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Journal of Medicinal Chemistry - Volume 8 - Issue 3 (1965)

Journal of Medicinal Chemistry - Volume 8 - Issue 3 (1965)

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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155Sixteenth Street N.W., Washington, DC 20036
Structure-Activity Relationships in the Field of Antibacterial Steroid Acids
Josef Fried, Gerald W. Krakower, David Rosenthal, and Harold Basch
J. Med. Chem.
,
1965
, 8 (3), 279-282• DOI: 10.1021/jm00327a001 • Publication Date (Web): 01 May 2002
Downloaded from http://pubs.acs.org on April 11, 2009
More About This Article
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Journal
of
Medicinal
Chemistry
0
Copyright
1965
by
the American Chemical Society
YOLKME
,
KCMBER
APRII
26, 1965
Structure-Activity Relationships in the Field
of
Antibacterial Steroid Acids
JOSEF
FRIED,^
GERALD
Y.
I<RAKO\T-ER,
AVID
OSENTHAL,
ND
HAROLD
ASCH
Squihh
Institute for Medical Research, n'ew Brztnswick, Yew JerseyReceived November
10,
1964
The antibacterial activity
of
a variety of steroidal and triterpenoid acids has been determined using
Staph-
Activity was found to be less dependent on specific structural andAll active compounds have
n
rigid polycyclic skeleton with
ylococcus aureus
209P
as the test organism.stereochemical features than had been anticipated.a carboxyl group close
to
an oxygen function or a double bond.
Recent investigations leading to the establishnient ofthe structure of the antibiotics fusidic acid
(Ij12
el-volic acid
(11),3,4
nd cephalosporin
PI5
as tetracyclictriterpenoids closely related to the steroids have docu-mented the biological versatility of this importantnucleus
in
yet another area. The subsequent conver-sion of the structurally related triterpenoid acid eburi-coic acid itito an antibacterially active ring
A
seco-acid
(111)
by means of microbial enzymes6 has prompted usto undertake
a
broader investigation
of
the antibac-
I
I1
COOR
111,
R=H
IIIa,
R=CH3
(1)
Ben ;\Is). Laboratory
for
Cancer Research and Department
of
Bio-chemistry, L-niversity
of
Chicago, Chicago
37,
Ill.
(2)
U-.
.
Godtfredsen and
S.
Vangedal,
Tetrahedron,
18,
1024 (1962);
D.
Arigoni,W.von Daehne,
W.
0.
Godtfredsen,
A.
Melera, and
9.
Vangedal,
Ezperientia,
20,
344 (1964).
(3)
N.
L. Allinger and
J.
L.
Coke,
J.
Org.
Chem.,
26,
4552 (1961).(4) S.
Okuda.
S.
Iwasaki,
K.
Tsuda.
Y.
Sano. T. Hata.
S.
Udagawa, Y.Nakayama, and H. Yamaguchi,
Chem. Pharm.
Bull.
Japan,
12,
121 (1964).
Structure
I1
was proposed by Professor
S.
Okuda at the Symposium on theChemistry of Satural Products, Nagoya, Oct.
1964;
cf.
Abstracts of Papers,
terial properties of steroidal and triterpenoid acids.
It
seenied
at
the outset that, because of the considerabledifferences in the stereocheinistry between the naturallyoccurring antibiotics and the seco-acid
111,
the struc-tural requirements for antibacterial activity might notprove to be too exacting. This inipression gainedfurther support when considering the fact that, whilein the steroid antibiotics the important acidic functionis located at C-21 and forms part of the side chain, thebiological activity of the seco-acid
I11
is dependent
on
the presence of
a
carboxyl group at
C-3
as demonstratedby the increase in activity attending methylation of the21-carboxyl group.7 The above impressions have beenfully borne out by the data reported in this paper.It appeared iiiost appropriate to begin such a studyby preparing additional ring
A
seco-acids from a varietyof sterols and triterpenes, and to assess the influence ofthe rigid portion of the steroid nucleus and of the sidechain on biological activity. These data are suninia-rized in Table I. With the exception of compounds
1,
2,
and
3,
all
those listed in this table possess the
anti-
trans-anti
backbone characteristic of the sterols.
How-
ever, the location of the angular methyl groups varieswidely and
so
does the nature of the side chain. Withthe exception of coiiipound
8,
all of the compounds wereactive arid one can conclude from these data that con-siderable structural variation is possible without loss
of
antibacterial activity. This is particularly evidentwhen one considers the lupeol derivative
7,
whichshows the most far-reaching deviation in skeletal struc-ture.
No
attempt is being made here to evaluate thequantitative differences in activity between the variouscompounds except in those cases where only a singlesubstituent is being varied. This
is
the case
for
2,
the21-methyl ester of
1,
which shows a 30-fold enhance-ment in activity over the latter. The conclusion appearsjustified that
a
second anionic site at
a
distant part of themolecule is detrimental to activity.
It
is felt, on struc-
p.
192.
(5)
B.
hl.
Baird,
T.
G.
Halsall,
E.
R.
H.
Jones, and
G.
Lowe,
Proc.
Chem.
Soc.,
257
(1961): 16 (1963).(6)
A.
I.
Laskin,
P.
Grabowich, C. de Lisle Meyers, and
J.
Fried,
J.
Med.
Chem.,
7,
406 (1964).
(7)
The necessity for the presence of at least one carboxyl group derivesfrom the fact that the dimethyl ester of
I11
was inactive at the
100--,/ml.
level,
the highest level employed in this investigation. Similarly, reductionof bothcarboxyl groups to primary alcohols led to inactive compounds:
cf.
ref.
6.
279
 
