Synthesis of diosgenin prodrugs: anti-inflammatory and antiproliferative activity evaluation

Article abstract of DOI:10.1007/s12039-020-01808-y

Abstract: In this work, we evaluated the antiproliferative and anti-inflammatory activities of two diosgenin prodrugs. The prodrugs were obtained by esterification of diosgenin at position 3 with 4-oxo-4-(prop-2-yn-1-yloxy)butanoic acid followed by click reaction on terminal alkyne with 3-azidopropan-1-ol N-alkylated dendrons, resulting in a prodrug with methyl ester end-groups and a derivative with tert-butyl ester end-groups, hydrolysis of tert-butyl ester derivative afforded a prodrug with carboxylic acid terminals. All compounds were fully characterized by ¹H and ¹³C NMR, ATR-FTIR and HR-ESI TOF. Studies of the anti-inflammatory effects on mouse ear edema of prodrugs methyl ester and carboxylic acid, ended, using diosgenin and dexamethasone as positive controls, showed the superiority of methyl ester ended prodrug with an ED₅₀ four times lower than that of dexamethasone. Further, carboxylic acid ended prodrug was found to be more active than diosgenin as an antiproliferative agent, according to crystal violet assay. Graphic abstract: Diosgenin was transformed to ester and acid prodrugs through succinic ester and a 1,2,3-triazole linkers. The prodrug with methyl ester terminals was four times more active than dexamethasone as anti-inflammatory compound, while prodrug with carboxylic acid terminals improved antiproliferative activity over MCF-7 cells.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-020-01808-y

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or a l c ont r a ce p ti ve s, a s we ll a s ot he r st e ro id al dr ugs .
Add iti ona ll y, th er e a re se ve r al st udie s on th e p ote ntia l
of di osge ni n f or th e tr e a tm en t of va r iou s type s of
di sor de r s suc h a s le uk em ia , in fla m ma ti on, hype r c -
Di o sg e n in (2 5 R-s pi ro st - 5- en -3 b- ol ), a st e ro id a l sa po-
g e n in is wi d el y d is tr i bu te d i n pl a nt s, o bt ai ne d m ai nly
fr o m s o me wi ld s pe ci es o f M ex i can y am ( Dioscorea
s p . ) o r, a s a n a lt er na t iv e, f ro m f enu gr ee k ( Trigonella
foenum-graecum L. ). Th i s me ta bo l it e ha s b ee n th e
s t a r ti n g ma t e ria l o f t he co rt i co st er o i ds ( pr ed n isol one ,
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tr e a tm en t a nd pr e ve nti on of in fla m ma to ry r ea c tion s in
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supplementary material, which is available to authorized users.

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t
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l
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t
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d
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s
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n
d
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n
u
a
t
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t
o
t
a
l
r
e
fl
c
on a Var ia n 6 00 - I R
t
a
n
c
e
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f
o
u
r
i
e
r
-
t
r
a
n
s
-
t h e e ffe c t o f d io s g en in i n ma cr op ha ges , fin di ng th at
t hi s st er oi da l sap o ge n i n i n hi b i t s ma c ro p h ag e- de r iv e d
i n fla mm a t o ry me di at o rs t hr ou gh d own re gu lat ion of
f
o
r
m
i
n
f
r
a
r
e
d
(
A
T
R
-
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T
I
)
s
p
e
c
t
r
a
s
e
ri
e
s
s
pe
c
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r
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m
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r
.
H
i
g
h
es
o
lu
ti
o
n
m
as
s
s
p
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t
r
a
(
HR
MS
)
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e
r
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r
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c
o
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d
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d
o
n
a
n
a
g
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l
e
n
t
T
O
F
m
a
s
s
s
p
e
c
t
r
o
m
e
t
er
(
MS
6
1 3
T
O
F
)
u
s
i
n
g
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e
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S
I
(?
)
t
e
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h
n
i
q
u
e
.
C
N
M
R
a
s
s
i
g
n
m
e
n
t
o
f
i
n
fl
a
m
m
a
t
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y
m
e
d
i
t
a
t
o
r
s
.
d
i
o
s
g
e
n
i
n
d
e
r
i
v
a
t
i
v
e
s
w
a
s
m
a
d
e
b
y
c
o
m
p
a
r
i
s
o
he m ic al s hi ft s rep ort ed by P uri et al. fo r di os gen i n .
n
w
i
t
h
t
h
e
C o n c er n in g c a n ce r t re at me nt , st u di es u si n g F 344
ra t s h a v e s h o wn t ha t di o sg en in su pp r ess es t h e in ci -
d e n c e o f b o th in v as iv e an d no n -i nv as iv e co l o n a de -
n o c a rc in o m a s u p t o 60 % v ia at t en ua ti on of t umor c el l
1
7
c
7
2
.
