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Modern Steroid Problems.

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ANGEWANDTE CHEMIE
VOLUME 9 . N U M B E R 5
MAY 1 9 7 0
P A G E S 321-388
Modern Steroid Problems
By Rudolf Wiechert[*]
Dedicated to Professor R. Tschesche on the occasion of his 65th birthday
The present article is concerned primarily with the latest developments in the fields of
steroids exhibiting contraceptive, antiandrogenic, or cardiac activity and of steroid
metamorphosis hormones. Both the biological action and the current sources of raw
materials are considered.
1. Introduction
Of all the natural products, no group has had more
time and work devoted to it by a variety of scientists
than the steroids.
The history of the steroids is rich in scientific climaxes,
such as the isolation, structural elucidation, and synthesis of the sex hormones in the 1930's, and the beneficial discovery of the antiarthritic and antiinflammatory effects of the adrenocortical hormones.
The diversity of the biological effects of steroids and
their potentiation and variation by chemical modification are unequalled among the natural products.
As an extreme example of the versatility of these substances, the male sex hormone testosterone U J and
several pregnane derivatives 12-41 have been found in
surprising quantities as active substances in the prothoracic defensive gland secretions of some water
beetles.
The purpose of the present article i s to provide a picture of the latest developments and of some of the
problems that await solution. The evaluation and
[*] Dr. R. Wiechert
Hauptlaboratorium d e r Schering A G
1 Berlin 65, Mullerstrasse 170-172 (Germany)
[l] H . Schildknecht, H . Birringer, and (1. Maschwitz, Angew.
Chem. 79, 579 (1967); Angew. Chem. internat. Edit. 6, 558
(1967).
[2] H. Schildknecht and H . Dotz, Angew. Chem. 79, 902
(1967); Angew. Chem. internat. Edit. 6, 881 (1967).
[3] H. Schildknecht and W. Konig, Angew. Chem. 80,45 (1968);
Angew. Chem. internat. Edit. 7, 62 (1968).
141 H. Schildknecht, H. Tacheci, and U. Maschwitz, Naturwissenschaften 56, 37 (1969).
Angew. Chem. internat. Edit.
/ Vol. 9 (1970) / No. 5
selection of the topics are naturally subjective. Thus
no mention is made, for example, of the use of steroids
in mechanistic and steric studies or in the development of new physical methods.
2. Sources of Raw Materials
The raw material for by far most of the steroids produced at present is diosgenin ( 1 ) . The development of
this natural product, which occurs in the roots of
several types of Dioscorea, is due to the work of R. E.
Marker 151. The dried roots of the plants, which grow
wild, e.g. in Mexico, Guatemala, India, China, and
South Africa, contain about 5-6 % of diosgenin.
0
-- *
HO
(3)
[ 5 ] See L . Fieser and M . Fieser: Steroids. Reinhold, New York
1959.
321
Nearly all the steroids in therapeutic use can now be
obtained on the industrial scale from diosgenin via
3P-hydroxy-5,16-pregnadien-20-one (2) and 3P-hydroxy-5-androsten-7 7-one (3) 161.
Sih e f al. 181 converted 19-hydroxycholesterol 3-acetate
(6) directly into estrone (7) by means of a microorganism isolated from soil samples (CSA-10). (6) is
obtainable from cholesterol in only three steps 191.
Stigmasterol from soybean sterols is of limited importance as a raw material for the synthesis of corticosteroids.
Progress in stereochemistry, and particularly the recognition of the stereoelectronic principle in additions
to carbonyl and olefinic double bonds and of the importance of the energy of intermediates, as well as the
estimation of the accessibility of reaction centers, have
recently led to the development of total estrone syntheses for industrial use by the research groups of
Velluz [lo, 111, H . Smith [12-141, and Anachenko and
Torgov [15-171.
The successful use of enzymatic asymmetric reduction
has made total steroid syntheses capable of competing
As a result of the development of new microbiological
processes, cholesterol (4) or p-sitosterol could regain
interest as raw materials in the future, particularly for
the synthesis of 19-nor steroids. Whereas the oxidative
chemical degradation of the C-17 side chains, as used
in the past, gave only small yields, the microbiological
degradation to 17-ketones gives yields of more than
70% in some cases.
Using cultures of Mycobacterium phlei with added
nickel sulfate, a group of Dutch workers has been able
CH,O
&
OH
'
to degrade cholesterol (4), with simultaneous oxidation, double-bond isomerization, and dehydrogenation at C-1 and C-2, to the 1,4-diene-3,17-dione ( 5 ) [7J.
(5)
HO
0
[6] N . Applezweig: Steroid Drugs. McGraw-Hill, New York
1962.
[7] J . de Flines and W . F. van der W a a r d , Brit. Pat. 1113887
(7968), Koninklijke Nederlandsche Gist en Spiritusfabrik, Delft.
322
0
economically with partial syntheses from plant or animal material.
By enzymatic reduction of one keto group in the prochiral diketone (8), Gibian et al.[18,19J obtained the
compound (9), in which the later centers of asymmetry
C-13 and C-17 already have the same configuration as
[8] C h . J . Sih, S. S . L e e , Y . Y . Tsong, K . C. Wang, and F. N .
Chang, J . Amer. chem. SOC.87, 2765 (1965).
191 J . Kalvoda, K . Heusler, H . Ueberwasser, G. Anner, and A .
Wettstein, Helv. chim. Acta 46, 1361 (1963).
1101 L . Velluz, G. Nomind, and J . Mathieu, Angew. Chem. 72,
725 (1960).
[ l l ] L . Vellua, J . Vallis, and G. Nomind, Angew. Chem. 77, 185
(1965); Angew. Chem. internat. Edit. 4 , 181 (1965).
1121 G.H . Douglas, J . M . H . Graves, D . Hartley, G . A . Hughes,
B . J . McLoughlin, J . SiddaN, and H . Smith, J. chem. SOC.
(London) 1963, 5012.
1131 H . Smith, G. A . Hughes, and B. J . McLoughlin, Experientia
19, 177 (1963).
[14] H . Smith, G. A . Hughes, G. H . Douglas, D . Harthley, B . J .
McLoughlin, J . B. SiddaN, G. R . Wendt, G. C. Buzby, j r . , D . R .
Herbst, K . W . Ledig, J . R . McMeramin, T . W . Pattison, J . Suida,
J . Tokolics, R . A . Edgren, A . B. A . Jansen, B. Gadsby, D . H . R .
Watson, and P . C. Phillips, Experientia 19, 394 (1961).
[l5] S . N . Anachenko and J . V . Torgov, Doklady Akad. Nauk
SSSR 127, 553 (1959).
1161 S . N . Anachenko and J . V . Torgov, Tetrahedra-n Letters
1963, 1553.
[I71 A . V . Zaknarychev, S. N . Anachenko, and J . V . Torgov,
Tetrahedron Letters 1964, 171.
[18] H . Gibian, K . Kieslich, H . J . Koch, H . Kosmol, C. Rufer,
E . Schroder, and R. Vossing, Tetrahedron Letters 1966, 2321.
