Synthesis of S-(1-diazo-2,2,2-Trifluorethyl) Cysteine Dioxide : A Potential Gutamine Antagonist
Thesis - Open Access
Master of Science (MS)
Department / School
Compounds affecting the utilization of L-glutamine have a comparatively long history in the field of cancer chemotherapy. The Streptomyces antibiotics, azaserine (0-diazoacetyl-L-serine) and DON (6-diazo-5-oxo-L-norleucine) inhibit to varying extents those aminations in which glutamine serves as an amino group donor. This inhibition is achieved in at least one case by the glutamine antagonists alkylating the sulfhydryl group of the enzyme that catalyzes the amino group transfer of glutamine. A distinguishing feature of the diazo analogs of glutamine is the very reactive diazo group that enhances nucleophilic reactions on the adjacent carbon atom. Because of the increased reactivity created by the diazo group, the diazo analogs of glutamine irreversibly inhibit the glutamine requiring enzymes. Although having gone through exhaustive clinical tests, the L-glutamine antagonists, azaserine and DON, readily declined in interest because of their ineffectiveness in treatment of human malignancies. The recent success of L-asparaginase in the therapy of certain human neoplasms has prompted a reconsideration of compounds which can alter L-glutamine metabolism because: (1) L-glutamine is necessary in most mammalian systems, for the synthesis of L-asparagine; (2) both azaserine and azotomycin appear to be synergistic with L-asparaginase against the L5178Y mouse leukemia; and (3) L-asparaginase from E. coli (EC-2) of the form in clinical use in the United States has intrinsic L-glutaminase activity. EC-2 preparations appear to be more active against certain tumor cells than. guinea pig or agouti serum preparations that lack L-glutaminase activity. Whether this is due to the additional L-glutaminase activity remains to be proven. The purpose of making compounds which are structurally similar to the two antibiotics is threefold. These are to produce a compound which (1) is more active against the tumor, (2) is less toxic to the patient and (3) will help elucidate the mechanism and nature of its bonding to active sites of enzymes in various biological reactions. The history is divided into two parts; the first section deals with the importance of L-glutamine in metabolic and biosynthetic pathways, the second part concentrates on glutamine antagonists and their inhibitory effect with the biosynthesis or metabolic roles of the parent compound.
Library of Congress Subject Headings
Cancer -- Chemotherapy
Cancer -- Research
Number of Pages
South Dakota State University
Olson, Robert M., "Synthesis of S-(1-diazo-2,2,2-Trifluorethyl) Cysteine Dioxide : A Potential Gutamine Antagonist" (1974). Electronic Theses and Dissertations. 4748.