Riboflavin antagonists

Anemia. Anemia has been produced experimentally in human subjects given galactoflavin, a riboflavin antagonist. The anemia, along with other symptoms, respond rapidly to riboflavin therapy. 

Antagonists of riboflavin include isoriboflavin, lumiflavin, aiaboflavin, hydroxyethyl analogue, formyl methyl analogue, galactoflavin, and flavin-monosulfate. Synergists include vitamins A. B, B(l, and B12, niacin, pantothenic acid, folic acid, biotin, tetraiodothyronine (thyroxine), insulin, and somatotrophin (growth hormone). 

This approach has the possible advantage over using a combination of two inhibitors, that it eliminates all the pharmacokinetic variables and synchronizes the inhibitory action at the two enzyme sites. However, there is a competition between the two enzymes for the inhibitor, since each molecule of the latter can bind only to one enzyme therefore, the relative extent of inhibition of the two metabolic reaction steps depends on the relative affinities (ratio of the Kj values) of the inhibitor for the two enzymes. This, of course, is determined by the structure of the inhibitor, and it should be amenable to change via structural modifications (e.g., by providing 71 with a hydroxyalkyl side chain and thus making it more closely similar in structure to riboflavin and more antagonistic to it). Although this approach has inherent limitations in scope, its further exploration appears to be of interest. 

Ethyl-9-(i -D-ribityl)isoalloxazine (6-ethylflavin), is a low potency antagonist of riboflavin in the nutrition of the rat with an inhibition index of approximately 400. It has been found to possess about 3% of the activity of riboflavin when used as the sole flavin in the nutrition of L. casei ... 

Diethyl-9-(i -D-ribityI)isoalloxazine (diethylriboflavm), is a competitive antagonist of riboflavin for growth in the rat with an inhibition index of about 6. When any but very small quantities are administered to the riboflavin-deficient rat, a growth response is obtained . The compound does not, however, serve as a replacement of riboflavin in the nutrition of the animal because it does not permit survival - . It can serve as the sole source of flavin in the nutrition of L. casei for which organism it has 100% of the activity of equivalent amounts of riboflavin up to the concentration of 8.22 lO moles per ml. At higher concentrations its activity levels off at about 90%. It is also able to serve as the sole source of flavin for B. lactis acidi. ... 

The compound is a potent, reversible antagonist of riboflavin in the nutrition of L. casei with an inhibition index of 76. When L. casei ATCC 7469 is incubated for several days in a medium containing a mixture of this flavin and a small amount of riboflavin a modified form of L. casei emerges. This modified form is able to utilize either riboflavin or the b-chloro-y-methyl-flavin as its sole flavin - . 

A wide variety of artificial analogs of riboflavin have been prepared in order to explore the structural versus functional essentials of the molecule. Some of these analogs have riboflavin-like activity others are inactive, while a number are antagonists, and can cause functional deficiency. These structural changes... 

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