[19] H . Kosmol, K . Kieslich, R . Vossing, H . J . Koch, K . Petzold,
and H . Gibian, Liebigs Ann. Chem. 701, 198 (1967).
A n g e w . Chem. internat. Edit. Vol. 9 (1970)
No. 5
the natural steroids. With Saccharomyces uvarum
(CBS 1508), this reduction gave a yield of 75 %.
Another prochiral intermediate, the triketone ( I ] ) ,
also undergoes stereoselective enzymatic reduction to
(12) with Rhizopus arrhizus Fischer 1201.
An entirely new approach is found in a total synthesis
of racemic 16,17-didehydroprogesterone (16) that was
recently reported by Johnson et aZ.[21]. The key react ion is a non-enzymatic biogenesis-like olefin cyclization with stereospecific formation of five centers of
asymmetry.
c=O
Germany, about one woman in every seven of child-bearing
age now uses steroid contraceptives.
The steroids used are thought to act by reducing the
secretion of a series of proteohormones and so preventing maturation and release of the o v u m [ W The
administration of gestagenic and estrogenic hormones
inhibits ovulation as a result of their braking action
on the hypothalamus and pituitary gland.
The steroids are mainly administered as a mixture of
the two components over a period extending from the
5th to the 24th day of the cycle. Sequential therapy,
which is based on the natural rhythmic formation
conditions of the hormones, represents another method of administration. Only estrogens are given in this
case from the 5th to the 19th day of the cycle, and a
combination of gestagens and estrogens is then given
from the 19th to the 24th day. The subsequent pause
in consumption is followed in both cases by withdrawal bleeding resembling menstruation.
Since the natural ovulation inhibitors, i.e. the estrogens (estrone, estradiol, estriol) and the endogenous
gestagen progesterone are inactive when administered
orally, it was necessary to develop orally active compounds.
The only estrogenic components in use at present are
17a-ethynylestradiol (17) [2S1 or its 3-methyl ether.
The tetraenol (13) is stereospecifically cyclized to the
tetracyclic diene (14) by the action of triffuoroacetic
acid at -78 OC, and oxidation with osmium tetroxide
followed by double alkaline ring closure in the intermediate triketo aldehyde (IS) yields (16).
In view of the constantly growing demand for steroids
and the limited quantities of natural raw materials,
total syntheses can be expected to increase in importance in the future. Total syntheses also have the advantage of a wide scope for variation in the preparation
of new steroids.
3. Contraceptive Steroids
The groundbreaking work of Pincus L221 has led in the
last decade to the use of steroids for fertility control.
The sociopolitical and biological consequences of hormonal
contraception are among the most discussed topics of our
time. According to Mohr1231, the greatest dangers to man’s
existence at present are ideologies, atomic or microbiological
warfare, and population explosion. It should be possible to
entrust the first two problems to the sagacity of the politicians. Birth control could offer an escape from the dangers
that will come with the huge increase in the earth’s population
even in the next few decades.
The possibility of hormonal birth control has found remarkably rapid acceptance by women. In the Federal Republic of
[20] P . Betlet, G . Nominh, and J . Mathieu, C. R . hebd. Seances
Acad. Sci. 263, 88 (1966).
(211 W. J . Johnson, M . F. Semmelhack, M . U . S . Suitanbawa,
and L . A . Dolak, J . Amer. chem. SOC.90, 2994 (1968).
[22] G. Pincus: The Control of Fertility. Academic Press, New
York 1965.
[23] H. Mohr: Wissenschaft und menschliche Existenz. Verlag
Rombach, Freiburg 1967.
Angew. Chem. infernat. Edit.
/ Vol. 9 (1970)1 No. 5
CICH
CXH
HO
In the great majority of preparations, the gestagen is
a 17a-ethyny1-17-hydroxy-19-norsteroid. The interesting chemical history of the first compound of this
type, 17u-ethynyl-17-hydroxy-l9-nor-4-androsten-3one (18) [261 has recently been described by Djerassi 1271Development began as early as 1938 with the ethynylation
of the 17-keto group by Inhofen et 01. [251 and the first synthesis of a 19-nor progesterone by Ehrenstein in 1944rzal.
Variants of the compound ( 2 ) that have proved themselves
in clinical trials were obtained by displacement of the
C-4-C-5 double bond into the 5(10) position to give
(19) 1291, acetylation of thel7-hydroxyl group to form (20) 1301,
and introduction of additional double bonds into positions
9 and 11 to give [ Z I ) [3*1, and of a methyl group into position (18) to give (22) 1141.
[24] J . HaNer: Ovulationshemmung durch Hormone. ThiemeVerlag, Stuttgart 1968.
[25] H . H. Inhoffen, W . Lagemann, W . Hohlweg, and A . Serini,
Ber. dtsch. chem. Ges. 71,1024 (1938).
1261 C. Djerassi, L . Miramontes, G . Rosenkranz, and F. Sondheimer, J. Amer. chem. S O C . 76, 4092 (1954).
[27] C. Djerassi, Science (Washington) 151, 1055 (1966).
1281 M . Ehrenstein, J . org. Chemistry 9,435 (1944).
[29] F. B. Colron, US-Pat. 2725389 (1955), Searle; Chem.
Abstr. 50, 9454e (1956).
[30] 0. Engelfried, E . Kaspar, A . Popper, and M . Schenck,
German Pat. 1017166 (1957), Schering AG; Chem. Zbl. 1959,
2232.
(311 L . Velluz, J . Mathieu, and G . Nomine, Tetrahedron Suppl.
8, 405 (1966).
323
CECH
A second route that can be used for the practical synthesis of 19-nor steroids (28) is the elimination of the
methyl group from C-10 [39s4*1 after oxidation to the
formyl or carboxyl group [(31)+(28)].
The key reaction in this multi-step sequence from
(25) via (29), (30), and (31) to (28) is a 1,3-diaxial
“functionalization” of the unactivated angular methyl
group via intermediate 6p oxygen radicals [(29)+
(30)] 1411 which are produced by nitrite photolysis 1421,
hypoiodite reaction 1431, or direct oxidation with lead
tetraacetate [441.
CECH
@
0
OCH3
CECH
&
7%
0
’
COCH,
6
fc
(32a),
(32b/,
(32c),
(32d),
=
R
R
R
=
=
=
H
CH3 [45]
CH3 A6 [46,47]
Cl+ A6 148,491
+
The second group of progestagenic steroids that are
currently used with estrogens for fertility control are
the 17a-acetoxyprogesterones (32a) -(32d), which are
structurally much closer to progesterone than the 19nor-l7u-ethynyl compounds (18) to (24).
The development of these compounds followed from
Junkmann’s observation [501 that esterification of the
Further changes in the A ring gave the 3P-acetoxy-4-ene
(23) 1321 and the 3-deoxy-4-ene (24) [331. The steroids (21)
and (22) are prepared by total synthesis.
In the synthesis of 19-nor steroids from compounds of
animal or plant origin, a technically satisfactory solution to the central problem, i.e. the elimination of the
methyl group from C-10, has now also been found.
j.