2
S
y
n
t
h
e
s
i
s
o
f
d
i
o
s
g
e
n
i
n
p
r
o
d
r
u
g
s
p ro l ife ra ti o n . Ad di ti o na ll y , in vitro ac t iv i ty of di os-
g e n in a g a in s t v a rio u s h uma n ca nc er ce l l l in es ha s be e n
s t u di e d e x te n s i v e l y, sh owi n g i nh ib i ti on of M CF - 7 a nd
T
h
e
m
e
t
h
o
d
o
l
o
g
y
f
o
r
c
a
r
r
y
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n
g
o
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t
t
h
e
s
t
r
u
c
t
u
r
a
l
m
o
d
i
fi
c
a
-
8
M DA h u ma n b re as t ca rc i no ma, HT- 29 an d H CT- 11 6
t
i
o
n
d 3
o
f
d
i
o
s
g
e
n
i
n
i
s
s
u
m
m
a
s
r
i
z
e
d
i
n
S
c
h
e
m
e
1
.
C
o
m
p
o
u
n
d
s
2
1
8
a
n
w
e
r
e
s
y
n
t
h
e
s
i
z
e
d
a
p
r
e
v
i
o
u
s
l
y
d
e
s
c
r
i
b
e
d
.
3
hu m an c olo n a de n o ca r c in o ma , PC -3 an d DU14 5
9
1
0
1
1
h u ma n p ro s t at e c a nc er ce l ls , an d pa nc re at i c ca nc e r
a m on g o th e r s .
2.2 a Compound
yloxy)butanoic acid:
6,
K
4-oxo-4-(prop-2-yn-1-
O
H
(
1
.
5
g
,
2
.
6
7
m
m
1
o
l
)
w
a
s
mL o f
T h e v e rs a til e an t ic an ce r an d an t i- i nfl amm at or y
a ct i v ity e x h ib ite d by d io sg en in i nd ic at es t h at th is
m o l e c u le c o u ld b e a st a rt i ng p oi nt f or de ve l o ping a
n e w me d i c in e , a s an al t er na t iv e dr u g of na t ur al or ig in
c ap a b le o f d im in i sh in g t he si d e- ef fe ct s ca u se d by
a l lo p at h ic d ru g s . Ho weve r, di o sg en in i s pr a ct ic a lly
i n s ol u b le in p h y s i ol og ic al me di a an d ha s l ow a bsor p-
t i o n a n d a h ig h pe rc en t age of t he ab so rb ed dr ug is
g
r
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m
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w
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f
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d
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o
t
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i
s
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e
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9
6
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(
1
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9
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m
m
o
l
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f
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e 5
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p
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(
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L
C
)
b
e
t
w
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e
1
5
a
n
3
0
m
i
n
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h
e
s
o
l
i
d
w
a
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t
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t
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w
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t
h
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%
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C
l
s
o
l
u
t
i
o
t
o
p
H
2
a
;
a
n
d
e
x
t
r
a
c
t
e
d
w
i
t
h
C
H 2
C
l 2
/
H 2
O
(
3 9
O 4
2
0
m
L
)
.
T
h
e
o
r
g
a
n
i
c
l
y
e
r
w
a
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r
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e
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v
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r
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s
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S
1
2
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n
d
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o
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t
r
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d
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t
w
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c
r
y
s
t
a
l
l
i
z
e
d
f
r
o
m
m e t a b o liz e d ra p id ly . Th er ef or e, wi th t he a im of
i m p ro v in g th e a d mi ni s tr at i on di s tr i bu ti on me tab oli sm
h
e
x
a
n
e
t
o
g
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v
e 6
(
a
-
s
a
b
r
i
g
h
t
w
h
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t
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o
l
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d
.
Y
i
e
l
d
4
8
%
(
0
.
8
1
2
g
)
.
