J O U R N A L OF THE AMERICAN CHEMICAL SOCIETY (Registered in U. S. Patent Office)
(Copyright, 1954, by the American Chemical Society)
FEBRUARY 19, 1954
VOLUME76
[CONTRIBUTION FROM
THE
NUMBER 3
BIOCHEMICAL INSTITUTE AND THE DEPARTMENT OF CHEMISTRY, THE UNIVERSITY OF TEXAS, AND THE CLAYTON FOUNDATION FOR RESEARCH]
Synthesis and Biological Activity of Homologs of Pyridoxal and Pyridoxamine BY MIYOSHI IKAWAAND ESMOND E. SNELL RECEIVED SEPTEMBER 21, 1953 The synthesis of 2-ethyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine (w-methylpyridoxal), of 2-ethyl-3-hydroxy-4aminomethyl-5-hydroxymethylpyridine(w-methylpyridoxamine) and of their corresponding 5-phosphoric acid esters is described. These homologs of vitamin B,j are without growth-promoting activity for yeast, but act as antagonists of vitamin Befor this organism. Under the conditions tested they have growth-promoting activity for lactic acid bacteria varying from 1 t o 34% that of vitamin B6 itself.
A homolog of pyridoxine, 2-ethyl-3-hydroxy-4,5bis- (hydroxymethyl)-pyridine (w-methylpyridoxine (I)), synthesized by Harris and Wilson1 was found by Rabinowitz and Snel12 to be the most potent antagonist of vitamin Be for yeast so far tested. For this reason, the corresponding homologs of pyridoxal and pyridoxamine and their phosphoric acid esters become of considerable interest. CHzOH
CH=NOH
----f
CzHa
I CHzNHz
IV
I1
J
CHzNHz CHzOP03Hz
V
aminomethyl-5-pyridylmethylphosphoric acid (wmethylpyridoxamine phosphate (V)), which on oxidation with manganese dioxide yielded 2-ethyl-3hydroxy-4-formyl-5-pyridylmethylphosphoric acid (a-methylpyridoxal phosphate, (VI)). The structures of the products are based on analogy with the reactions of pyridoxine, which are almost identically followed. The effects of these compounds on growth vary remarkably with the test organism and the conditions, and will be considered in greater detail elsewhere. I11 Results of a preliminary screening (Table I) show each of the unphosphorylated compounds to act as vitamin ~6 antagonists for yeast. For lactic acid bacteria they show growth-promoting activity similar to VI but of a lower order than that of the corresponding forms of vitamin Bs.
Compound I was oxidized with manganese dioxide a t room temperature and the product, 2-ethyl3-hydroxy-4-formyl-5-hydroxymethylpyridine(wExperimental 3,4 methylpyridoxal (111)), isolated as its oxime (11). Oxime of 2-Ethyl-3-hydroxy-4-formyl-5-hydroxymethylI1 was converted to I11 with nitrous acid. I1 on pyridine (II).-A generous sample of 2-ethyl-3-hydroxyhydrogenation in the presence of platinum catalyst 4,5-bis-(hydroxymethyl)-pyridine hydrochloride (I), m.p. 188-189's was supplied by Dr. Karl Folkers of Mer& and gave 2 ~ e ~ ~ y ~ ~ 3 ~ ~ y ~ r o x y ~ 4 ~ a m i n o m e t h y lCo., - 5 - Inc. ~y~~ ~ y ~g.r 0of~Iy in ~ 22.5 ml. of 0.67 N hydroT5 o~ 0.915 methYlPYridine (w-methYlPYridoxamine ( I v ) ) * I v chloric acid was added 8.7 g. of powdered manganese dioxwas treated with phosphorus pentoxide in 85y0 ide. The mixture was shaken occasionally during two days phosphoric acid to give 2-ethyl-3-hydroxy-4- at room temperature. Hey15 has reported the oxidation of (1) S. A. Harris and A. N. Wilson, TKISJOURNAL, 68, 2526 (1941). (2) J. C. Rabinowitz and E. E. Snell, Arch. Biochcm. Biophys., 4S, 399, 408 (1953).
637
(3) All melting points are corrected. (4) Microanalyses in part by Dr. A. Elek. ( 5 ) D. Heyl, THISJOURNAL, 70, 3434 (1948).
_\lruos~rrIIC\will AND ESRZOND E.SNELL
63s TABLE I
COMPARATIVE ACTIVITIESO F O-AlETHYLHONIOLOGS O F VITAX I N B6 I6 P R O M O T I S C GROWTH OF ~fICROORGANISMS soc-
hctivitya for
ihavo-
iizyces caulsbey-, qensw 42280 , pyridox-
Compound
ine = 100)
o-Methylpyridosirie ( I ) 0.0' w-Methylpyridoxal(II1) .cIC w-Methylpyridoxaniine (IY) .O' o-Methylpyridoxamine phosphate (V) .o w-hlethylpyridoxal phosphate (VI) .o
Stveplococcus fa6calrs 8043d
Lartobacillys
Lactobacillus delbuueckii
96491 (pyridox(pyri7460 e amine dox(pyriphoeamine = doxal = phate = 100) 100) 100)
