Contents C 1 Two-Electron( Carbanion Mechanism C2 Carbanion Followed by Two One-Electron Transfers 21 C 3 One-Electron Mechanism C4 Hydride Mechanism 210) 4. 3. D Hem 212 4.3E Adenosine Triphosphate and Coenzyme A 216 4.5 General references 2l8 5.1 Why Inhibit an Enzyme,ation 5 Enzyme Inhibition and Inacti 29 5.2 Drug resistance 5.2.A What Is Drug Resistance? 5.2.B Mechanisms of Drug Resistance 232 B. 1 Altered Drug Uptake 232 B2 Overproduction of the Target Enzyme 232 B3 Altered Target Enzyme(or Site of Action) 232 B4 Production of a Drug- Destroying Enzyme B5 Deletion of a Prodrug-Activating Enzyme production of the Substrate for the Target Enzym B7 New Pathway for Formation of the Product of the Target Enzyme 2.9 B8 Efilux Pumps 239 5.3 Drug Synergism ( Drug Combination) ,239 5.3.A What Is Drug Synergism? 239 5.3. B Mechanisms of Drug Synergism B. 1 Inhibition of a Drug-Destroying Enzyme B 2 Sequential Blocking 24 B3 Inhibition of Enzymes in Different Metabolic Pathways B 4 Effux Pump Inhibitors B5 Use of Multiple Drugs for the Same Target 24 5.4 Reversible Enzyme Inhibitors 241 5. 4.A Mechanism of Reversible Inhibition 241 5. B Selected Examples of Competitive Reversible Inhibitor Drugs B.1 Simple Competitive Inhibition: Captopril, Enalapril, Lisinopril,and Other Antihypertensive Drugs ,242 Humoral Mechanism for Hypertension 243 b. Lead Discovery 243 c. Lead Modification and Mechanism of Actio d. Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors 250 B2 Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents(Sulfa Drugs a. Lead Discovery b. Lead Modification d. Drug Resistance 257
5.4.c Transition State Analogs and Multisubstrate Analogs C 1 Theoretical basis C 2 Transition State Analogs 259 b. Pentostatin c. Multisubstrate Analogs 5.4. Slow, Tight-Binding Inhibitors D 1 Theoretical Bas D2 Enal D3 Lovastatin and Simvastatin, Antihypercholesterolemic Drugs a. Cholesterol and Its Effects b. Lead discove c. Mechanism of Action 264 d. Lead modification 265 D 4 Peptidyl TriAuoromethy! Ketone Inhibitors of Human Leukocyte Elastase 5.4. Case History of Rational Drug Design of an Enzyme Inhibitor: rit E1 Lead Discovery 268 E2 Lead Modification 5.5 Irreversible Enzyme Inhibitors 5.5.a Potential of irreversible Inhibition 5.5.B Affinity Labeling Agents B. 1 Mechanism of Action 275 B2 Selected Affinity Labeling Agents ,,,277 a. Penicillins and Cephalosporins/Cephamycins 277 5.5.C Mechanism-Based Enzyme Inactivators C1 Theoretical Aspects Drug Design Re 86 C3 Selected Examples of Mechanism-Based Enzyme Inactivators... 287 a. Vigabatrin, an Anticonvulsant Drug Eflornithine, an Antiprotozoal Drug and Beyond c. Tranylcypromine, an Antidepressant Drug d. Selegiline(L-Deprenyl), an Antiparkinsonian Drug e. 5-Fluoro-2 -Deoxyuridylate, Floxuridine, and 5-Fluorouracil Antitumor Drugs 5.6 General References 5.7 Problems 303 5.8 References 307 6 DNA- Interactive agents 6.1 Introduction ,324 6. 1.A Basis for DNA-Interactive Drugs 6. 1. B Toxicity of DNA-Interactive Drugs 6. 1.C Combination Chemotherapy 327
