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Deaminothiamine Pyrophosphate a Strong Carboxylase Inhibitor.

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yield from the biphenyl derivative (5). On autoxidation, (7u)
gives dibenzo[a,e]cyclohepta-1,3,5-triene (Su), m.p. 133 O C
(45 'I;), and (76) gives dibenzo[e,floxepin (Sb), m.p. 111 "C
(52
Received, December 18th, 1963 [Z 643/470 IE]
x).
German version: Angew. Chem. 76, 226 (1964)
.-
[ I ] H. 1. 5esrmnnn and 0. Kratier, Chem. Ber. 96, 1899 (1963).
mouse ears (I. U.), and in the cocarcinogen test on the back
skin of mice, but does not produce any papillomas within
12 weeks without pretreatment with subthreshold doses of a
carcinogen. The substance loses its biological activity on
treatment with acids or alkalies. The parent alcohol ( I ) is not
active in the amounts applied (Table I), while the triacetate
(2) shows a strongly decreased - but still significant - activity compared with A l .
[Z 654/476 IE]
Received, December 27th, 1963
German version: Angew. Chem. 76, 225 (1964)
Publication withheld until now at the request of the authors
Cocarcinogen A 1 - the First Pure, Highly Active
Constituent of Croton Oil
By Doz. Dr. E. Hecker, Dip1.-Chem. H. Bresch.
and Dip1.-Chem. Ch. v. Szczepanski
Max-Planck-Institut fur Biochemie, Munchen (Germany)
The pharmacologically active principle of croton oil [1,2]
contains the substance groups A and B which cause the toxic,
inflammatory, and cocarcinogenic activity [3] of the oil.
Substance group A can be separated further by countercurrent distribution into the inactive component A2, m.p.
72 " C , and the pure, highly active component A l .
The pure cocarcinogen A1 [*I C36H5608 is a colorless resin,
that is insoluble in water but dissolves in nearly all organic
solvents; [a]L4 = + 49" (1 % in dioxan); Amax = 232 and
333 mp, cmax= 5400 and 73 in ethanol; infrared spectrum in
KBr: hydroxyl 2.96 p, ester carbonyl 5.75 p, ketone carbonyl
5.80-5.85 p, C=C double bonds 6.15 p; N M R spectrum 6 =
0.9, 1.3, 1.7, 2.1, 2.5, 3.2, 3.9, 4.3, 5.2, 5.4, 5.6, 7.5 ppm (in
CC14 with tetramethylsilane as internal standard).
Cocarcinogen A1 is not aromatic, contains a n w,P-unsaturated
carbonyl group that does not react with 2,4-dinitrophenylhydrazine or semicarbazide, as well as three free and two
esterified hydroxyl groups. The latter carry an acetic and a
myristic acid residue, respectively [2]. One of the free hydroxyl groups may be esterified practically quantitatively with
4'-nitroazobenzene-4-carbonyl chloride [4]. Fission of this
ester (C49H63011N3), m.p. 86-87 OC [ 2 ] , with K M n 0 4
affords the corresponding ester of glycolic acid. The esterifiable hydroxyl group is therefore primary and occurs in a n
ally1 configuration; the two remaining free hydroxyl groups
are tertiary. Other chemical data (see [5]) have been obtained for compaunds which have riot yet been shown to be pure.
Cocarcinogen A1 may be degraded by fission of the ester
linkages to give a crystalline parent alcohol C20H2806, m.p.
116' (0.4 % in dioxan); A,,
= 234
238-40°C, [a]&9=
and 335 mp, cmaX = 5000 and 75 in ethanol; infrared
spectrum in KBr: hydroxyl 2.87 and 3.05 p, carbonyl 5.88 p,
C=C double bonds 6.10 p ; NMR spectrum: 6 = 0.52, 0.88,
1.10, 1.67, 2.32, 2.91, 3.77, 4.17, 5.44, 7.52 ppm (in perdeuterodimethyl sulfoxide, standard: tetramethylsilane). A triacetate C26H3409, [a]&*= 68 o (1 "/, in dioxan), is obtained
by acetylation. The spectral and chemical properties of the
parent alcohol show that it is not aromatic and contains a
carbonyl as well as five hydroxyl groups, one of which is
primary and allylic; two other are tertiary.
+
+
The natural product A1 proved to be highly active in the
toxicity test in frogs ( L D ~ o ) ,in the inflammation test on
[*I Formerly denoted by "a" (cf. [2]).
