Novel Antiinflammatory Compounds: Copper- And Manganese - Ethylenediamine - Diacetic Acid Complexes.
Date of Award
1-1-1985
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
Abstract
Copper and manganese complexes of bridged ethylene derivatives of twenty physiological amino acids were synthesized, and tested for their ability to quench superoxide and antiinflammatory activity for use as drugs for rheumatoid arthritis. The synthesis was accomplished by nucleophilic substitution of ethylene dibromide by the amino group of the amino acids. The derivatized amino acid complexes of copper that showed the greatest activity were leucine, alanine, serine, phenylalanine, tryptophan, tyrosine, arginine and glutamine. Valine, isoleucine and threonine ethylene copper complexes showed low reactivity. The glycine complex is unreactive. The manganese complexes showed reactivity at a concentration of a factor of ten higher than the copper complexes.The copper complexes also varied in effectiveness as in vivo antiinflammatory agents while the manganese complexes and ligands without the metals showed no in vivo activity. Uncomplexed copper ion had very low activity. The tryptophan which had the highest activity in the carrageenan-induced rat paw edema assay shows great promise as an effective antiinflammatory drug. In contrast the underivatized tryptophan amino acid copper complex had very low activity.In the second part of this study, a model of the etiology of rheumatoid arthritis was developed. In this model, the immune system functions properly but not the neuroendocrine system, which exerts control of the inflammatory process by release of glucocorticosteroids. Hypophysectomized rats were used to study the effect of a disturbance in the hypothalmic-hypophyseal tract.The results were in accordance with proposed model. With a carrageenan insult, hypophysectomized rats developed swelling of greater intensity and longer duration than the control rats. Cortisol controlled inflammation only when administered within 5 minutes of the carrageenan insult. When carrageenan was administered in multiple doses, cortisol had an effect only on the first administration but not on successive doses. The interpretation of the results support the hypothesis that (1) an initial inflammatory attack will not be affected by cortisol; (2) only the by-products of the inflammation will be affected by the steroid. These by-products perpetuate the inflammation if not checked by the endogenous glucocorticosteroids.
Recommended Citation
Katz, Bernice February, "Novel Antiinflammatory Compounds: Copper- And Manganese - Ethylenediamine - Diacetic Acid Complexes." (1985). Theses and Dissertations. 8621.
https://commons.und.edu/theses/8621