1
A
T
R
-
F
T
I
R
c
m
)
: mO– H
3
4
0
0
–
2
5
0
0
, mC – H,
3 28 8
a l k yn e
,
1
1
3
e x c re tio n a n d to x ic i ty ( ADM ET) p ro per t ie s a nd
t a ki n g in t o c o n s id er at i on t ha t t he t ri az ol e r in g h as be e n
mC – H a l ip h
H
2
9
1
7
,
2
8
4
9
, mC = O e s te r
,
1
7
2
9
, mC = O a ci d
:
1
6
9
1
.
-
N
M
R
(
4
0
0
M
H
z
, d
H
p
p
m
i
n
C
D
C
l3
)
1
1
.
4
1
(
b
r
s
,
1
H
,
1
4
s h o wn to in c r e as e an t ic an ce r as wel l as an ti fu nga l
I n t hi s st udy,
C
O
=
O
H
)
,
4
.
7
2
(
s
,
2
H
,
3
-
5
)
,
2
.
7
0
(
,
(
m
,
4
H
,
H
-
2
,
H
-
3
)
,
2
.
5
1
(
d
,
1
i n CD Cl 3 ) :
H
15 ,16
a ct i v ity o f d io s g e ni n d eri v at iv es .
1
J
1
.
8
H
z
,
H
-
7
)
.
C
-
N
M
R
1
0
0
M
H
z
,
d
,
p
.
p
m
d i o sg e n in p ro d ru g s wer e d esi g ned as h emi su c ci na te
e s t ers wh i ch we re l in ke d t o 3 -az i do pr opa n- 1 -ol de n-
1
7
8
.
5
,
1
7
1
.
4
,
7
7
.
3
,
7
5
.
1
,
5
2
.
3
2
8
.
8
a
n
d
2
8
.
6
d
r
o
n
v
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a
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l
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c
k
r
e
a
c
t
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m
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r
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v
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t
h
e
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r
b
i
o
l
o
g
i
c
a
l
2
.
2
b
C
o
m
p
o
u
n
d
8
,
P
r
o
p
-
2
-
y
n
-
1
-
y
l
(
3
b
,
2
5
R
)
-
s
p
i
r
o
s
t
-
a
c
t
i
v
i
t
y
b
y
i
n
c
o
r
p
o
r
a
t
i
o
n
o
f
a
t
r
i
a
z
o
l
e
r
i
n
g
.
I
n
a
d
d
i
t
i
o
n
,
5
-
e
n
-
3
-
y
l
-
s
u
c
c
i
n
a
t
e
:
S
t
e
g
l
i
c
h
e
s
t
e
r
i
fi
c
a
t
i
o
n
w
a
s
u
s
e
d
:
t
o
a
t h e d e n d ro n s im p ro ve wat e r so l ub il i ty i n t he de r iva ti ve
1 a n d s h o w a ffi ni t y t o sk i n ad mi ni s tr at i on i n de r iva -
t i v e 9.
T o e v a l u a t e t h e p e r f o r m a n c e o f t h e n e w p r o -
d r u g s , in vivo a n t i - i n fl a m m a t o r y t e s t s w e r e p e r -
f o r m e d o n m o u s e e a r e d e m a a s w e l l a s
a n t i p r o l i f e r a t i v e a s s a y s o n b r e a s t c a n c e r c e l l l i n e
M C F - 7 a n d n o r m a l h u m a n fi b r o b l a s t u s i n g t h e
c r y s t a l v i o l e t ( C V ) t e s t .
5
0
m
L
r
o
u
n
d
-
b
o
t
t
o
m
fl
a
s
k
e
q
u
i
p
p
e
d
d
w
i
t
h
a
m
a
g
n
e
t
i
c
s
t
i
r
r
n 7
e
r
1
w
a
s
i
m
m
e
r
s
e
d
i
n
a
b
a
t
h
a
t
0 °
p
C
,
a
n
0
.
1
0
0
g
o
f
d
i
o
s
g
e
n
i
(
0
.
2
4
m
m
o
l
)
,
0
.
0
7
5
g
o
f
c
o
m
o
u
n
d 6
,
(
0
.
4
8
m
m
o
l
)
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n
d
0
.
0
1
8
g
n
a
o
5
f
d
i
m
e
t
h
y
l
a
m
i
H 2
n
o
p
y
r
i
d
i
n
e
(
D
M
A
P
0
r
. 1
N 2
5
m
m
o
l
)
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i
s
s
o
l
v
e
d
i
m
l
L
o
f
d
r
y
C
C
l 2
w
a
s
a
d
d
e
d
u
n
d
e
a
t
m
o
s
p
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e
.
