The organic chemistry of medicinal agents

Cover
Title Page
Copyright
Contents
Contributors
Preface
1. The Nature of Bonding in Organic Molecules
	Introduction
	The Nature of Covalent and Ionic Bonds
	Box 1.1—Drawing organic molecules
	Polarization of Covalent Bonds
	Atomic Orbitals and Valence Bond Theory
	Hybridization of Orbitals and Tetrahedral Carbon
	Hybrid Orbitals of Oxygen and Nitrogen and Common Functional Groups
	Box 1.2—Functional groups containing phosphorus or sulfur
	Aromaticity
	Heteroaromatic Ring Systems in Drug Structures
	Summary
	Exercises
2. Non-Covalent Interactions
	Introduction
	Enthalpic and Entropic Contributions to Ligand/Drug Binding
	The Strength of Non-Covalent Interactions
	Desolvation and the Hydrophobic Effect
	Ionic Interactions
	Box 2.1—Ionic interactions in a proton channel from influenza virus
	Hydrogen Bonds
	C–H Bonds as Hydrogen Bond Donors
	Aryl Rings as Hydrogen Bond Acceptors
	Box 2.2—A π-hydrogen bond in glutathione S-transferase
	Aryl-Aryl Interactions
	Cation-π Interactions
	Box 2.3—Hydrophobic and cation-π interactions in the binding of neurotransmitters and drugs
	Halogen Bonds
	Box 2.4—C–F bonds as hydrogen bond acceptors and in orthogonal interactions with carbonyl groups
	Summary
	Case Study—Inhibitors of Factor Xa as Anticoagulants
	Exercises
3. Stereochemistry
	Introduction
	Chirality and the Shape of Molecules
	Stereoisomers—Some Important Definitions
	Box 3.1—Determining isomeric and stereochemical relationships between molecules
	Avoiding Confusion
	Stereoisomers of 1,3-Dimethylcyclohexane
	Chirality Centers
	Assigning the Configuration of Chirality Centers
	Box 3.2—Cahn–Ingold–Prelog rules in brief
	Configurational Assignment and Stereochemical Relationships
	Meso Compounds
	Chirality Centers at Non-Carbon Atoms
	Other Sources of Chirality and Stereoisomerism
	Box 3.3—Atropisomerism
	Summary
	Case Study—Racemic and Non-Racemic Drugs
	Exercises
4. Conformations of Organic Molecules
	Introduction
	Newman Projections and Dihedral Angles
	Conformations and Energies of Ethane—Torsional Strain
	Conformations and Energies of Larger Acyclic Molecules—Steric Strain
	Conformations of Small Rings
	Box 4.1—The three major types of strain in organic molecules
	Conformations of Cyclohexane and Related Six-Membered Rings
	Estimating the Conformational Preferences of Substituted Cyclohexanes
	Box 4.2—Drawing chair conformations
	Conformationally Constrained Ring Systems
	Box 4.3—Conformational constraint in opiate analgesics
	Summary
	Case Study—Neuraminidase Inhibitors and the Influenza Virus
	Exercises
5. Acid-Base Chemistry of Organic Molecules
	Introduction
	Three Theories of Acids and Bases
	Self-Ionization of Water and the pH Scale
	Avoiding Confusion—Use of “Acid” and “Base” and Related Terms
	The Acid Dissociation Constant Ka and pKa as a Measure of Acid Strength
	Electronegativity and Size of Atoms and Acid/Base Strength
	Atom Hybridization and Acid/Base Strength
	Resonance Electronic Effects on Acid/Base Strength
	Inductive Electronic Effects of Substituents on Acid/Base Strength
	Combined Inductive and Resonance Effects on Acid/Base Strength
	Proximity and Through-Space Effects on Acid/Base Strength
	The Henderson–Hasselbalch Relationship and Acid/Base Equilibria as a Function of pH
	Summary
	Case Study—Discovery of Tagamet
	Exercises
6. Nucleophilic Substitution, Addition, and Elimination Reactions
	Introduction
	Nucleophiles
	Electrophiles
	Box 6.1—Electrophiles in cancer drugs
	Leaving Groups
	Nucleophilic Aliphatic Substitution Reactions—SN2
	Box 6.2—SN2 reactions in biological chemistry
	Nucleophilic Aliphatic Substitution Reactions—SN1
	Neighboring Group Assistance in SN1 Reactions
	Nucleophilic Aromatic Substitution—SNAr
	Addition Reactions
	Elimination Reactions—E1 and E2
	Summary
	Case Study—Drugs That Form a Covalent Bond to Their Target
	Exercises
7. Reactions of Carbonyl Species
	Introduction
	Nature of the Carbonyl Group
	Relative Reactivity of Carbonyl-Containing Functional Groups
	Hydration of Aldehydes and Ketones
	Reactions of Aldehydes and Ketones with Alcohols
	Box 7.1—Glucuronidation in the metabolism of drugs
	Imines and Enamines
	Box 7.2—Imines in drug-protein conjugates
	Oximes and Hydrazones
	Chemical Hydrolysis of Ester and Amide Bonds
	Enzymatic Hydrolysis of Peptide Bonds by Proteases
	Box 7.3—Drugs designed to inhibit proteases
	Summary
	Case Study—Odanacatib
	Exercises
8. Radical Chemistry
	Introduction
	Formation, Stability, and Molecular Orbital View of Radicals
	Radical Reactions
	Reactions of Molecular Oxygen
	Iron-Mediated Radical Reactions in Drug Metabolism
	Box 8.1—Fenton chemistry in the action of antimalarial drugs
	Summary
	Case Study—Calicheamicin γ1
	Exercises
Solutions to Exercises
Index