and no anti-bonding orbitals occupied. This gives a total of 4n+2π electrons. - As for example: Benzene has 6π electrons. Its first 2π electrons fill the lowest energy orbital, and it has 4π electrons remaining. These 4 fill in the orbitals of the succeeding energy level. The criteria for Antiaromaticity are as follows: 1) The molecule must be cyclic and completely conjugated 2) The molecule must be planar.
    [Show full text]
  • United States Patent (19) 11 Patent Number: 4,880,935 Thorpe 45 Date of Patent: Nov
    United States Patent (19) 11 Patent Number: 4,880,935 Thorpe 45 Date of Patent: Nov. 14, 1989 (54. HETEROBIFUNCTIONAL LINKING Wang et al., Israel Journal of Chem., vol. 12, 1974, pp. AGENTS DERVED FROM 375-389. N-SUCCNMDO-DTHO-ALPHIA Vallero et al., Science, 222, 1983, pp. 512-515. METHYL-METHYLENE-BENZOATES Camber et al., Method of Enzymol, 112, 1985, pp. 201-225. 75 Inventor: Philip E. Thorpe, London, England Langone et al., Method of Enzymol, 93, 1983, p. 280. Masuho et al., J. Biochem, 91, 1982, pp. 1583-1591. 73 Assignee: ICRF (Patents) Limited, London, Carlsson et al., Biochem. J., 1978, 173, pp. 723-737. England Calombatti et al., J. Immunol, 131, 1983, pp. 3091-3095. Brown et al., Cancer Res., vol. 45, 1985, pp. 1214-1221. 21 Appl. No.: 90,386 Ramakrishnonet al., Cancer Res., 44, 1984, pp. 201-208. 22 Filed: Aug. 27, 1987 Gras et al., J. of Immunol Methods, 81, 1985, pp. 283-297. Related U.S. Application Data Primary Examiner-Alan L. Rotman Attorney, Agent, or Firm-Nixon & Vanderhye 63 Continuation of Ser. No. 884,641, Jul 11, 1986, aban doned. (57 ABSTRACT The efficacy of immunotoxins having an antibody that 51) Int. Cl.".................. C07D 207/46; CO7D 207/48; recognizes a tumour associated antigen linked to a cyto CO7D 401/12 toxin through a heterobifunctional agent of the disul 52 U.S. Cl. ..................................... 546/281; 548/542 phide type is improved by providing in the heterobi 58 Field of Search ......................... 548/542; 546/281 functional agent a molecular grouping creating steric 56 References Cited hindrance in relation to the disulphide link.
    [Show full text]
  • Chapter 14 – Aldehydes and Ketones
    Chapter 14 – Aldehydes and Ketones 14.1 Structures and Physical Properties of Aldehydes and Ketones Ketones and aldehydes are related in that they each possess a C=O (carbonyl) group. They differ in that the carbonyl carbon in ketones is bound to two carbon atoms (RCOR’), while that in aldehydes is bound to at least one hydrogen (H2CO and RCHO). Thus aldehydes always place the carbonyl group on a terminal (end) carbon, while the carbonyl group in ketones is always internal. Some common examples include (common name in parentheses): O O H HH methanal (formaldehyde) trans-3-phenyl-2-propenal (cinnamaldehyde) preservative oil of cinnamon O O propanone (acetone) 3-methylcyclopentadecanone (muscone) nail polish remover a component of one type of musk oil Simple aldehydes (e.g. formaldehyde) typically have an unpleasant, irritating odor. Aldehydes adjacent to a string of double bonds (e.g. 3-phenyl-2-propenal) frequently have pleasant odors. Other examples include the primary flavoring agents in oil of bitter almond (Ph- CHO) and vanilla (C6H3(OH)(OCH3)(CHO)). As your book says, simple ketones have distinctive odors (similar to acetone) that are typically not unpleasant in low doses. Like aldehydes, placing a collection of double bonds adjacent to a ketone carbonyl generally makes the substance more fragrant. The primary flavoring agent in oil of caraway is just a such a ketone. 2 O oil of carraway Because the C=O group is polar, small aldehydes and ketones enjoy significant water solubility. They are also quite soluble in typical organic solvents. 14.2 Naming Aldehydes and Ketones Aldehydes The IUPAC names for aldehydes are obtained by using rules similar to those we’ve seen for other functional groups (e.g.