R
/
CHO. COOH
I n addition to the thermal free-radical aromatization 134,351 of 1,4-dien-3-ones (26), a low-temperature
ionic aromatization with lithium in biphenyl solution
has also been known since 1963 [361. 19-Nor-4-en-3ones (28) and 5(10)-en-3-ones are then formed from
(27) via 3-methoxy-2,5-(1O)-dienes by Birch reduction [37,381.
[32] P. D . Klimstra, US-Pat. 3176013 (1965) corresponding to
Belg. Pat. 650922; Chem. Abstr. 62, 14776h (1965).
[33] M. S . de Winter, C. M . Siegmann, and S . A. Szpilfogel,
Chern. and Ind. 1959, 905.
[34] H . H. Inhoffen, Angew. Chem. 53, 471 (1940).
[35] H . H . Inhoffen and G. Ziihlsdorf, Ber. dtsch. chem. Ges. 74
1911 (1941).
[36] H . L. Dryden, G . M . Webber, and J . J . Wieczorek, J.
Amer. chern. SOC.86, 742 (1964).
[37] A, J . Birch, Quart. Rev. (chem. S O C . , London) 4,69 (1950).
[38] A. L. Wilds and N . A . Nelson, J. Amer. chem. S O C . 75,5366
(1953).
324
[39] H . Hagiwana, S . Noguchi, and M . Nishikawa, Chem. pharmac. Bull. (Tokyo) 8, 84 (1960).
1401 T . B. Windholz and M . Windholz, Angew. Chem. 76, 249
(1964); Angew. Chern. internat. Edit. 3 , 353 (1964).
[41] K . Heusler and J . Kalvoda, Angew. Chem. 76, 518 (1964);
Angew. Chem. internat. Edit. 3, 525 (1964).
1421 D . H. R. Barton, J . M . Beaton, L. E . Geller, and M . M .
Pechet, J. Amer. chem. SOC.82, 2640 (1960).
[43] J . Kalvoda, K . Heusler, H . Ueberwasser, G . Anner, and A .
Wettstein, Helv. chim. Acta 46, 1361 (1963).
[44] A. Bowers, R. Villotti, J. A . Edwards, E. Denot, and 0.Halpern, J. Amer. chern. S O C . 84, 3204 (1962).
[45] J. C. Babcock, E. S . Gutsell, M . E . Herr, J . A. Hogg, J . C .
Stucki, L. E. Barnes, and W . E. Dulin, J. Arner. chern. S O C . 80,
2904 (1958).
[46] H . J . Ringold, J . P. Riilas, E. Batres, and C. Djerassi, J.
Arner. chern. S O C . 81, 3712 (1959).
[47] B. Ellis, D . N . Kirk, V. Petrow, B. Waterhouse, and D . M .
Williamson, J. chem. S O C . (London) 1960, 2828.
[48] H . J. Ringold, E. Batres, A . Bowers, J . Edwards, and J .
Zderic, J. Amer. chem. S O C . 81, 3485 (1959).
[49] K . Briickner, B. Hampel, and U . Johnson, Chern. Ber. 94,
1225 (1961).
[50] K . Junkmann, Naunyn-Schmiedebergs Arch. exp. Pathol.
Pharmakol. 223, 244 (1954).
Angew. Chern. internat. Edit.
Vol. 9 (1970) 1 No. 5
progestationally inactive 17a-hydroxyprogesterone to
(32a) gives a gestagen that exhibits strong activity
when administered subcutaneously or orally.
The gestagenlestrogen combinations d o not always
prevent conception by inhibiting ovulation. According
to investigations by Goldzieber et al. 1511, ovulation
was not suppressed in about 7 % of the cycles in
women.
With the compound (32d), almost total fertility
prevention could be achieved without the addition of
estrogens by daily oral administration of 0.5 mg,
while ovulation was maintained 152-551.
This new principle of action of the gestagens probably results
from a change in the cervical mucus and prevention of penetration by the sperm. It may be expected that future work on
contraceptives will be concerned less with the synthesis and
investigation of new ovulation-inhibiting steroids with
stronger or longer-lasting effects than with the investigation
of new modes of action. Increasingly difficult methods will
be used, e.g. to try t o obtain information about sperm transport, sperm capacitation, egg transport, and implantation.
Indications that the biological spectrum, particularly
of progesterone derivatives, can be varied by chemical
modification are shown in Table 1. The variation of
the partial effects in both directions is very clearly
recognizable in the 6,7?-epoxide (33) [561 and in the
la, 2a; 16a. 17a-dimethylene steroid (34) [571.
4. Antiandrogenic Steroids
It has been known since 1938 that the actions of androgenic hormones are influenced by estrogens [5*1. However, this effect occurs indirectly via gonadotropin
inhibition.
The term “antiandrogen” should be applied to compounds that directly influence the receptors of all organs or systems of organs that are in any way functionally or morphologically androgen-dependent [591.
They thus have no effect on the biosynthesis of testosterone.
This action has been found in various types of steroids
in recent years in the systematic search for antiandrogenic substances. The antiandrogenic steroids that
have been investigated belong mainly to the androstane and pregnane series.
Compounds from the pregnane series that exhibit antiandrogenic effects include progesterone (35%) [60-621,
its derivatives with methyl, hydroxyl, or halogeno
substituents in positions 2, 6,11, 16, 17,‘and 21, e.g.
(3Sb) -(35h) L60-651, 19-norprogesterone (35i) [631, and
A-norprogesterone (36) 163,663.
CH3
CHS
c=o
c=o
1
t
7%
7H3
c=o
c=o
Table I. Relative oral complete inhibition of ovulation (tube inspection in rats) and relative oral progestational action (Clauberg test o n
rabbits) of some progesterone derivatives.
Relative inhibition
of ovulation
(37)
Relative progestational
action
(38)
CH,
1
1
1
1
10
35
130
0.04
[51] J. W . Goldzieher, L . E. Moses, and U.L . T . Ellis,J. Amer.
med. Assoc. 180, 359 (1962).
[52] H. W. Rudel and J . Martinez-Manatou, Proc. I1 Int.
Congr. Hormonal Steroids, Milan, Int. Congr. Ser. No. 132;
Excerpta Med.-Foundation 1967, 884.
1531 J. Martinez- Manautou, J . Giner- Velasquez, and H . Rudel,
Fertil. Steril. 18, 57 (1967).
(39)
(35a), R
/35b), R
( ~ S C )R
,
/35d), R
(35e ), R
(35f/, R
/35g), R
(35h), R
(35i), R
[54] J. mar finer-Manautou, J. Giner- Velasquez, V. CortesGallegos, R . Aznar, B . Rojas, A . Guitterez-Najar, and H . W .
Rudel, British med. J. 5554, 730 (1967).
[55] J . Zamartu, G. Rodriguez-Moore, M . Popkin, 0. Salas, and
R . Guerrero, British med. J. 5600, 263 (1968).
(561 H. Laurent, G. Schulz, and R . Wiechert, Chem. Ber., in
press.
[57] R . Wiechert and F. Neumann, Brit. Pat. 1095858 (1968),
Schering AG.
(581 V. Regnier, C. R. Seances SOC. Biol. Filiales 127, 519
(1938).
