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149
MIETZSCH, F. 1936 Behavior of certain dyes and chemotherapeutics on the introduction of neutral substituents.
Med. u. Chem. Abhandl. med. chem. Forschungsstiitten I.
G. Farbenind., 3, 348-356. In Chem. Abstr., 31, 5865
(1937).
NEUBERG, C. AND ROBERTS, I. S. 1949 Remarkable properties of nuicleic acids and nucleotides. Arch. Biochem.,
20, 185-210.
STERN, A. E. AND STEARN, E. W. 1924 The chemical mechanism of bacterial behavior, III. The problem of bacteriostasis. J. Bacteriol., 9, 491-510.
STEINER, R. F. AND BEERS, R. F., JR. 1958 Spectral changes
accompanying binding of acridine orange by polyadenylic
acid. Science, 127, 335-336.
VALKO, E. I. AND DuBoIs, A. S. 1945 Correlation between
antibacterial power and chemical structure of higher alkvl
ammonium ions. J. Bacteriol., 50, 481-490.
of Tetracycline
J. LEIN, L. F. SAWMILLER, AND L. C. CHENEY
Research Division, Bristol Laboratories, Inc., Syracuse, New Yor1k
1956).
An alternative method of inhibiting chlorination
was reported by Sekizawa (1955). He found that certain organic compounds had the property of shifting
synthesis from chlortetracycline to tetracycline. The
most active compound reported was 2-mercaptobenzothiazole. It was most effective at levels which were
somewhat toxic since the highest percentages of tetracycline were obtained with amounts that inhibited
the over-all synthesis of the antibiotics. The problem
was further examined in this laboratory and a variety
of compounds tested to determine if any structure-
Texas.
150
- - -
-N\\
_ _-
- -
-N\
C-SH
TABLE 1
Effect of variouts compounds on the relative production of
tetracycline and chlorination
Leviel
Compound
Tetracycline
lents)
Inactive
1.
Compouinds
HS-CH2-CO2H
lAg/ml
%70
0.002
1575
< 50
0.002
1805
< 50
0.002
2165
<50
0.004
1475
<50
0.002
1650
< 50
0.002
1450
<50
0.006
1415
55-60
0.005
2145
50
Thioglycollic acid
(mercaptoacetic acid)
2.
CH:,- (CH2)1o-CH2-SH
1 -Dodecanethiol
3.
H,N-C-NH-C-NH2
2, 4-Dithiobillret,
4.
H2N-C-NH-NH2
Thiosemicarhazide
NaSCN
5.
Thiocyanic acid
(sodiuim
salt)
6.
NH-C
CH3-C
NH
CH-C
(HC)
6-Methyl -2-thiomracil
Slightl.y Active
NH2
7.
SH
2-Aminobenzenet,hiol
SH
N=C
C=--S
CH3-C
II
Total Activity
(Tetracycline
Equiva-
8.
-x/
[VOL. 7
CH-C-CH3
CH3
19591
TABLE 1-Continued
Level
Compound
9.
H2C-N
J C-SH
H2b
Total
Activity
(Tetracycline
Equivalents)
Tetracycline
0.003
Ug1/ml
3070
%
65
0.005
2935
50-55
ACKNOWLEDGMENTS
2-Mercapto-2-thiazoline
Moderately Active
l0.
H3C-C-N
H3C-I-S
0.003
0.005
2470
2030
65
80-85
SUMMARY
2-Mercapto-4,5-dimethylthiazole
N
11.
0.003
C-SH
3888
2160
2805
50-55
65
80
0.004
0.006
2600
3380
93-95
0.004
2360
90-95
0.004
0.006
2-Mercaptobenzothiazole
Very Active
N
12.
C-SH
90
0
2-Benzoxazolethiol
13.
Hs_t
t-SH
N
REFERENCES
ARISHMA, M., SEKIZAWA, Y., SAKAMATO, J. M., MIWA, K.,
AND OKADA, E. 1956 On the tetracycline fermentation.
J. Agr. Chem. Soc., Japan, 30, 407-409.
DOERSCHUK, A. P., MCCORMICK, J. R. D., GOODMAN, J. J.,
SZUMSKI, S. A., GROWICH, J. A., MILLER, P. A., BITTER,
B. A., JENSEN, E. R., PETTY, M. A., AND PHELPS, A. S.
1956 The halide metabolism of Streptomyces aureofaciens
mutants. The biosynthesis of 7-chloro, 7-chloro-36, and
2,5-Dimercapto-1,3,4-thiadiazole
14.
0.006
1510
90-95
C-SH
NH
2-Mereaptobenzimidazole
Differences in structure at sites other than the activity-promoting group can affect the over-all activity. Comparison of compound 9 with 10 and 11
with 14 demonstrates influences of relatively small
differences.
GOUREVITCH, A., MISIEK, M., AND LEIN, J. 1955 Competitive inhibition by bromide of incorporation of chloride into
2,763,591.
Pharmacopeia of the United States 1955 Vol. 15, p. 931. J. B.
Lippincott Co., Philadelphia.
SEKIZAWA, Y. 1955 A biochemical chlorination in streptomyces. J. Biochem., (Tokyo), 42, 217-219.
SENSI, P., DEFERRARI, G. A., GALLO, G. G., AND ROLAND, G.
1955 Un nuovo antibioteco: la bromotetraciclina. Nota
I. Farmaco (Pavia) Ed. sci., 10, 337-345.