    [Show full text]
  • Carbonyl Compounds
    CARBONYL COMPOUNDS PART-4, PPT-4, SEM-3 Dr. Kalyan Kumar Mandal Associate Professor St. Paul’s C. M. College Kolkata CONTENTS: CARBONYL COMPOUNDS PART-4 • Formation of Acetal/Ketal • Formation of Thioacetal Reaction of Carbonyl Compounds with Alcohols • Carbonyl compounds react with alcohols. The product of this reaction is known as a hemiacetal, because it is halfway to an acetal. This reaction is analogous to hydrate formation from aldehydes and ketones. The mechanism follows in the footsteps of hydrate formation: ROH is used instead of HOH (water). This Lecture is prepared by Dr. K. K. Mandal, SPCMC, Kolkata Formation of Cyclic Hemiacetal • Hemiacetal formation is reversible, and they are stabilized by the same special structural features as those of hydrates. However, hemiacetals can also gain stability by being cyclic. • Cyclic hemiacetal is formed when the carbonyl group and the attacking hydroxyl group are part of the same molecule. The reaction is an intramolecular (within the same molecule) addition, as opposed to the intermolecular (between two molecules) ones. This is an example of ring-chain tautomerism. This Lecture is prepared by Dr. K. K. Mandal, SPCMC, Kolkata Formation of Cyclic Hemiacetal • Although the cyclic hemiacetal is more stable, it is still in equilibrium with some of the open-chain hydroxyaldehyde form. Its stability, and how easily it forms, depend on the size of the ring. • Five- and six-membered rings involve less strain (their bonds are free to adopt 109° or 120° angles) in comparison to the three- membered rings, and therefore five or six-membered hemiacetals are very common.
    [Show full text]
  • AROMATIC COMPOUNDS Aromaticity
    AROMATICITY AROMATIC COMPOUNDS Aromaticity Benzene - C6H6 H H H H H H H H H H H H Kekulé and the Structure of Benzene Kekule benzene: two forms are in rapid equilibrium 154 pm 134 pm • All bonds are 140 pm (intermediate between C-C and C=C) • C–C–C bond angles are 120° • Structure is planar, hexagonal A Resonance Picture of Bonding in Benzene resonance hybrid 6 -electron delocalized over 6 carbon atoms The Stability of Benzene Aromaticity: cyclic conjugated organic compounds such as benzene, exhibit special stability due to resonance delocalization of -electrons. Heats of hydrogenation + H2 + 120 KJ/mol + 2 H2 + 230 KJ/mol calc'd value= 240 KJ/mol 10 KJ/mol added stability + 3 H 2 + 208 KJ/mol calc'd value= 360 KJ/mol 152 KJ/mol added stability + 3 H2 + 337 KJ/mol 1,3,5-Hexatriene - conjugated but not cyclic Resonance energy of benzene is 129 - 152 KJ/mol An Orbital Hybridization View of Bonding in Benzene • Benzene is a planar, hexagonal cyclic hydrocarbon • The C–C–C bond angles are 120° = sp2 hybridized • Each carbon possesses an unhybridized p-orbital, which makes up the conjugated -system. • The six -electrons are delocalized through the -system The Molecular Orbitals of Benzene - the aromatic system of benzene consists of six p-orbitals (atomic orbitals). Benzene must have six molecular orbitals. Y6 Y4 Y5 six p-orbitals Y2 Y3 Y1 Degenerate orbitals: Y : zero nodes orbitals that have the 1 Bonding same energy Y2 and Y3: one node Y and Y : two nodes 4 5 Anti-bonding Y6: three node Substituted Derivatives of Benzene and Their Nomenclature
    [Show full text]
  • Prodrugs Design Based on Inter- and Intramolecular Chemical Processes
    Chem Biol Drug Des 2013; 82: 643–668 Review Prodrugs Design Based on Inter- and Intramolecular Chemical Processes Rafik Karaman1,2,* compound satisfies a number of preset criteria to start clinical development. The number of years it takes to intro- 1Bioorganic Chemistry Department, Faculty of Pharmacy, duce a drug to the pharmaceutical market is over 10 years Al-Quds University, P.O. Box 20002, Jerusalem, Palestine with a cost of more than $1 billion dollars (1,2). 2Department of Science, University of Basilicata, Via dell’Ateneo Lucano 10, 85100, Potenza, Italy Modifying the absorption, distribution, metabolism, and *Corresponding author: Rafik Karaman, elimination (ADME) properties of an active drug requires a [email protected] complete understanding of the physicochemical and bio- logical behavior of the drug candidate (3 6). This includes This review provides the reader a concise overview of – the majority of prodrug approaches with the emphasis comprehensive evaluation of drug-likeness involving on the modern approaches to prodrug design. The prediction of ADME properties. These predictions can be chemical approach catalyzed by metabolic enzymes attempted at several levels: in vitro–in vivo using data which is considered as widely used among all other obtained from tissue or recombinant material from human approaches to minimize the undesirable drug physico- and preclinical species, and in silico or computational pre- chemical properties is discussed. Part of this review dictions projecting in vitro or in vivo data, involving the will shed light on the use of molecular orbital methods evaluation of various ADME properties, using computa- such as DFT, semiempirical and ab initio for the design tional approaches such as quantitative structure activity of novel prodrugs.