1591 F. Neumann, Sympos. for Methods on Drug Evaluation,
Milan 1965, p. 548, North Holland Publ., Amsterdam.
Angew. Chem. internaf. Edit.
Vol. 9 (1970)
No. 5
(40)
=
=
=
=
=
=
=
=
=
CH3
CH3+
CH3+
CH3+
CH,
CH3+
CH3+
CH3+
H
2a-CH3, 11 = 0
11@-OH,21-F
Ila-OH
+ 17-OH
l6a-CH3, 21-OH
A6-6-CI, 17-OAc
A6-6-CH3, 17-OAc
R. J. Dorfmann, Methods Hormone Res. 2, 315 (1962).
R. J . Dorfmann, Acta endocrinol. 41, 268 (1962).
R. J . Dorfmann, Proc.Soc. exp. Biol. Med. 111, 441 (1962).
R . J. Dorfmann, Steroids 2, 185 (1963).
W . W . Byrnes, R . 0. Stafford, and K . J . Olson, Proc. exp.
Biol. Med. 82, 243 (1953).
[651 E . L . Jones and L . Woodbury, J. invest. Dermatol. 43, 165
[60]
[61]
I621
[63]
[641
(1964).
[661 L . J. Lerner, Recent Progr. Hormone Res. 20, 435 (1964).
325
Active androstane derivatives include compounds
such as A-nortestosterone (37) l66-681, the B-nor
(38) [69,7@1 and 18-nor compounds (39) [63,711, and
D-ring lactones (40) 163.721.
Hamada, Neumann, and Junkrnann 1733 discovered a
new, extremely powerful antiandrogen in 1963 by accidental observation of intrauterine feminization
phenomena in animal experiments. Pregnant rats
treated with this substance apparently bore only
female offspring. The Qevelopment of the rudimentary
male genitalia had &n suppressed.
the trienone system (41) with dimethyloxosulfonium methylider79J. Because of a side reaction of the cc-acetoxy ketone
side chain, however, hydrolysis of (41) is essential as a n
intermediate operation [SO]. Stereoselective epoxidation with
peroxy acids leads from (43) t o the 6a,7a-epoxide (44). On
treatment of (44) with hydrogen chloride in glacial acetic
acid, (45) is obtained by diaxial epoxide cleavage and elimination of hydrogen with simultaneous opening of the lcr,2a
three-membered ring. Treatment of (45) for a short time
with a base finally leads to (46).
To illustrate purely empirical relations between structure and antiandrogenic action, Table 2 shows the
most active of the many subsequently investigated
This comppltnd, 6-chloro-l1~,2cr-methylene-l7-acet- compounds with structures similar to cyproterone
oxy-4,B:py~~adiene-3,20-dione (46) (cyproterone
acetate. The complete inhibition of the effects of exoacetate) hgd been synthesized for the purpose of the
genous testosterone propionate on the seminal vesicles
and prostates of rats requires 30 times as much cypro&yelapment of luteohormones 174,751.
terone acetate, while 10 times as much is required to
inhibit the effect on cocks' combs.
7H3
7%
c=o
7%
c=o
C'O
FH3
c=o
Replacement of the 6-chloro substituent with fluorine
or alteration of the stereochemistry of the threemembered ring to a 1@,2$methylene group leads in
(46)to total loss of the antiandrogenic action.
The first observations by Hamada, Neumann, and
Junkmann [731 and their logical interpretation as an
antiandrogenic effect led to a series of biological and
clinical studies with new antagonists.
Table 2. Relative antiandrogenic action I S 1 1 of derivatives of cyproterone acetate (46) against the effect of testosterone propionate o n subcutaneous application in rats.
f 43)
7%
(44)
p
c=o
..-.OAc
H*&
Hog
3
0
"
c1
I
changes in (46)
-4-H
4-CI
-1a,2a-CH2
1-H 2-H
-la,2a-CH2
la-CH3
-3-0
3-OH -I- 3-H
+
The synthesis of the antiandrogen begins with the trienedione
(41) 1761. 1,3-Dipolar addition of diazomethane leads stereoselectively, by a-side attack on the C-1-C-2 double bond, t o
the I-pyrazoline (42). Thermal or Lewis acid catalyzed
cleavage of (42) gives the la,2a-methylene compound
(43) 1771, which is also formed by direct methylenation "81 of
1671 L . J . Lerner, Steroids 6 , 215 (1965).
[68] L . J . Lerner, Steroids 6 , 223 (1965).
(691 H . L . Saunders, K . Holden, and J . Kerwin, Steroids 3, 681
(1964).
[70] H . L . Saunders and J . F. Kerwin, Proc. 11. Int. Congr. Hormonal Steroids, Milan 1967, 599.
[711 A . Segaloffand R . B. Gabbard, Steroids 4 , 433 (1964).
[72] L . J . Lerner, A . Bianchi, and A . Borrnan, Cancer 13, 1201
(1960).
[73] H . Hamada, F. Neumann, and K . Junkmann, Acta endocrinol. 44, 380 (1963).
[74] R . Wiechert, German Pat. 1158966 (1961), Schering AG;
Chem. Abstr. 59, 722h (1963).
[75] R. Wiechert and F. Neumann, Arzneimittelforsch. I S , 244
(1965).
[76] W . Hiersemann, E. Kaspar, and U.Kerb, US-Pat. 2962510
(1960); Chem. Abstr. 56, 14373f (1962).
1771 R . Wiechert and E. Kaspar, Chem. Ber. 93, 1710 (1960).
326
+
+
-64
+
+
+ 6-H
-17-OAc f 17-OH
D ring homorearrangement
as in (46a)
Relative antiandrogenic
action
I
Ref
1
1
0.3
0.3
0.9
0.6
0.5
0.7
[781 H . 4 . Lehmnnn, German Pat. 1183500 (1962); Chem.
Abstr. 62, 6540 (1965).
[791 E. J . Corey and M . Chaykovsky, J. Amer. chem. Soc. 84,
867 (1962).
[SO] H.-G. Lehmnnn, Angew. Chem. 77, 808 (1965); Angew.
Chem. internat. Edit. 4, 783 (1965).
[Sll R . Wiechert, H . Steinbeck, W . Elger, and F. Neumann,
Arzneimittelforsch. 17, 1103 (1967).
[82] R . Wiechert, Experientia 21, 767 (1968).
1831 H . - J . Ringold, E. Batres, A. Bowers, J. Edwards, and J .
Zderic, J. Amer. chem. SOC.81, 3485 (1959).
1841 K . Briickner, B. Hampel, and U . Johnson, Chem. Ber. 94,
1295 (1961).
[SSl R . Wiechert, 1963, unpublished.
[86] R . Wiechertand F. Neumann, Belg. Pat. 690011 (1967),
Schering AG.
1871 J . Hader, F. Neumann, and R . Wiechert, Belg. Pat. 690965
(1967), Schering AG.
Angew. Chem. internat. Edit.
1 VoI. 9 (1970)/ No. 5
It was possible for the first time to eliminate the effects
of testosterone by means of cyproterone acetate,
without disturbing other factors that are important to
sexual differentiation 1881.