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e
x
t
,
0
s
o
u
t
i
o
n
o
f
0
.
1
1
8
g
o
f N, N
o
-
d
i
c
y
c
l
o
h
e
x
y
l
c
a
r
b
o
d
i
i
m
i
d
e
(
D
C
C
,
d
h
0
.
5
e
5
m
m
o
l
)
i
n
2
m
L
f
d
r
y
C
H 2
d
C
l 2
w
a
s
a
d
d
e
d
d
r
o
p
w
i
s
e
,
a
n
t
h
r
e
a
c
t
i
o
n
m
i
x
t
u
r
e
w
a
s
s
t
i
r
r
e
f
o
r
1
h
a
t
0
°
C
a
n
d
t
h
e
n
f
o
r
1
2
a
t
r
o
o
m
t
e
m
p
e
r
a
t
u
r
e
(
2
5
–
2
8
°
C
)
.
T
h
e
p
r
e
c
i
p
i
t
a
t
e
d
u
r
e
a
w
a
s
/
fi
l
t
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r
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d
o
f
f
a
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d
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g
a
n
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w
a
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x
t
r
a
c
t
e
d
w
i
t
h
C
H 2
C
l 2

J. Chem. Sci.
(
2
0
2
0
)
1
32
:1
04
P
ag
e
3
of
9
10 4
Scheme 1.
d
S
y
n
t
t
i
h
v
e
e
s
i
c
s
o
o
m
f
p
r
u
o
n
d
d
r
u
g
s 9
an
d 11
f
ro
m
d
i
o
s
g
e
n
i
n
t
h
r
o
u
g
h
e
s
t
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r
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fi
c
a
t
i
o
n
a
n
d
cl
i
c
k
r
e
a
c
t
i
o
n
a
s
an
t
i
-i
nfl
am
m
a
to
r
y
a
n
a
n
t
i
p
r
o
l
i
fe
ra
po
s
.
H 2
O
,
w
a
s
h
e
d
w
i
t
h
0
.
5
N
H
C
l
(
3 9
5
m
L
)
,
s
a
t
u
r
a
t
e
d
s
o
l
u
t
O 4
i
o
n
o
f
2.2 c Methodology for click reaction:
c
I
n
a
r
o
u
n
d
-
Na
H
C
O 3
a
(
3 9
o
5
m
L
)
.
,
d
r
i
e
d
o
v
e
r
a
n
h
y
d
r
o
u
s
N
d
a 2
S
a
n
d
n
d
5
b
o
t
t
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m
fl
a
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k
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d
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m
a
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t
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s
t
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r
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e
r
,
s
o
d
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u
m
e
c
c
v
a
p
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r
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e
d
t
d
r
y
n
e
s
s
T
h
e
p
r
o
d
u
c
t
w
a
s
p
u
r
i
fi
e
b
y
c
o
l
u
m
a
e
s
c
o
r
b
a
t
e
(
A
s
N
a
)
,
(
0
.
4
1
e
q
u
i
v
a
l
e
(
n
t
s
)
,
b
e
n
z
o
i
c
a
c
i
d
(
2
.
0
h
o
r
o
m
a
t
o
g
d 8
a
r
a
p
h
y
u
s
i
n
g
i
n
c
r
e
a
s
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n
g
s
o
l
v
e
n
t
p
o
l
a
r
i
t
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Onc e 6 wa s ob ta ine d, S te gli ch e ste r ifi c at io n w ith
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F or ma ti on of c om poun d 8 wa s c or r obor a te d by H a nd
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r es pond ing to th e f r ag me nt de r ive d f r om 6, e xce pt f or
th e a ci dic pr ot on ( Fi gur e 1 ) . F ur the r e vid enc e of
e ste r ifi c at ion wa s th e c he mi ca l shi f t ob ser ve d f or H -3
f r om 3.5 1 in di osge ni n to 4.6 1 ppm in c om pou nd 8.
C lic k r ea c ti on of c om poun ds 2 a nd 3, ha vi ng a z ide
a s f oc al po int wit h di osge ni n de r iva ti ve 8, hav ing a
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J. Chem. Sci.
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Figure 1.