Hozc@
O
!I
5
I
.\liiiiiii\~ni
iihihitory
coiicentritti~~ti
f
steroid
itcidb
iii
two-
fold
,elid
dilutioil
asxiy
agaiiht
s.
(J((j'?!(.q
2OOP.
i
Ilef.
6.
c
This
\~ork.
Ref.
S.
Ref.
2.
turd
grounds,
that
8
which larlied artivity at
50
y
iiiight have
been
avtive
when
tested
at a higher level.
I3ui
thi.5
iri
to
be
expected
if
an arbitrary upper limit
is
sct
for
testing.Table
I1
suiiiii~ariz~s
ur
data
oil
ring
A
seco-acids,
iii
n-hivh substitueiits attached
to
"ring
A"
are
varied arid
tlic
reiiiainiiig portioli
of
the
steroid skeletoii is
that
ofcholestane. Since
the
hydroxy acids
1-4
all
showedaviivity,
tlic
degrec
of iiiethylatioii at
C-4
has little
in-
fluciic~
n
acsiivity. "CIoinpouiids"
3
aiid
4
representappioxiiiiat
cly
ecluin1olar iiiixturcs of
t
he
two
isoniericahydroxy avids
shown
iii
Table
IJ.y
Xi
least
oiie
of
the
18)
1)
lt~~s~~ntl~~~l
\,
0
Yie~lf~riiey~r.,
iid
.J.
i.rie~1,
1.
Org.
C/#eni..
0,
J10
1
1
!I
,,? I
two>
f
Iiot
both
isoiiwrs>
iiust
therefore, be
considt:red
active. Xniong the dirarhosylic acids only
thr
two
lrans-acids
5
and
7
shon.ed
activity, the
two
cis-acGdsbeing inactive
ai
ihc
100-7
level.
AI^
interesting
roil-
t
rast
in
activity 11-as shoivi1 between
the
wcll-l~iio~~-ii
keto acid
9
and
its 5-deoxo derivative
10.
The
fol~tici.
was
active
at
the
2-y
level, whereas the latter was iliac,-tive
at
100
y.
The
preseiicc
of
aii
oxygen fuiivtioil
iit
the
y-
or
6-positioii with respect to
the
carboxyl grouphas beeri
a
characaterist
ic,
feature
of
all
act,ive csoinpouiids
'I'h(1
r, aid,
iiideed, it is
a
charact'ei
irriitg
steroid
antibiotics. as
~~11.

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