Studies o n male fetuses have provided important information on the decisive early role of testosterone in
the development of the genital tractls8-921 and of the
sexual center in the brain [93-981.
Information about the differentiation of the mammary
glands was also obtained by treatment of pregnant
animals with antiandrogens. Male rats and mice do not
normally develop nipples. Feminized males, on the
other hand, had nipples that were indistinguishable
from those of female animals 199-1011,
Central processes induced by testosterone, e.,g. testicular functions in male animals 1*02-*041 and ovulation
in females I1.05.1*6!, can be inhibited in adult animals.
Fig. l a .
300 ..).
Skin section
intact iiiale nioLtse. untreated (niagniiication
The activity and size of the sebaceous glands of
humans1107,108J and of animals 1109,1JOJ depend o n
androgens. The antihormones were found to eliminate
the effect of testosterone o n the sebaceous g l a n d s " ~ ~ ] .
The atrophy of the sebaceous glands as a result of
treatment with cyproterone acetate is clear in Figures
l a and l b .
. ..
1881 W. Elger, Arch. Anatom. rnicroscop. Morphol. experiment.
55, 658 (1966).
1891 F. Neumann, W . Elger, and M. Kramer, Endocrinology 78,
628 (1966).
1901 F. Neumann, Proc. Int. Syrnpos., Milan 1965.
[91] F. Neumann, R . Y . Berswordt- Wallrabe, W . Elger, H . Steiubeck, and J . D. Hahn, Excerpta Med. int. Congr., Ser., in press.
1921 F. Neumann, W . Elger, and H . Steinbeck, J. Reproduct.
Fertil., in press.
[93] F. Neumann and W. Elger, Ghent. Excerpta Med. int.
Congr., Ser. No. 101, 168 (1965).
I941 F. Neumann and W . Elger, 5. Acta Endocrinologica Congress, Hamburg 1965; Acta endocrinol., Suppl. 100, 174 (1965).
[95] F . Neumann and W . Elger, Endokrinologie 50, 209 (1966).
I961 F. Neumann and M . Kramer, Excerpta Med. int. Congr.,
Ser. N o . 132, 932 (1967).
I971 F . Neumann, W . Elger, and R . Y . Berwordt- Wallrabe, Excerpta Med. int. Congr., Ser. No. 111, p. 276 (1966).
[981 F. Neumann, J . D. Hahn, and M . Kramer, Acta endocrinol.
5 4 , 227 (1967).
[991 F. Neumann and W . Elger, J . Endocrinology 36, 347(1966).
[loo] F. Neumann, W. Elger, and R. v. Berswordt- Wallrabe, J.
Endocrinology 36, 353 (1966).
[ l o l l W . Elgerand F. Neumann, Proc. SOC.exp. Biol. Med. 123,
637 (1966).
11021 F. Neumann and R. v . Berswordt- Walirabe, J. Endocrinology 35, 363 (1966).
I1031 F . Neumann, W . Elger, R . v. Berswordt- Wallrabe, and M .
Krarner, Naunyn-Schmiedebergs Arch. exp. Path. Pharmakol
255, 236 (1966).
I1041 F. Neumann, H . Steinbeck, W . Elger, and R . v . BerswordtWallrabe, Acta endocrinol. 5 7 , 639 (1968).
[IOS] F. Neumann and R . Y . Berswordt- Wallrabe, Excerpta Med.
int. Congr., Ser. No. 133, 129 (1967).
I1061 F. Neumann, W . Elger, and R . v . Berswordt-Wallrabe,
Acta endocrinol. 52, 63 (1966).
[lo71 J . S. Strauss and P . E. Pochi, Recent Progr. Hormone
Res. 19, 385 (1963).
[I081 P.E . Pochi, J . S . Strauss, and H . Miscon, J. invest. Derrnatol. 39, 475 (1962).
[lo91 F. J . Ebling, Endocrinology 15, 297 (1957).
I1101 C. LapiPre, C . R. Stances SOC.Biol. Filiales 167, 1302
(1953).
11111 F. Neumann and W . Elger, J.invest.Dermatol.46, 501
(1966).
Angew. Chem. internat. Edit. / Vol. 9 (1970)
1 No. 5
Fig. 1 b. Skin section, intact male mouse, treated with I rng of c y p r o ternne acetate &in.) every second d a y for 4 weeks (magnification 300x1.
Since testosterone is presumably an important contributory cause of acne, this skin disorder should be alleviated by antiandrogens 1112-1141.
Another interesting clinical possibility is the use of
antiandrogens to control the libido of males with
disturbed instincts, such as sexual offenders f115-1171.
Investigations on the inhibition of the partly androgendependent growth of carcinomas of the prostate by
antiandrogens could also be important L118, 1191.
5. Cardioactive Steroids
Steroid glycosides from several types of digitalis have
been in use for almost 200 years for the treatment of
cardiac insufficiency. Plant extracts have been increasingly replaced in recent years by homogeneous pure
glycosides.
I1121 K . Winkler, Aestet. Med. 16, 315 (1967).
[113] K . Winkler, Ann. Derrnatol. Syphiligraphie (Paris) 95,
147 (1968).
I1141 K . Winkler, Arch. klin. exp. Dermatol. 233,296 (1968).
[I 151 U.Laschet and L . Laschet, Klin. Wschr. 45, 324 (1967).
I1161 U . Laschet, L . Laschet, H . R . Fetzner, H . U . Clasel, G .
Mall, and M . Naab, Acta endocrinol., Suppl. 119, 54 (1967).
I1171 F. O t t and H . Hoffet, Schweiz. med. Wschr. 98, 1812
(1968).
[118] J . Geller, G. Vazakas, B. Fruchtmann, H . Newman, K .
Kakao, and A . Loh, Surgery, Gynecol. Obstr. 127,749 (1968).
I1191 W . W. Scott and H . K . A . Srhirmer, Trans. Amer. Assoc.
genitourin. Surgery 58, 54 (1966).
327
The historical development of this field, the contributions of
various laboratories, and the biological mode of action of
this class of substances have been described by Tschesche [1201, Fieser [51, and Haede and Lindner 11211. The chemistry of the sugar residues is summarized in articles by Zorbuch [I221 and Reichstein [1231.
14P-Hydroxy steroids have become more readily obtainable through the possibility of microbiological
hydroxylation in the 14a,15a, or 15P positionC1251.
The most difficult problem in the synthesis of the
steroid part of the digitalis ingredients, e.g. of digitoxigenin (47) from readily obtainable steroids is the preparation of the 14-hydroxy-CD-cis-17P-butenolide
structure.
~ H z C I G
@
OH
HO
H
(47)
The 14P-hydroxyl group is easily removed. Another
difficulty is the fact that the 17P-side chain in CD cisfused steroids is thermodynamically less stable than
the 1 7 side
~ chain. Furthermore, undesirable side reactions frequently occur between the 17P side chain
and the 149 hydroxyl group as a result of the steric
arrangement. .
Following the fundamental work carried out in the
1940's by the research groups of Plattner, Reichstein,
Ruzicka, and Elderfield, an elegant synthesis of digitoxigenin from the 280x0 pregnane derivative (48)
was achieved in 1962 by Danieli, Mazur, and Sondheimer 11241.
