NOTES
November, 1963
TABLEI1 BACTERIOSTATIC ACTIVITIES (m.i.c., 1/X X 10-3)' NO.
I IT I11 Iv
M . pyogenes
M . pyogenes
var. a w e u s (5)
var. aureus (R)
OF
817 PHENOLIC DERIVATIVES Pseudo-
Sarcina lutea
Streptococcus Escherichia faecalzs colt N o . 198
Aerobacter aerogenes
Salmonella pullorum
monas aeruginosa
Proteus mirabalis
Pioteus vulgaris
80 80 80 10 10 20 20 20 20 10 1280 1280 640 20 20 20 10 10 10 1280 2560 1280 10 20 20 10 10 640 640 320 80 10 20 10 40 10 v 10 640 640 640 20 20 20 10 20 VI 10 .io0 mg. kg. with repeated daily i.p. dosagc, 17
I) -1 Kainotskh t u b e desc11bad
Sovember, 1963
819
NOTES
43 9
H G O
lo----N 27.8
11.0
12.8
47.Y
5.8
33.5
13.0
35.6
13.6
45.6
5.3
35.3
13.i
4.4
27.7
12.7
42.3
4.4
27.3
12.3
48 5
6.4
23.6
10.8
48.3
6.5
23.6
11.1
45 6
4.7
29.5
13.5
45.5
5.1
29.4
13.4
43 4
5.0
41.3
4?J.s
5.4
44.3
49.3
6.0
44.7
49.0
6.2
45.0
s
5.4
46.8
47.3
5.7
46.4
42.5
4.5
37.2
42.7
4.8
37.4
49 1
5.5
38.2
49.4
5.5
38.0
46 6
4.9
40.8
47.0
5.1
40.4
49.1
5.5
38.2
19.4
5.5
38.6
43.3
5.2
43.3
43 .O
5.2
42.8
Calcd.,
~~~
-_ _Found,
r
S
C
28.2
i0.i
5.6
3 3 .6
45.7
5.1
42 7
C'
H
pi
44 3
6.1
48 0
47
addition of glacial acetic acid to pH 7.
8
Compound recrystallized from boiling H20with addition of sufficient ethanol toeffert solution.
dissolved in formamide (3 ml.) and heated at 170' for 1 Iir. Addition of ethanol and ether gave a formrl derivative (0.16 E.), m.p. above 300". A n a l . Calcd. for C ~ H I O S ~ OC, ? : 43.2; H, 4.5; S , 37.8. Found: C. 42.9: H , 4.7: S , 38.1. The formyl compound (0 1 g.) was deformylated by solution in water and treatment with a fen drops of XH,OH. A solid soon separated mhich \%ascollected and rerrvstallized from water to J ield white needles ( 0 065 g ) I
Hydroxymethylglyoxal Bisguanylhydrazone' TI Lr Loo, ROBERTL. Dion-, JACK D. DAVIDSOX, RICHARD H. ADAMSON, Clinical Pharmacology and Experimental TherupLutics Service, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesdu, lMuryland AND
ROBERTR. EXGLE?
Riker Laboratories, I n c . , Sorthridge, California Received M a y 21, 1963
Several derivatives of guaiiylhydrazine have been reported to be active in inhibiting animal and human tumor^.^^-^ One of the most active compounds of this group, hydroxymethylglyoxal bisguanylhydrazone, was purportedly prepared by an osazone type of reaction between 1 mole of hydroxyacetone and 3 moles of aminoguanidine sulfate in aqueous acetic a ~ i d . ~ The b (1) The correct chemical name is 1 , l - [(hydroxyrnethyl)ethanediylidine dinitrilo Idiguanidine. (2) The work at Riker Laboratories, Inc.. was supported by Contract S.4-43-ph-3764 from t h e Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health, Public Health Service. (3) (a) B. L. Freedlander and F. A. French, Came? Res., 18, 360 (1958); (b) B. L. Freedlander and F. A. French, ibid., 18, 1286 (1958); (c) J. F. Holland, E. Milhioh, B. Bryant, and A . I. Mulhern, ibid., 21, (1961).
detailed synthetic procedure and the characterization of the compound have so far not been published. From available chemical, physicochemical, and biological evidence4 it soon became apparent that the presumed hydroxymethylglyoxal bisguanylhydrazone mas actually methylglyoxal bisguanylhydrazone instead. In view of the ready isomerization of dihydroxyacetone into m e t h y l g l y ~ x a l ~and ~ - ~the possible failure of the osazone reaction we decided to prepare the hydroxymethylglyoxal bisguanylhydrazone by the direct condensation of aminoguanidine ivith hydroxymethylglyoxal freshly prepared by the mild oxidation6 of dihydroxyacetone. This proved to be successful, and the product so obtained was significantly different from the compound previously reported. 3b Because elementary analysis cannot differentiate between methylglyoxal bisguanylhydrazone dihydrochloride monohydrate (C5HlsClzN80) and hydroxymethylglyoxal bisguanylhydrazone dihydrochloride (C5H14C12S80) it was necessary to resort to n.m.r. spectroscopy. The data reported below are consistent with the conclusion that the present condensation product is indeed hydroxymet hylglyoxal bisguanylh ydrazon e. Experimental' Hydroxymethylglyoxa1.-This was prepared according to the published procedure6 from dihydroxyacetone by oxidation either (4) J. D. Davidson, R . R. Engle, a n d R. W. Xancuso. Cancer Chemotkera p v Rept., in rress. ( 5 ) (a) K. Bernhauer and H . Gorlich. Biochem. Z . , 212, 462 (1929); (b) H. 0. L. Fischer and L. Feldmann, Ber., 62, 863 (1929); (c) H. 0. L. Fischer and C. Traube, ibid., 17, 1502 (1924): (d) G . Pinkus, i b i d . . 81, 36 (1898). (6) G . Hesse. F. Ramisoh, and K. Rennet, ibid., 89, 2137 (1956). (7) All melting points are corrected.
