Synthesis and Biological Activity of 7-Methyl-8-bromo-10-(1-d-ribityl)iso-alloxazine,an Analog of Riboflavin 1

Abstract

Dichlororiboflavin (7, 8-dichloro-10- (1′-d-ribityl)isoalloxazine) (Fig. 1, II) was the first antagonist of riboflavin (Fig. 1, I) to be described (1). It was found to temporarily inhibit Staphlococcus aureus and Streptobacterium plantarum P-32, neither of which require an exogenous source of riboflavin. Later it was shown (2) that the compound was essentially inert for Lactobacillus casei, an organism dependent on an exogenous source of riboflavin. The findings for L. casei were confirmed and it was also shown that the compound was inert for the rat (3).

Two analogs of riboflavin whose structures did not depart so extensively from the structure of riboflavin were synthesized (4) for biological evaluation. These two analogs were 7-chloro-8-methyl-flavin (7-chloro-8-methyl-10-(1′-d-ribityl)isoalloxazine) (Fig. 1, III) and 7-methyl-8-chloro-flavin (7-methyl-8-chloro-10-(1′-d-ribityl)isoalloxazine) (Fig. 1, IV). It was found that 7-chloro-8-methyl-flavin is a potent, reversible antagonist of riboflavin in L. casei and in the rat. The growth response in the riboflavin-deficient rat when small quantities of this analog are given, was approximately equal to that caused by the administration of riboflavin when the latter was given in quantities equal to one-half the quantities of analog used. Larger amounts are lethal to the rat. This compound is, therefore, the most potent vitamin-like analog of riboflavin in terms of growth of the rat and it is also the most potent antagonist of riboflavin in terms of its lethal properties (5). During the administration of this flavin, the riboflavin-deficient animals recover from the visually observable signs of the deficiency (6). The isomeric 7-methyl-8-chloro-flavin was found to be the most potent reversible antagonist of riboflavin for L. casei to have been described. It is able to produce only a small growth response and only moderate improvement in the animals appearance when large amounts are given to rats (3).