7%
c=o
AcO
H
The partial formulas (52)-(55) are to be understood
as representing the synthesis of other butenolides
from the corticosterone side chains.
(54) was obtained from (52al by Horner olefination with
diethyl cyanomethyl phosphate via the imino lactone 11261.
Fritzsch, Stache, and Ruschig[1271 obtained the butenolide
ring directly from (52b) with diethyl methoxycarbonylmethyl
phosphate.
The same authors synthesized (54) via (55) from (52c) by
intramolecular cyclization [128,1291.
The necessary activation of the condensing methylene group
can also be achieved with phosphonate ester or phosphonium
salt groups. Thus the butenolide ring was obtained in this
way from (52d) or (52e) in yields of up to 50% [1301.
Another cardenolide synthesis is based on the ability
of 17P-fury1 steroids to be converted into cardenolides [1311.
The second group of cardioactive steroids are the
bufadienolides, which occur in toad secretions and
plants. The characteristic structural features of these
compounds are an a-pyrone ring in the 17P position
and either a hydroxyl group in the 14P position or a
14P,lSP-epoxide.
The first natural bufadienolides to be synthesized
(Sondheimer et al.11321) were bufalin (56) and resibufalin (57).
Mild acid treatment of the ethoxyacetylene alcohol
(49) gave (50) which reacted with selenium dioxide
in boiling benzene to give the butenolide (51).
[120] R . Tschesche in Lettri-Tschesche-Inhoffen: Sterine, Gallensauren und verwandte Naturstoffe. Enke-Verlag, Stuttgart
1954, Vol. 1.
[121] W. Haede and E . Lindner in Ehrhard-Ruschig: Arznei-
mittel. Verlag Chemie GmbH, Weinheim 1968, Vol. 1.
11221 W . W. Zorbach and K . V . Bhat, Advances of Carbohydrate Chem. 21, 273 (1966).
11231 T . Reichstein, Naturwissenschaften 54, 53 (1967).
I1241 N . Danieli, Y.Mazur, and F. Sondheimer, J. Amer. chem.
SOC.84, 875 (1962).
328
.___
I1251 F. Sondheimer, Chem. in Britain I , 454 (1965), and literature cited therein.
I1261 G. R. Petit and J . P . Yardley, Chem. and Ind. 1966, 533.
[127] W . Fritzsch, U. Stache, and H . Ruschig, Liebigs Ann.
Chem. 699, 195 (1966).
[128] W. Frirzsch and H . Ruschig, Liebigs Ann. Chem. 655, 39
(1962).
[129] W . Fritzsch, U. Stache, W. Haede, K . Radscheit, and H .
Ruschig, Liebigs Ann. Chem. 721, 168 (1969).
[I301 H . - G . Lehmann and R . Wiechert, Angew. Chem. 80, 317
(1968); Angew. Chem. internat. Edit. 7 , 300 (1968).
[131] R . Deghenghi, J. org. Chemistry 31, 2427 (1966).
[1321 F. Sondheimer, W. McCrae, and W. G . Sahnod, I . Amer.
chem. Soc. 91, 1228 (1969).
Angew, Chem. internat. Edit.
1 Vol. 9 (I9701 / No. 5
Two independent multi-stage syntheses of the molting
hormone starting with ergosterol (62) [141-1441 and
stigmasterol (63) 1145,1461 were published in 1966.
HO
H
H
O
H
8
Ho&OH
W
157)
156)
Starting from a readily obtainable 14a,17~,21-trihydroxy 20-one (St?), these authors synthesized the upyrone structure (60) -by an interesting multistage
synthesis with final Reformatzky reaction of an enolized
3-dialdehyde (59) with methyl bromoacetate.
HO
---*
'
OH
HO
(62)
(61)
H O
H0
(63)
While great progress has been made in the synthesis of cardioactive steroids, treatment with those compounds has advanced very little.
The therapeutic range is extremely narrow, and the use of the
drugs is consequently difficult. However, the use of these
steroids for nearly two hundred years shows their value as
drugs that are as yet irreplaceable. It remains t o be seen
whether structural modifications, as in the case of steroid
hormones, lead t o fundamental or advantageous changes in
the biological effects of the natural steroids.
In this connection, mention should be made o f the cytotoxic
effects observed with cardenolides [133-1371.
6. Steroid Metamorphosis Hormones
In 1954, Butenandt and Karlson"3R1 succeeded in isolating the hormone responsible for molting in the
development of insects, which they called ecdysone,
from the pupae of silkworm moths. The steroid structure of ecdysone was recognized nine years later [*39J,
and after a further two years its complete structure
was found by X-ray analysis [1401 as 22 R-2@,3@,14a,22,
25-pentahydroxy-5f5-cholest-7-en-6-one
(61).
11331 J . E . Pike, J . E . Grady, J . S . Evans, and C . G. Smith, J.
med. Chem. 7, 348 (1964).
[1341 S. M . Kupchan, R . J . Hemingway, and R . W. Doskotch,
J . med. Chem. 7, 803 (1964).
11351 S. M . Kupchan, J . R . Knox, J . E . Kelsey, and J . A. S.
Renault, Science 146, 1685 (1964).
[136] R . B. Kelly, E. G . Daniels, and L . B. Spaulding, J. med.
Chem. 8, 547 (1965).
[137] S. M . Kupchan, M . M o k o t o f , R . S . Sandhu, and L . E .
Hokin, J. med. Chem. 10,1025 (1967).
[1381 A . Butenandt and P . Karlson, Z . Naturforsch. 9 b , 389
( 1 954).
[I391 P . Karlson, H . Ho@meister, W . Hoppe, and F. Huber,
Liebigs Ann. Chem. 662, 1 (1963).
[1401 R . Huber and W . Hoppe, Chem. Ber. 98, 2403 (1965).
[1411 U. Kerb, P . Hocks, R . Wiechert, A . Furlenmeier, A . Fiirst,
A . Langemann, and G . Waldvogel, Tetrahedron Letters 1966,
1387.
11421 R. Wiechert, U. Kerb, P . Hocks, A . Furlenmeier, A . Fiirst.
A . Langemann, and G. Waldvogel, Helv. chim. Acta 49, 1581
(1966).
Angew. Chern. internat. Edit.
Vol. 9 (1970)
1 No. 5
The syntheses were based on the ability of 2@,3@-dihydroxy-6-0x0-AB-trans steroids (64) to be converted
into AB-cis 6-ketones (65), which had first been
postulated from models and then demonstrated.
CH3
I\.
HO
H
HO
The preferred stable AB ring fusion of 6-0x0 steroids
is the trans linkage. The 1,3-diaxial interaction between the 2B-hydroxyl group and the 19-methyl group
in (64) favors the displacement of the equilibrium
toward the cis compound (65).
A second insect molting hormone, which also initiates
molting in crustaceans, is 20-hydroxyecdysone (crustecdysone). It can be isolated from insects [147-1501
and lobstersI1sll, and has now also been synthesized 1152,1531. A 20,26-dihydroxyecdysone has been
[143] A . Furlenmeier, A . Fiirst, A . Langemann, G . Waldvogel,
KJ. Kerb, P . Hocks, and R . Wiechert, Helv. chim. Acta 49, 1591
(1966).