[I] E. Hecker, Chemiker-Ztg. 86, 272 (1962).
[2] E. Hecker, Angew. Chem. 74, 722 (1962); Angew. Chem.
internat. Edit. 1 , 602 (1962).
[3] E. Hecker, Z . Krebsforsch. 65, 325 (1963).
[4] E. Hecker, Chem. Ber. 88, 1666 (1955).
[5] 5.L. van Duuren, E. Arroyo, and L. Orris, J. medical Chem.
6 , 616 (1963); Nature (London) 200, 1115 (1963).
Deaminothiamine Pyrophosphate, a Strong
Carboxylase Inhibitor 111
By Dr. habil. A. Schellenberger and Dr. W. Rodel
Institut fur Organische Chemie der Universitat HalleWittenberg (Germany)
Deaminothiamine ( I ) was synthetized as follows : 4-Chloro5-ethoxycarbonylmethyl-2-methylpyrimidine[2] was converted with NaSH into the 4-mercapto compound, m.p.
185"C, in 91 % yield. Elimination of the mercapto group
with Raney nickel in boiling water gave 5-ethoxycarbonylmethyl-2-methylpyrimidine,
b.p. 104 OC/3 mm, in 34 % yield ;
this was converted via the hydrazide, m.p. 160 "C, 98 % yield,
by twofold treatment with NaN02 into 5-hydroxymethyl-2methylpyrimidine, m.p. 105 "C, in 31 % yield. Heating this
with HBr and glacial acetic acid at 100°C gave the bromide
which reacted unpurified with 5-(~-hydroxyethyl)-4-methyl
thiazole to give deaminothiamine bromide (hydrobromide ?).
When this was shaken with a suspension of AgCl in methanol,
the chloride (hydrochloride?) was produced and was purified by chromatography on a cellulose column (Schleicher
and Schull, No. 123a). The product crystallized after standing for several weeks. Deaminothiamine can be obtained
analytically pure as its perchlorate, n1.p. 204 "C (decomp.),
which crystallizes well.
Phosphorylation of ( I ) with anhydrous orthophosphoric
acid [3] yielded a mixture of the mono-, di-, and triphosphoric esters in addition to inorganic phosphate. This mixture was separated using paper or thin-layer electrophoresis.
The separated fractions were eluted with water.
I f deaminDthiamine pyrophosphate is added to resynthetized
carboxylase in a molar ratio cocarboxylase: deaminococarboxylase = 0.96: 1, the activity of the enzyme is reduced
by 8 4 % (optical assay according to [4]). If, however, the
inhibitor is added in the resynthesis of carboxylase before
thiamine pyrophosphate, then the inhibition is almost
complete.
Received, January 2nd, 1964
[Z 644/471 IE]
German version: Angew. Chem. 76, 226 (1964)
Table I. Biological activity of the pure cocarcinogen A l , of its parent
alcohol ( I ) , and of the triacetate ( 2 ) of (I). Tests according to [3].
~~
stance
Al
(1)
(2)
1
1
[wg/50 g]
10
5000
150
1
1
I
1
[ ~ g l e a r ] ~dapplication
Ibl
0.009
2.4
1.5
'
10
500
SO
I
papilloma/mouse
[Cl
1 i.,
[a] Carcinogen: 1 irmole of 9,10-dimethylbenzanthracene.
[ b ] Application: twice weekly for 12 weeks.
[c] Alter I 2 weeks
Angew. Chem. internat. Edit. / Vul. 3 (1964) / No. 3
[I] Investigations into the function of the amino group in cocarboxylase, Part 2. - Part 1 : A . Schellenberger and KI. Winter,
Hoppe-Seylers Z. physiol. Chem. 322, 164 [1960].
[2] H. Andervzg and K . Wesiphal, Chem. Ber. 70, 2035 (1937);
L. R . Cerecedu and F. D . Pickel, J. Amer. chem. SOC. 59, 1714
(1937).
[ 3 ] P . Karrer et al., Helv. chim. Acta 32, 1478 (1949); 34, 1384
(1951).
[4] E. Holzer, H . - D .Soling, H.- W .Goedde, and H . Holzer, in H . U.
Bergmeyer: Methods of enzymatic Analysis. Verlag Chemie.
Weinheim/Bergstr., and Academic Press, New York 1963, p. 602.
227
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