H
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d e riv a t iv e s 9 a n d 10. Ch ar ac te ri s t ic si g na ls i n th e H th e qua t er na r y c ar bo n of th e t- but yl gr ou p a t 28 .9 ppm ,
NM R s p e c tra o f d io sg en in (7) , co mp ou nd s 8, 9 a nd 10 whi le th e r es t of th e si gna ls a re not si gni fi ca nt ly
a re s h o wn in F ig u re 1. A co mp ar is on o f t he spe c tr a m odifi e d. F ina ll y, th e f or ma t ion of 11 wa s c or r obo-
a l lo ws c o rro b o ra ti o n of t he f or mat i on of t he 1,2 ,3- r at e d by HR -M S TOF whi ch sho ws th e m ole c ul ar ion
t ri a z o ly l mo i e ty i n 9 an d 10 f ro m t he si g na ls a t 7.7 4 a t 79 7.469 8, in a gr ee m en t wit h th e f or mul a
?
a n d 7 . 72 p p m, res pe ct i ve ly , as wel l as f ro m th e di s- [ C H N O ?H] .
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a l ky n e (H- 3 4 ) p ro to n i n co mp ou nd 8. Si mi l ar ly, th e m el tin g poi nts of pr od ru gs 9 ( 89– 90°C ) and 11
s i g na ls a s s o c ia te d wi th me th yl es t er an d tert- but yl (15 9–160°C ) we r e be lo w th at of di osge ni n ( 205-
e s t er g ro u p s we re as si g ne d at 3 .66 an d 1 .42 pp m f or 20 8 °C ), e vid en ci ng th at f or ma t ion of a n e ste r link ag e
c o mp o u n d s 9 a n d 10, r esp ec ti v el y, co nfi rmi ng th e in th e 3- O po siti on of di osge ni n de c re a se s hy dr oge n
2
4
fo r m a tio n o f th e p ro du ct s. Th e HR- M S TOF sho ws th e bon d in te ra c ti ons
m o l e c u la r io n fo r 9 at 8 25. 50 07 co rr es po nd i ng to th e c ohe sio n.
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s h o ws th e M at 9 09. 59 47 i n ag re em ent wit h th e
t h e or e tic a l v a lu e . Fi g ur e 1 d epi c ts t he mo st r epr e se n-
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Hy d ro ly s i s o f co mp ou nd 10 co nt a in in g tert-bu tyl Ac co rd ing to th e e sta bl ishe d m et hodo log y, the pe r -
e s t er te rm in a l g ro up s u si ng t ri flu or oa ce ti c aci d wa s c en ta ge s of in hibi tio n of in fla m ma ti on in m ou se e a r
c o n fi rme d b y d is a p pea ra nc e o f t he si g na l at 1.4 2 pp m e de ma we r e de te r mi ne d in gr ou ps of fi ve w ith
(
1
t-B u g ro u p ) in th e H NM R sp ec tr u m an d t he ob ser - in fla m ma ti on in duc e d by TP A. I n th e in iti al a ss a y, a ll
v a t i o n o f a n e w s ig na l at 1 1.9 pp m du e t o t he p r oton of c om poun ds we r e te st ed a t 0.5 m g/e a r, a nd on ly dios -
t h e a c id ; th i s in d u c e s a sh i ft i n t he si g na l o f t he tr i az ol e ge ni n a nd pr od ru g 9 sho wed a n a ct ivi ty hi ghe r tha n
ri n g to 8 . 13 p p m du e t o i nt er ac t io ns be t wee n th e 50 %. To de te r mi ne th e ED5 0 of a ct ive c om pounds ,
n i t ro g e n in th e ri n g an d t he ca rb ox yl i c ac i d t erm in al s. se r ia l di lut ions we r e m ad e a nd de xa m et ha son e w as
1
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Table 1.
11.
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1. 49
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0. 37
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o f 5 0 % o f in fl am mat i o n i nh ib i ti on was o bta in ed 3.3 Evaluation of the antiproliferative activity
a cco r d in g to th e g ro up ex pe ri e nce . Th e pe rc ent ag e of
Dio sge nin 7 a nd pr od ru gs 9 a nd 11 we r e sc r ee ne d f or
a nti pr oli fe r a tiv e a ct ivi ty a ga ins t a br e as t c an c e r c e ll
li ne ( MC F -7 ) a nd on hu ma n fi br obl as ts ( hF B) a s a
he a lth y c el l li ne . P re l im ina r y sc r ee ni ng of th e c om-
po unds wa s c ar r ie d ou t f r om 3.8 2 to 10 0 lM; how e ve r,
th e C C5 0 wa s not r ea c he d a nd a ne w se t of c onc e n-
tr a ti ons up to 50 0 lM we r e te st ed . S ta r tin g f r om
c onc e ntr a ti ons of 26. 5 lM, di osge ni n a nd c ompo und
i n fla mm a t io n in h ib i ti on as a f un ct io n o f co nc e ntr a ti on
i s s h o wn in T ab l e 1.