[I441 U . Kerb, G. Schulz, P . Hocks, R . Wiechert, A . Furlenmeier
A. Fiirst, A . Langemann, and G. Waldvogel, Helv. chim. Acta 49,
1601 (1966).
f1451 J . B . Siddull, J . P . Marshall, A . Bowers, A . D . Cross, J . A .
Edwards, and J . H . Fried, J. Amer. chem. SOC.88, 379 (1966).
11461 J . B. Siddall, A. D . Cross, and J . H . Fried, J. Amer. chem.
SOC.88, 862 (1966).
11471 P. Karlson, Vitamins and Hormones 14, 227 (1956).
[148] P . Hocks and R . Wiechert, Tetrahedron Letters 1966,
2989.
11491 H . Hoffmeister and H . F. Griitzmocher, Tetrahedron Letters 1966, 401 7.
[150] J . N . Kaplanis, M . J . Thompson, R . T . Yamamoto, W . E .
Robbins, and S . J . Louloudes, Steroids 8, 605 (1966).
[151] F. Hympshire and D . H . S . Horn, Chem. Commun.
1966, 37.
[152] G. Hiippi and J . B. Siddull, J . Amer. chern. SOC.89, 6790
(1967).
[ 1 5 3 ] U. Kerb, R . Wiechert, A . Furlenmeier, and A . Fiirst, Tetrahedron Letters 1968, 4277.
329
isolated from the tobacco hornworm (Protoparce
sexta) 11541.
A wave of publications, which has not yet stopped,
resulted from the surprising first isolation of ecdysonelike compounds, the ponasterones, from the conifer
Podocarpus nakii by Nakanishi et al. [1551. Ecdysone [156,1571 and 20-hydroxyecdysone [156-1611 have
also been found in the plant kingdom. To provide
some idea of the range, Table 3 shows the structures
Table 3.
Plant steroids having an ecdysone-like action [a].
A
OH H
OH H
H
H
H
H
H
H
H
O
H
O H H
n
H
H
H
H
H
H
H
H
H
C6HIOOJ
HO OH
R = *OH
polypodine 1162. 1631
ponasterone A [155, 164-1661
inokosterone [167]
pterosterone [I681
ponasteroside A [I661
makisterone A [169, 1701
HO
B
R = H&ClizOH
The side chain attached to C-17 of ecdysone can be
varied within certain limits without loss of molting
hormone activity.
Table 4 lists a number of results which were obtained
under identical conditions in the Calliphora test and
which illustrate relationships between structure and
activity.
The significance of the 14a-hydroxy group and the
high activity of the compound having an unsubstituted cholesterol side chain are worthy of note, while
changes in the stereochemistry or a shortening or loss
of the side chain practically leads to inactivation.
HO
R'O
and names of steroids related in structure and action
to the natural molting hormones and isolated from
the leaves, wood, or roots of Podocarpaceae, Taxaceae,
Polypodiceae, Amaranthaceae, and Verbenaceae.
rnakisterone B [169, 1701
rnakisterone C [169--171]
makisterone D 1169, 1701
A complete change in the action of this class of compounds occurs on inversion of the AB ring linkage to
give the trans series. Certain ecdysone-antagonistic
effects, such as inhibition of post-ecdysonal molting
andsclerotization of the larva cuticulae were observed,
inter alia, with a number of Z,3-dihydroxy-6-oxo-Sa
steroids of the pregnane (66a), (66b) and cholestane
series 1177,1781 (66~)-(66e).
[157] G . Heinrich and H . Hoffmeister, Experientia 23, 995
(1967).
[I581 M . N . Galbraith and D . H . S. Horn, Chem. Cornmun.
1966, 904.
11591 H . Rimpler and G . Schulz, Tetrahedron Letters 1967,
2033.
[160] H . Hoffmeister and G . Heinrich, Naturwissenschaften 54,
471 (1967).
[I611 J . Jizba, V . Herout, and F. Sorm, Tetrahedron Letters
1967, 1689.
[162] J . Jizba, V . Herout, and F. Sorm, Tetrahedron Letters
1967, 5139.
[I631 G . Heinrich and H . Hoffmeister, Tetrahedron Letters
1968, 6063.
[I641 H . Moriyama and K . Nakanishi, Tetrahedron Letters
1968, 1111.
I1651 G. Hiippi and B. Siddall, Tetrahedron Letters 1968, 1113.
cyasterone 1172,1731
ajugasterone B 11741
R= &
H
capitasterone [I751
[I 661 T . Takemoto, S . Arihara, and H . Hikino, Tetrahedron
Letters 1968, 4199.
(1671 T . Takemoto, Y . Hikino, S . Arihara, and H . Hikino, Tetrahedron Letters 1968, 2475.
[168] T . Takemoto, S . Arihara, Y . Hikino, and H . Hikino, Tetrahedron Letters 1968, 375.
[I691 S. Imai, M . Mori, S . Fujioka, E. Murata, M. Goto, and
K. Nakanishi, Tetrahedron Letters 1968, 3883.
[I701 S. Imai, S . Fujioka, E. Murata, Y . Sasakawa, and K . Na-
kanishi, Tetrahedron Letters 1968, 3887.
[I711 T . Takemoto, Y . Hikino, T . Arai, and H . Hikino, Tetrahedron Letters 1968, 4061.
R1
=
R1 =
H, ponasterone B [I761
OH, ponasterone C 11761
HO
[a] The configuration of the side chain is unknown insections B and C.
[I 541 M . J . Thompson, J . N . Kaplanis, W . E . Robbins, and R . 7
Yamampto, Chem. Commun. 1967, 650.
[I 551 K . Nakanishi, M . Koreeda, S . Sasaki, M . L . Chang, and
H . Y . Hsu, Chem. Commun. 1966, 915.
[I561 J . N . Kaplanis, M. J . Thompson, W . E. Robbins, and B.
M . Bryce, Science (Washington) 157, 1436 (1967).
330
[I721 T . Takemoto, Y. Hikino, K. Nomoto, and H . Hikino,
Tetrahedron Letters 1967, 3191
[I731 H . Hikino, Y . Hikino, N . Nomoto, and T . Takemoto,
Tetrahedron Letters 24, 4895 (1968).
[174] S. Imai, Chern. Commun. 1969, 82.
[175] T . Takemoto, K . Nomoto, Y . Hikino, and H . Hikino,
Tetrahedron Letters 1968, 4929.
[I761 K . Nakanishi and M . Koreeda, Tetrahedron Letters 1968,
1105.
(1771 J . Hora, L . Labler, A . Kasal, V . Cerny, F. Sorm, and K .
Slama, Steroids 8, 887 (1966).
[178J H . Velgova, L . Labler, and V. Cerny, Collect. czechoslov.
chern. Commun. 33, 242 (1968).
Angew. Chem. internat. Edit.
1 Vol. 9
(1970)
1 No.
5
Table 4. Relations between structure a n d action in derivatives of
ecdysone (61). I n t h e Calliphora test, 0.05 xg of 161) were required For
pupation of o n e larva.
