Exploring QSAR Volume 2: Hydrophobic, Electronic, and Steric Constants

by Hansch, Corwin; Leo, Albert; Hoekman, David

• ISBN13: 9780841229914
• ISBN10: 0841229910
• Format: Hardcover
• Copyright: 1995-05-05
• Publisher: American Chemical Society

Summary

This two-volume set investigates the interaction of organic compounds with various forms of life, including macromolecules, enzymes, and organelles. It provides an introduction to the Hammett equation and its applications, as well as a discussion of the design of bioactive compounds. Volume 2 includes extensive tables of approximately 17,000 partition coefficients from octanol-water and a comprehensive listing of electronic and steric parameters in the design and study of bioactive organic compounds.

Table of Contents

Preface	xiii
Electronic Effects on Organic Reactions	1	(24)
Hammett Equation	1	(2)
Limitations of the Hammett Equation	3	(2)
Through-Resonance (σ0, σ-, σ+)	5	(4)
Field-Inductive Effect	9	(2)
Separation of Inductive and Resonance Effects	11	(3)
Yukawa-Tsuno Equation	14	(1)
Radical σ Constants	15	(1)
σ for Substituents Attached to Phosphorus (σ&phis;)	16	(1)
Aryl Values (σa)	16	(1)
Recently Formulated Electronic Parameters	16	(2)
Hammett Equation and Thermodynamics	18	(1)
Molecular-Orbital Parameters	19	(3)
Summary	22	(3)
Applications of the Hammett Equation and Its Extended Forms	25	(44)
Introduction	25	(1)
Effects of Temperature, Pressure, and Solvent	26	(3)
Ionization of Phenols and Thiophenols	29	(1)
Transmission of Substituent Effects	29	(6)
Solvolysis	35	(8)
Nucleophilic Substitution	43	(5)
Electrophilic Substitution	48	(2)
Elimination Reactions	50	(2)
Addition Reactions	52	(1)
Intramolecular Cationic Rearrangements	53	(8)
Radical Reactions	61	(2)
Oxidation-Reduction Reactions	63	(2)
Summary	65	(4)
Steric Effects on Organic Reactions	69	(28)
Introduction	69	(1)
Taft's Approach to Steric Effects	70	(1)
Modification in the Definition of Es	71	(5)
Sterimol Parameters	76	(2)
Molecular Refractivity as a Steric Parameters	78	(7)
Comparative Molecular-Field Analysis (CoMFA)	85	(3)
Applications of Steric Parameters in Physical Organic Chemistry	88	(4)
Summary	92	(5)
The Hydrophobic Parameter: Measurement and Calculation	97	(28)
Introduction	97	(2)
History of Partitioning as a Hydrophobic Parameter	99	(1)
Calculation From Other Equilibria or Other Physical Constants	100	(3)
Calculation From Solute Structure	103	(15)
Measurement of Octanol-Water Partition Coefficients by Shake-Flask	118	(3)
Conclusions	121	(4)
Calculation of Octanol-Water Partition Coefficients by Fragments	125	(44)
Historical Perspectives and Development of CLOGP Software	125	(4)
Bond Environments	129	(1)
Fragment Classes	130	(2)
Correction Factors	132	(21)
Tautomers	153	(3)
Zwitterions	156	(2)
Ion Pairs	158	(3)
Current Developments and Conclusions	161	(8)
QSAR of Nonspecific Toxicity	169	(54)
Introduction	169	(1)
QSAR of Model Systems	170	(3)
Linear QSAR with Slopes Near 1	173	(7)
Linear QSAR with Slopes Less Than 1	180	(4)
Linear QSAR with Large Intercepts	184	(1)
Linear QSAR for Whole Animals	185	(3)
Nonlinear QSAR for Nonspecific Activity	188	(10)
Other Approaches to Nonspecific Toxicity	198	(7)
Empirical Models of Similarity	205	(1)
Reverse Hydrophobic Effect	206	(1)
Environmental Toxicology	206	(11)
Summary	217	(6)
QSAR of Proteins and Enzymes	223	(76)
Model Systems	223	(2)
QSAR of Protein-Ligand Binding	225	(4)
QSAR of Nonspecific Enzyme Inhibition	229	(2)
QSAR of Specific Enzyme-Ligand Interactions	231	(56)
Summary	287	(12)
QSAR in Metabolism	299	(50)
Introduction	299	(2)
Phases of Drug Metabolism	301	(8)
Phase-II Processes	309	(2)
Cytochrome P450 Binding and Induction	311	(13)
QSAR of Microsomal Oxidation	324	(5)
QSAR of Microsomal Inhibition	329	(4)
Glucuronidation	333	(2)
Sulfation by Phenol sulfotransferase (PST)	335	(2)
Conjugation with Glycine	337	(1)
Elimination	337	(6)
Summary	343	(6)
QSAR of Mutagenesis, Carcinogenesis, and Antitumor Drugs	349	(38)
Introduction	349	(1)
Mutagenesis	350	(12)
Carcinogenicity	362	(5)
Cancer Chemotherapy	367	(16)
Summary	383	(4)
QSAR of CNS Agents	387	(24)
Introduction	387	(1)
Blood-Brain Barrier (BBB)	388	(2)
Prodrugs	390	(2)
Nonspecific CNS Agents	392	(4)
General Anesthetics	396	(1)
Anticonvulsants	397	(6)
CNS Stimulants	403	(1)
QSAR of Serotonin Receptors	404	(3)
Summary	407	(4)
Microbial QSAR	411	(48)
Introduction	411	(1)
Antiviral QSAR	412	(4)
Antibacterial QSAR	416	(26)
Antiprotozoal QSAR	442	(4)
Antifungal QSAR	446	(8)
Summary	454	(5)
Pesticide QSAR	459	(54)
Introduction	459	(3)
Herbicides	462	(23)
Insecticides	485	(24)
Summary	509	(4)
Notes on the Design of Bioactive Compounds	513	(32)
Introduction	513	(2)
Bioisosterism	515	(6)
Substituent Selection	521	(10)
Building a QSAR	531	(2)
New Lead Generation	533	(2)
Regression Analysis	535	(6)
Summary	541	(4)
Index	545