Robert B. Angier

SYNTHESIS OF PTEROYLGLUTAMIC ACID (LIVER L. CASEI FACTOR) AND PTEROIC ACID

Upon completion of the degradation of the Luctobacihs c a m factors and the synthesis of the fragments, the structure of the liver L. casei factor was proposed. The fermentation factor and the liver factor differed in the number of glutamic acid residues. The structure for the liver compound showed only one glutamic acid, while the fermentation factor appeared to contain three such residues. Both factors yielded p-aminobenzoic acid and the same pteridines upon degradation. On this basis, both factors appeared to have the same pteridine nucleus attached to the p-aminobenzoic acid, as indicated in the proposed structure for the liver factor. The chemical name is obviously too long for general usage. For the basic nucleus, a name iodicating its pterin nature is desirable. Thus, the name “Pteroylglutamic Acid” is proposed for the liver L. casei factor. The fermentation L. casei factor and analogous cornpounds containing various amino acids can also be named as pteroyl derivatives. The basic structure for these compounds would, accordingly, be called “Pteroic Acid.” The syntheses of pteroylglutamic acid and pteroic acid are reported herein.

α-Nitro-epoxides, a new class of compounds

The first examples of α-nitro-epoxides have been prepared; some chemical properties are reported.

STRUCTURE AND SYNTHESIS OF THE PTERIDINE DEGRADATION PRODUCTS OF THE FERMENTATION L. CASEI FACTOR

The two preceding papers of this series have indicated the nature of the degradation products obtained from the fermentation Lactobacillus casei factor1: namely, the dl liver L. cnsei factor, p-aminobenaoic acid, pyrrolidonecarboxylic acid, 1 (+ ) glutamic acid, 2-amino4 hydroxy 6 pteridinecarboxylic acid,+ and 2 amino 4 hydroxy 6 methylpteridine. The first four of these substances were known compounds and could be readily identified, whereas the two pteridine compounds were new substances which required further degradation, as well as synthesis, in order to establish their structure. The above 2-amino-4-hydroxy-6-pteridinecarboxylic acid was first isolated from the oxidative alkaline hydrolysate of the fermentation L. casei factor. The empirical formula determined from analytical data, the ultraviolet absorption spectrum, the titration curve, and the positive test for guanidine, all of which have been described in the preceding papers, led us to suspect the presence of a pteridinecarboxylic acid. Decarboxylation of a few milligrams of the substance liberated a little less than one mole of carbon dioxide, and the residue, when purified, appeared to resemble 2-amino-4-hydroxypteridine, a substance which we had synthesized by reacting 2,4,5-triamino-6-hydroxypyrimidine with glyoxal. The synthesis of the 2-amino-4-hydroxy-6-pteridinecarboxylic acid was then effected by reacting 2,4,5triamino-6-hydroxypyrimidine with kctomalonic ester, to give isoxanthopterin carboxylic acid2 which was chlorinated with a mixture of phosphorus pentachloride and phosphorus oxychloride. The chlorine group wag then replaced with hydrogen by reduction of the chloro com-

Chapter 14. Antifungal Agents

Publisher Summary This chapter describes the development of antifungal agents. Amphotericin B has been found useful in treatment of the diseases such as rhinocerebral phycomycosis, rhino-orbital mucormy lastomycosis, and mycotic endocarditis due to Cryptococcus neoformans . The degree of susceptibility of a variety of C. neoformans strains to amphotericin B was shown by an in vitro study in which 65 human and 25 environmental isolates of C.n. were treated with various concentrations of the antibiotic. A mode of action study of azalomycin F on Candida albican indicates that at its minimum growth inhibitory concentration, the antibiotic strongly inhibited amino acid incorporation into cellular protein and generally prevented the substrate respiration of amino acids. In an effort to obtain an increased concentration of griseofulvin in the blood the 4′-oxime and 4′-alcohol derivatives were prepared and then tested in rabbits. Oral dosing gave plasma levels of griseofulvin as high as or higher than when the antibiotic itself was used but the high levels were of short duration. A critical review and evaluation of the laboratory investigations and clinical uses of the antifungal drug tolnaftate (IV) have also been presented in the chapter.

Chapter 15. Antifungal Agents

Publisher Summary Considerable effort has been given to the study of the mode of action of various antifungal antibiotics. This chapter is divided primarily into sections on polyene and nonpolyene antibiotics as well as synthetic compounds. Polyene Antibiotics are of considerable usefulness, primarily for the treatment of systemic mycoses and conditions caused by various species of Candida. These antibiotics cause a change in the permeability of the fungal cell membrane with attendant depletion of essential cellular constituents and that this change in permeability is in some way triggered by a binding of the antibiotic to the cell membrane via a steroid-antibiotic complex. Recently, the mode of action of nonpolyene antibiotics such as griseofulvin is also receiving attention. Griseofulvin interferes with the replication mechanism of fungal cells. As for synthetic antifungal agents, the most interesting of the antifungal agents developed recently is probably tolnaftate—a synthetic antifungal. This compound is a highly effective and extremely well tolerated specific agent in the treatment of superficial mycoses caused by dermatophytes. It is noteworthy, however, that two cases of tinea nigra caused by Cladosporium wernecki are found not to be cured. It is indicated that tolnaftate does not adversely affect rat or mouse fetal and postnatal development. Other agents, such as thiabendazole—a synthetic anthelmintic—is useful in superficial fungus infections of the skin, particularly dermatophytic infections of the groin and feet.