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Basic Concepts in Medicinal Chemistry, 2Nd Edition

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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 09:50 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 09:50 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 09:50 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 09:50 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 09:50 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
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