6. 1. D Drug Int 6. 1.E Drug Resistance 327 6.2 DNA Structure and Properties 6.2.a Basis for the Structure of dna 6.2. B Base Tautomerization 6. 2.C DNA Shap 6.2. D DNA Conformatic 341 6.3 Classes of Drugs That Interact with DNA 6.3.A Reversible DNA Binders 344 A 1 External Electrostatic Binding 345 A 2 Groove Binding A3 Intercalation and Topoisomerase-Induced DNA Damage a. Amsacrine an Acridine Analog in analor c.Doxorubicin(Adriamycin)and Daunorubicin(Daunomycin Anthracycline Antitumor Antibiotics 351 d. Bisintercalating A 6.3. B DNA Alkylators B. 1 Nitrogen Mustards b. Chemistry of Alkylating Agents Lead Modification 356 d. Drug resistance B2 Ethylenimine B 3 Methanesulfonates 358 B4(+)-CC-1065 and Duocarmycins B5 Metabolically Activated Alkylating Agents ,36l b. Triazene Antitumor drugs 363 c. Mitomycin C d. Leinamycin 6.3. c DNA Strand Breakers 368 C 1 Anthracycline Antitumor Antibiotics C2 Bleomycin 371 C3 Tirapazamine 377 C 4 Enediyne Antitumor Antibiotics a, Esperamicins and Calicheamicins b. Dynemicin A c. Neocarzinostatin(Zinostatin) C5 Sequence Specificity for DNA Strand Scission 6.4 Epilogue to Receptor-Interactive Agents 386 6.5 General References 6.7 References 7 Drug Metabolism 7.2 Synthesis of Radioactive Compounds 408
7.3 Analytical Methods in Drug Metabolism 411 7.3.A Isolation 412 7.3. B Separation 412 413 3. D Quantificatio 414 7.4 Pathways for Drug Deactivation and Elimination 415 7. 4.A Introduction 7.4.b Phase I Transformations 418 B. 1 Oxidative Reactions Alkene Epoxidati Oxidations of Carbons Adjacent to sp2 Centers 428 d. Oxidation at Aliphatic and Alicyclic Carbon Atoms 430 Oxidations of Carb 430 f. Oxidations of Carbon-Oxygen Systems g. Oxidations of Carbon-Sulfur Systems 444 h. Other Oxidative reaction i. Alcohol and Aldehyde Oxidations 447 B 2 Reductive Reactions 448 Carbonyl Reductio b. Nitro reduction c. Azo Reduction 451 d. Azido Reduction e. Tertiary Amine Oxide Reduction 452 f. Reductive Dehalogenatic B3 Carboxylation Reaction 53 B 4 Hydrolytic Reactions 454 7. 4.C Phase II Transformations: Conjugation Reactions C 1 Introduction C 2 Glucuronic Acid Conjugation C 3 Sulfate Conjugation 460 C4 Amino Acid Conjugation C5 Glutathione Conjugation C 6 Water Conjugation 466 C7 Acetyl Conj ugation C 8 Fatty Acid and Cholesterol Conjugation 468 C9 Methyl Conjugation 7. 4. Hard and Soft Drugs; antedrugs 471 7.5 General References 7.6 Problems 475 7.7 References 8 Prodrugs and Drug Delivery Systems 8. 1 Enzyme Activation of Dru ..498 8.1.a Utility of Prodrugs A 1 Aqueous Solubility 499 A 2 Absorption and Distribution A 3 Site Specificity
A4 Instability A.5 Prolonged Release 4 A6 Toxicity 7 Poor Patient Acceptability A8 Formulation Problems 5X) 8. 1.B Types of Prodrugs 8.2 Mechanisms of Drug Activation 8. 2.A Carrier-Linked Prodrugs A 1 Carrier Linkages f Functional grou 50)1 a. Alcohols, Carboxylic Acids, and Related Groups 503 c. Sulfonamides d. Carbonyl Compounds A2 Examples of Carrier-Linked Bipartate Prodrugs a. Prodrugs for Increased Water Solubility 50)5 b. Prodrugs for Improved Absorption and Distribution 507 c. Prodrugs for Site Specificity 507 d. Prodrugs for Stability e. Prodrugs for Slow and Prolonged Release.......,.. 51 f. Prodrugs to Minimize Toxicity 5l4 g. Prodrugs to Encourage Patient Acceptance 5l4 h. Prodrugs to Eliminate Formulation Problen 516 eneral Strategy 56 Poly(a acids) 517 d. Other Macromolecular Suppo 519 A4 Tripartate Prodrugs A. 5 Mutual Produ 525 8.2. B Bioprecursor Prodrugs 526 B. 1 Origins B2 Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole B3 Hydrolytic Activation B 4 Elimination Activation 530 B5 Oxidative Activation a. N-and O-dealkylations b. Oxidative Deamination 530 c. N-Oxidation 532 d. S-Oxidation e. Aromatic Hydroxylation .536 f. Other Oxidatio 536 B6 Reductive Activation a. Azo Reduction 537 b. Azido Reduction c. Sulfoxide Reduction