?H
-O
.. H
HO
H
C h a n g e in ( 6 / 1
Relative
activity
Relative
activity
Change in 1611
(%)
(%)
HO O H
inactive
1 2 5 S 170
I!?--0 1i
Molting hormones were also found to cause a dosedependent increase in the incorporation of 14C-leucine
into the protein of mammalian livers~ls6l. Some
ecdysone-like steroids have protein-anabolic effects o n
mice [187,1881~
The possibility of obtaining molting hormones readily
by synthesis or from plants provides a broad base for
biological studies on this interesting class of compounds e.g. in plant protection, in pharmacology, or
for fundamental growth processes in warm-blooded
animals.
inactive
25
7. Novel Steroids
POH
6-
The investigations on the role of ecdysone in protein
synthesis proceed beyond the bounds of entomology,
and are of general importance. It has been shown experimentally that ecdysone increases and initiates DNA
and RNA synthesis [180-1*31. Karlson Ilfi41 derived a
general hypothesis on the mode of action of hormones
on the basis of the direct activation of certain gene
sites as observed together with Clever 11851.
O
H
15
inactive
70
inactive
20
inactive
From cultures of the aquatic fungus Achlyu bisexualis,
McMorris and Burksdule (1967) [I891 isolated a crystalline substance that causes the growth of cell filaments
or hair-like outgrowths at points where the propagative cells develop in the male plant. It thus induces the
sexual reproduction in this species. This plant sex
hormone, which the authors called antheridiol, has the
structure of the steroid lactone (67) [190J.
OSI
6
OH
Correspondingly substituted steroids of the androstane series (66fl, (66g) [I791 exhibited a toxic action
towards the final larva stage of Pyrrhocoric Cysterus
L. In addition, compound (66f) is reported to have a
sterilizing effect on the common house fly.
Antheridiol has now been synthesized from stigmasterol [1911. This presents possibilities for a broad
investigation of this interesting steroid.
[180] V . B. Wigglesworth, J . exp. Biology 40, 231 (1963).
11811 P . P . Dukes, G . E . Sekeris, and W. Schmidt, Biochirn. biophysics Acta 123, 126 (1966).
[182] G.R . Wyatf and B.Linzen, Biochim. biophysica Acta 103.
588 (1963).
nl
[I831 C.M . Williams, Science (Washington) 148, 670 (1965).
[184] P . Karlson, Dtsch. med. Wschr. 86, 668 (1961).
HO
[185] (I. Clever and P . Karlson, Exp. Cell Ress. 20, 625 (1960).
[179] L . Labler, K. Slama, and F. Sorm, Collect. czechoslov.
chem. Commun. 33, 2226 (1968).
Angew. Chem. internal. Edit.
1 Yo!. 9 (1970) j No. 5
[I861 W . J . Burdette and R . L . Coda, Proc. SOC.exp. Biol. Med.
112, 216 (1963).
I1871 S.Okui, T . Okata, M . Uciynma, T . Takemoto, H. Hikino,
S . Ogawa, and N . Nishimoto, Chern. pharmac. Bull. (Tokyo) 16,
384 (1968).
11881 T . Takemoto, S. Arihara, Y. Hikino, and H . Hikino,
Chem. pharmac. Bull. (Tokyo) 16, 762 (1968).
11891 7'. C. McMorris and A . W . Barksdale, Nature (London)
2f5, 320 (1967).
[190] G. P . Arsenault, K . Biemann, A . W . Barksdale, and T . C .
McMorris, J. Amer. chem. SOC.90, 5635 (1968).
11911 J . A . Edwards, J . S . Mills, J . Sundeen, and J . H . Fried, J.
Amer. chem. Soc. 91, 1248 (1969).
33 1
The Cholo Indians of western Colombia use the venom
of the poison frog (Phyllobates aurotaenia) for hunting.
Witkop et al. were able to isolate several poisons, the
batrachotoxins, from the secretion obtained from the
animals on heating 11921. These compounds are the
strongest known cardiotoxins. Paralysis and convulsions are followed by death within a few minutes.
An artifact of the batrachotoxins is batrachotoxinin A
(68), which is equivalent to strychnine in its toxicity.
X-ray structure analysis [I931 of (68) gave the unusual
steroid alkaloid structure indicated.
Interesting new synthetic developments in the steroid
field include the bis-quaternary piperidinium com-
7%
H-C-OH
pound (69) and the 21-fluoro-6-dimethylaminomethyl-1 7cc-acetoxyprogesterone derivative (70).
When the compound (69) is administered to humans
in small doses, it causes a neuromuscular block, which
can be removed by neostigniinerl941. The authors
classify the action as being of the curare type.
A remarkable analgesic action, which is superior to
that of codeine and cannot be eliminated by morphine
antagonists, is shown by the steroid (70) in animal
experiments 11951.
I am grateful to Dr. H . Steinbeck and Dr. A . Jager
(Schering AG) for supplying the biological results in
Tables I , 2, and 4.
Received: July 14, 1969
[A 746 IEI
German version: Angew. Chem. 82, 331 (1970)
Translated by Express Translatlon Service, London.
[192] J. W . Daly, B. Witkop, P . Bommer, and K . Biemann, J.
Amer. chem. SOC.87, 124 (1965).
[193] T . Tokuyama, J . Daly, B. Witkop, I . L . Karle, and J .
Karle, J. Amer. chem. S O C . YO, 1917 (1968).
11941 W. L . M . Baird and A. M. Raid, Brit. J. Anaesthesia 39,
775 (1967).
[195] Ch. D. Craig, J. Pharmacol. exp. Therapeut. 164, 371
(1968).
Macromolecular Chemistry and Medicine
By Garth W. Hastingsf*]
Macromolecular substances are used in medicine both as materials and as reagents. In the
former category polymers serve as replacements for soft tissue, as cardiovascular and
orthopedic implants, and as adhesives. When employed as reagents, macromolecules
interact with living tissue and play an active part in bodily repair processes.
1. Introduction
One of the earliest uses of a macromolecular material
in surgery was that of celluloid in 1890, but only the
past decade has seen really significant developments
in this field. One of the factors in this increasing application is that the needs of the surgeon have changed,
as the whole concept of surgical care has been transformed from a passive repair role to a much more
aggressive attack upon disease embracing reconstruction or replacement of diseased or damaged organs.
[ * ] Dr. G. W. Hastings
Department of Polymer Science
University of New South Wales
Sydney (AustraIia)
332
There are problems associated with the collection and
storage of human organs, in addition t o the questions
of possible rejection of the transplant by the host
tissues, and in consequence there has been great use of
non-biological materials. The use of metals for devices
intended for permanent implantation within the
human body dates back to the sixteenth century. Nowadays, and in the future too, metals continue to play
an important role in surgery. Metals undoubtedly
offer a satisfactory solution where strength and resistance to the bodily environment are required, but
limitations have led to the search for alternative
materials. Metallic corrosion is one factor in the very
hostile bodily environment, but there is no agreement
as to its importance. A more serious limitation is that
Angew. Chem. internat. Edit.
Vol. 9 (1970)
No. 5
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