The Metabolism of Folic Acid (pteroyl-L-glutamic acid):the Synthesis and Tumor Inhibitory Properties of Simple Hydrazines

Abstract

Pteroyl-L-glutamic acid (folic acid) is a vitamin which is now known to be widely distributed in nature, being found, usually in a reduced form, in plant and mammalian tissues and in bacteria. These reduced forms and their derivatives play a vital role asco-enzymes in biochemical systems, and it as such that one of their number is an essential participant in the multiplication processes of normal cells. There is increasing evidence to suggest that folic acid is implicated in the metabolism of tumour cells also characterised as they are by uncontrolled cell multiplication. An understanding of the biosynthetic and degradative pathways of this important vitamin would therefore seem desirable. Although the biosynthesis of folic acid is now fairly well elucidated, very little is known about its biochemical degradation, and it is with the latter that the first part of this thesis is concerned. Isoxanthopterin, was considered to be a possible ultimate degradation product of folic acid. The development of a technique for the isolation and quantitative estimation of the is oxanthopterin found to be present in human urine, is described. The results of investigations into the metabolic degradation of folic acid in the rat using the above technique to isolate the end products, are reported and discussed. During the last four years, a series of 1,2 disubstituted hydrazine derivatives have emerged as potent tumour inhibitors. Early work on the structure-activity relationship of these compounds suggested that the group CH3NHNHCH2C6H4-R was a common structural feature essential to tumour inhibition. The synthesis and chemotherapeutic estimation of a series of alkyl and aryl substituted hydrazines essentially designed to test the validity of this relationship, is described. The tumour inhibitory properties of the synthesised hydrazines are discussed in relation to the current theories as to their mode of action, including their possible reaction with folic acid derivatives.