    [Show full text]
  • Converting Disulfide Bridges in Native Peptides to Stable Methylene Thioacetals
    Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Converting disulfide bridges in native peptides to stable methylene thioacetals† Cite this: Chem. Sci.,2016,7, 7007 C. M. B. K. Kourra and N. Cramer* Disulfide bridges play a crucial role in defining and rigidifying the three-dimensional structure of peptides. However, disulfides are inherently unstable in reducing environments. Consequently, the development of strategies aiming to circumvent these deficiencies – ideally with little structural disturbance – are highly sought after. Herein, we report a simple protocol converting the disulfide bond of peptides into highly stable methylene thioacetal. The transformation occurs under mild, biocompatible conditions, enabling the conversion of unprotected native peptides into analogues with enhanced stability. The developed Received 23rd May 2016 protocol is applicable to a range of peptides and selective in the presence of a multitude of potentially Accepted 24th July 2016 reactive functional groups. The thioacetal modification annihilates the reductive lability and increases the DOI: 10.1039/c6sc02285e serum, pH and temperature stability of the important peptide hormone oxytocin. Moreover, it is shown www.rsc.org/chemicalscience that the biological activities for oxytocin are retained. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Introduction disulde bond engineering emerged as an important strategy to improve the metabolic stability of disulde-containing peptides, Peptides have recently been enjoying a renewed interest in whilst maintaining their biological activity. For instance, their application as therapeutic agents.1 They provide a large replacements of the disulde group with a lactam,10 thioether,11 a chemical space with a diverse array of molecular frameworks selenium12 or dicarba13 analogues have been reported.5 Many of for the development of novel therapeutics for a plethora of these methods require signicant modication of the synthetic biomedical applications.
    [Show full text]
  • Structure Property Relationships of Carboxylic Acid Isosteres † † † ‡ † Pierrik Lassalas, Bryant Gay, Caroline Lasfargeas, Michael J
    Article pubs.acs.org/jmc Structure Property Relationships of Carboxylic Acid Isosteres † † † ‡ † Pierrik Lassalas, Bryant Gay, Caroline Lasfargeas, Michael J. James, Van Tran, † ‡ † § † Krishna G. Vijayendran, Kurt R. Brunden, Marisa C. Kozlowski, Craig J. Thomas, Amos B. Smith, III, † † ‡ Donna M. Huryn,*, and Carlo Ballatore*, , † Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States ‡ Center for Neurodegenerative Disease Research, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States § National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20850, United States *S Supporting Information ABSTRACT: The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physico- chemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure− property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group. ■ INTRODUCTION ships (SPR) of the existing palette of isosteres is most desirable.
    [Show full text]
  • Reactions of Aromatic Compounds Just Like an Alkene, Benzene Has Clouds of  Electrons Above and Below Its Sigma Bond Framework
    Reactions of Aromatic Compounds Just like an alkene, benzene has clouds of electrons above and below its sigma bond framework. Although the electrons are in a stable aromatic system, they are still available for reaction with strong electrophiles. This generates a carbocation which is resonance stabilized (but not aromatic). This cation is called a sigma complex because the electrophile is joined to the benzene ring through a new sigma bond. The sigma complex (also called an arenium ion) is not aromatic since it contains an sp3 carbon (which disrupts the required loop of p orbitals). Ch17 Reactions of Aromatic Compounds (landscape).docx Page1 The loss of aromaticity required to form the sigma complex explains the highly endothermic nature of the first step. (That is why we require strong electrophiles for reaction). The sigma complex wishes to regain its aromaticity, and it may do so by either a reversal of the first step (i.e. regenerate the starting material) or by loss of the proton on the sp3 carbon (leading to a substitution product). When a reaction proceeds this way, it is electrophilic aromatic substitution. There are a wide variety of electrophiles that can be introduced into a benzene ring in this way, and so electrophilic aromatic substitution is a very important method for the synthesis of substituted aromatic compounds. Ch17 Reactions of Aromatic Compounds (landscape).docx Page2 Bromination of Benzene Bromination follows the same general mechanism for the electrophilic aromatic substitution (EAS). Bromine itself is not electrophilic enough to react with benzene. But the addition of a strong Lewis acid (electron pair acceptor), such as FeBr3, catalyses the reaction, and leads to the substitution product.
    [Show full text]
  • Bsc Chemistry
    Subject Chemistry Paper No and Title Paper 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No and Module 3: Hyper-Conjugation Title Module Tag CHE_P1_M3 CHEMISTRY PAPER No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 3: Hyper-Conjugation TABLE OF CONTENT 1. Learning outcomes 2. Introduction 3. Hyperconjugation 4. Requirements for Hyperconjugation 5. Consequences and Applications of Hyperconjugation 6. Reverse Hyperconjugation 7. Summary CHEMISTRY PAPER No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 3: Hyper-Conjugation 1. Learning Outcomes After studying this module you shall be able to: Understand the concept of hyperconjugation. Know about the structural requirements in a molecule to show hyperconjugation. Learn about the important consequences and applications of hyperconjugation. Comprehend the concept of reverse hyperconjugation. 2. Introduction In conjugation, we have studied that the electrons move from one p orbital to other which are aligned in parallel planes. Is it possible for electron to jump from p orbital to sp3 orbital that are not parallelly aligned with one another? The answer is yes. This type of conjugation is not normal, it is extra-ordinary. Hence, the name hyper-conjugation. It is also know as no-bond resonance. Let us study more about it. 3. Hyperconjugation The normal electron releasing inductive effect (+I effect) of alkyl groups is in the following order: But it was observed by Baker and Nathan that in conjugated system, the attachment of alkyl groups reverse their capability of electron releasing. They suggested that alkyl groups are capable of releasing electrons by some process other than inductive.
    [Show full text]