Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1995 A quantitative structure-activity relationship (QSAR) study of chlorinated cyclodiene insecticide analogs Jianbo Liu Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Entomology Commons, Organic Chemistry Commons, and the Toxicology Commons Recommended Citation Liu, Jianbo, "A quantitative structure-activity relationship (QSAR) study of chlorinated cyclodiene insecticide analogs " (1995). Retrospective Theses and Dissertations. 11070. https://lib.dr.iastate.edu/rtd/11070 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. 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Ml 48106-1346 USA 313.'761-4700 800.'52l-0600 A quantitative structure-activity relationship (QSAR) study of chlorinated cyclodiene insecticide analogs by Jianbo Liu A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Department: Entomology Interdepartmental major: Toxicology Approved: Signature was redacted for privacy. n Charge of Major Work Signature was redacted for privacy. For the Major Department Signature was redacted for privacy. For the Interdepartmental Major Signature was redacted for privacy. For the Graduate College Iowa State University Ames, Iowa 1995 DHI Number: 9610971 DHI Microform 9610971 Copyright 1996, by OMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 ii TABLE OF CONTENTS Page GENERAL INTRODUCTION 1 Cyclodiene Insecticides 1 Mode of Action for Cyclodiene Insecticides 2 Structure-Activity Relationships of Cyclodiene Insecticides 4 Dissertation Objectives 6 Methodology 6 Dissertation Organization 8 CHAPTER I: DETERMINATION OF LIPOPfflLICITY OF CHLORINATED ALICYCLIC COMPOUNDS BY REVERSED-PHASE fflGH PERFORMANCE LIQUID CHROMATOGRAPHY 10 Abstract 10 Introduction 11 Materials and Methods 12 Results and Discussion 13 Conclusions 19 References 20 CHAPTER II: STRUCTURE-ACTIVITY RELATIONSfflPS OF CHLORINATED ALICYCLIC INSECTICIDES 23 Abstract 23 Introduction 24 Ill Materials and Methods 26 Results and Discussion 29 References 41 CHAPTER III: A QSAR STUDY ON CHLORINATED CYCLODIENE INSECTICIDES BASED ON THEIR INHIBITORY ACTIVITY ON TBPS- BINDING AND MOLECULAR CONNECTIVITY 45 Abstract 45 Introduction 46 Materials and Methods 48 Results and Discussion 50 References 63 SUMMARY AND CONCLUSION 66 REFERENCES CITED 69 APPENDIX: DIRECTED SYNTHESIS OF NEW BIODEGRADABLE DDT- TYPE INSECTICIDES 76 iv ACKNOWLEDGMENTS I am very grateful to my major professor, Dr. Joel R. Coats, leading me to the field of toxicology, especially insecticide toxicology, and for his valuable guidance, advice and encouragement throughout the course of my graduate studies. I thank Drs. Todd Anderson, Bradley F. Binder, George Kraus, James A. Thomas and Mike H. Stahr, for serving on my advisory conmiittee and for providing input to the dissertation. Special appreciation is expressed to the people in Dr. Coats' group for assistance, friendship, and maintenance of an active scientific research atmosphere. This research was financially supported from USAF Office of Scientific Research Grant No. 91-0338. I appreciate the cooperation from Dr. Janice E. Chambers' research group at the Mississippi State University, for their effort of biological measurement for this research project. I extend my thanks to my family members especially to my wife, Hulan Shang, for their affection and support. 1 GENERAL INTRODUCTION Cvclodiene Insecticides Chlorinated cyclodienes constitute a major class of insecticides which include aldrin, chlordane, dieldrin, endosulfan, endrin and heptachlor. They are produced by the Diels- Alder diene reaction. Chlorination of cyclopentadiene gives hexachlorocyclopentadiene which undergoes a Diels-Alder reaction with an appropriate alkene intermediate to obtain a given compound. The toxicity, chemistry, photochemistry and metabolic fate of the cyclodienes are well defined (1-3). Some imdergo oxidative metabolism to form epoxides, and photolysis to yield epoxides and bridged photoisomers, e.g., heptachlor is oxidatively converted to heptachlor epoxide, and each in turn undergoes a photobridging reaction (1) to form photoheptachlor and photoheptachlor epoxide, respectively. Some of the parent cyclodienes and metabolites, e.g., isobenzan and 12-ketoendrin, are highly toxic convulsants. Additionally, conformational isomers exist for some of the chemicals, e.g., aldrin vs. isodrin, dieldrin vs. endrin, P- vs. a-endosulfan, trans- vs. cw-chlordane. Toxaphene, which is a mixture consisting of 177 different chlorinated bomane derivatives, is a chlorinated alicyclic compound and sometimes is also considered as a cyclodiene-type insecticide (4), though it is not produced by the Diels-Alder reaction, but rather by chlorination of camphene. 2 Mode of Action for Cvclodiene Insecticides The action of cyclodienes involves the y-aminobutyric acid (GABA) binding sites on postsynaptic membranes in the mammalian brain tissue. GABA is a major inhibitory neurotransmitter in the central nervous system (CNS) and at neuromuscular junctions in lower animals (5). This binding involves the GABA receptor ionophore complex (6). Chlorinated cyclodienes bind at the chloride ionophore channel and block the channel, inhibiting the CI" flux into the nerve. Ample evidence supporting the hypothesis has come from the biochemical and pharmacological studies using mammalian brain tissue preparations. The GABA receptor is a complex containing at least three binding sites 1) the GABA site, 2) another site where benzodiazepine tranquilizers bind, and 3) a chloride ion ionophore which binds the convulsants picrotoxinin and the bicyclophosphates, as well as the sedative hypnotic barbiturates (7,8). Activation of GABA receptors increases membrane conductance for CI" in postsynaptic membranes, such that when an excitatory impulse is delivered, e.g., by glutamate or acetylcholine, the postsynaptic membrane does not reach threshold, and transmission of the impulse does not occur (5). Picrotoxinin is a polycyclic epoxylactone from seeds of Anamirta L. It was a known GABA antagonist as proven by inhibition of GABA-stimulated chloride permeability (9-11). Bicyclophosphorus esters such as ^-butylbicyclophophorothionate (TBPS) were found in 1970 to 1976 to also be potent convulsants which antagonize the action of GABA (12,13). a-[8,10-^H]- Dihydropicrotoxinin ([^H]DHPTX) and [^^S]TBPS are highly specific noncompetitive allosteric inhibitors of GABA which bind to the CI" ion charmel of the GABA complex and 3 are commonly used as ligands for studying chemicals acting on the receptor (14, IS). Matsumura and Ghiasuddin (16) noted that the cyclodienes inhibit chloride flux and binding of ['H]DHPTX. The cyclodienes also inhibit [^^S]-TBPS binding to rat brain membranes (17). Electrophysiological studies with insects and mammals also support the action of the cyclodienes in the GABAergic system (18). Good agreement exists, for the most part, between the potencies of the cyclodienes and hexachlorocyclohexane (BHC) isomers in inhibiting [^^SJTBPS binding and their respective mammalian toxicities (19). y-BHC (lindane), which is not a cyclodiene chemically, is currently considered as a GABA antagonist due to the well-established relationship with the cyclodienes, i.e., cross-resistance and symptomology similarities. However, an interaction of lindane with a putative voltage- dependent chloride channel in electric organ of Torpedo californica has also been suggested (20,21). Mirex and chlordecone, which are chlorinated alicyclic insecticides, but not structurally similar to cyclodienes, act by a different