T h e d a ta in T ab l e 1 al l ows co rr o bo ra ti o n of t he a nti -
i n fla mm a t o ry e ffe ct of di o sg en in i nd uc ed by TP A,
wh i ch re s u lt s a lm os t t wic e as ef f ect i ve as de xa m -
e t ha s o n e , s in c e th e d ose ne ce ss ar y t o r eac h 54 a nd
5
3 % o f in h i b it io n was 1. 21 an d 2 .55 lmo l/ ea r f or
d i o sg e n in a n d d ex am et ha son e, r esp ec ti v el y. I nte r e st-
i n g l y , p ro d ru g 9 t ur ne d ou t t o be f ou r t im e s m or e
a ct i v e th a n d e x am et ha son e an d t wic e as act ive a s
d i o sg e n in , s in c e th e d ose r equ i re d t o ca us e 52% of
i n h i b it io n wa s 0 . 61 lmo l/ e ar . Th es e r esu l ts c an be
e x p la in e d c o n s id er i ng t ha t di o sg en in pr o dr ug 9 wit h 4
m e t h y l e s te r te rm i na l gr o up s p ro mot es st r at u m c or -
n e u m tr an s p o rt, a n d as t hi s di o sg en in pr o dr ug r ea c he s
t h e d e rmi s , s o lu b le es t er as es cl e ave of f t he e ste r
g ro u p s a n d re le a s e t he ac t iv e gr o up i nt o t he sys te mi c
11 di spla ye d a nti pr oli fe r a tive e ff e c t in a do se- de pe n-
de nt m an ne r on bot h MC F - 7 a nd hF B . C omp a r ed to
di osge ni n, c om poun d 11 sho wed im pr ov ed a ntipr ol if -
e ra t ive a ct ivi ty ove r MC F - 7, wit h a C C 5 0 of 211.7 0
lM, whi le th e C C5 0 of di osge ni n wa s [ 500 lM
(
Ta ble 2) . Add iti ona ll y, th e a ci d te r mi na ls in 11
c ha nge d th e sol ubi lit y, pr ov idin g th e pos sib ility of
a dm ini ste r ing it in tr av en ousl y a s a sa lt .
Howe ve r , th e sa m e te nd en cy wa s ob ser ve d on
2
5
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c i rcu l at io n mo re ef fic ie nt l y t ha n pr o dr ug 11 wit h
o n l y tw o e s te r g r ou ps . As a r esu l t, t he an t i-i nfl am -
m a t o ry e ffe c t in co mp ou nd 11 wi th ca rb ox yl ic a ci d
e n d -g ro u p s d e c re a se s. Th e ED50 f or 7 an d 9 we r e 1.0 2
a n d 0 . 61 lmo l /e a r , r esp ec ti v el y. Th e p ot en t a nti -i n-
fla mm a to ry a c ti o n of di o sg en in an d i ts an a log ue s
c o ul d b e a tt rib u ted t o t he i nh ib i ti on of pr o -i nfla m ma -
5
0
de te r mi ne d, whi le f or di osge ni n, th e va lu e wa s o ve r 500
lM. The se r es ult s in dic a te th at a c ha nge in sol ubili ty c a n
m odul at e th e a ct ivi ty, but th is im pr ov em e nt a ff e c ts both
c el l li ne s; th er e f or e, f ur the r st udie s on c el l de a th
m ec ha ni sm a re r eq uir e d to e sta bl ish th e opt im a l c he m-
ic a l m odifi c a tio n th at le a ds to im pr ov em e nt of AD MET
pr op er ti es wit hout a ff e c tin g nor m a l c el ls.
2
6
t o r y c y to k in e s li k e TNF -a, I L-6 an d I L-1 b.
Ta k in g in t o c o ns i der at i on t ha t d exa me th ason e c an
C onc er n ing c om poun d 9, th e r es pons e wa s une x-
pe c te d a nd wit h MC F - 7, th e r es pons e st ar t s a t 2 50 lM
2
7
c a us e s i de -e ffe c ts , t he t he ra pe ut i c us e of d ios ge nin
a n d p ro d ru g 9 as an t i- i nfl amma t or y t op ic al a ge nts
c o u ld b e b e n e fi ci a l, pr o vi de d f act o rs su ch as c yto tox-
i c it y , s k in re a c ti o ns an d bi o co nv er s io n as wel l a s th e
m e ch a n i s m o f a c ti on ar e t ak en i nt o ac co un t.
w
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t
h
a
C
C
[
5
0
0
l
M
.
T
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s
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d
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d
a
c
t
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v
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t
y
c
a
n
b
e
5
0
a ttr i bute d to th e la c k of sol ubi lit y. Non et he le ss , hF B
c el ls a re a ff e c te d st ar t ing a t do ses of 31 .3 lM , a nd
C C5 0 of 115 .62 lM; i.e ., c om poun d 9 ha s a high er

1
0
4
P
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8
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f
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J. Chem. Sci.
(
2
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2
0
)
1
3
2
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1
0
4
Table 2.
C
C
o
f
d
i
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s
g
e
n
i
n
a
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d
p
r
o
d
r
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s
9
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1
1
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7
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n
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F
B
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l
l
l
i
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e
s
.
5
0
CC50 (µM)
MCF-7
hFB
Compound
Diosgenin
Structure
> 500
> 500
Prodrug 9
>
500
115.62
248.72
Prodrug 11
211.70
a n t i p ro li fer a ti v e e ff ec t t ha n co mp ou nd 11 on hF B Acknowledgements
c el l s. In a d d it io n , co mp ou nd 9 ha d a gr ea t er eff e c t on
B
B
e
l
em
Vi
l
l
ag
´
om
ez
G
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a
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a
n
k
C
O
N
A
C
y
T
f
or t he
AC yT
h F B th a n o n M CF - 7 ce l ls . Ov er al l, i t i s pr o po se d th at
fu r t h e r re s e a rc h on t he me ch an is m of ce l l de a th
i n d uc e d b y th e s e co mp ou nd s i s n ece ss ar y.
M
S
c
f
e
l
l
o
w
s
h
i
p
a
.
T
h
e
a
u
t
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g
e
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(
f
p
o
r
r
o
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c
t
2
5
1
5
)
n
d
I
P
N
(
S
I
P
2
0
1
8
1
2
0
1
a
nd
S
I
P
2
0
1
9
5
a
5
1
5
)
fi
na
n
c
ia
l
s
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p
p
o
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,
M
a
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e
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f
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a
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f
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S
p
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i
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a
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k
n
o
w
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e
-
e
e
e
n
t
s
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g
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e
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t
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e
a
v
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t
t
a
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d
p
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o
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s
s
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i
t
u
s
a
t
4
. Conclusions
t
t
h
h
U
n
i
v
e
r
s
i
t
y
o
f
N
e
w
B
r
u
n
s
w
i
c
k
,
C
a
n
a
d
a
,
fo
r
r
e
v
i
e
w
i
n
g
l
a
n
gu
a
g
e
o
f
t
h
i
s
p
a
p
e
r
.
Tw o d io s g e n in p ro dr ug s wer e sy nt h es iz ed by e ste r ifi -
c at i o n wi th 1 ,2 ,3- t ri az ol e de nd ri me r ic f ra gm en ts to
p re s e rv e th e c h em ic al st r uc tu re o f di o sg en i n. The
i n c or p o ra ti o n o f th e d end ri me r ic f ra gme nt wi th m et hyl
e s t er 9 a n d c a rb o xy l ic ac i d 11 en d- gr o up s a llo wed
m o du la tio n o f th e so l ub il i ty , an d co ns eq ue nt l y, t he a nti -
i n fla mm a t o ry a n d an t ip ro l if er at iv e ac t iv i ty pr op er ti es
we re im p ro v e d . T h e r esu l ts sh ow t ha t co mp ou nd 9 wit h
m e t h y l e s te r e n d -gr o up s ma y be mo re su i ta bl e th an
d i o sg e n in a n d d exa me th aso ne as an t i- i nfl am at or y
c o mp o u n d fo r to p ic al ap pl i ca ti o ns . Fo r an t ip ro l i fe r a tiv e
a ct i v ity , p ro d ru g 11 wi th ca rb ox yl i c ac i d t er mi na ls wa s
m o r e e ffe c ti v e th a n di o sg en in o r co mp ou nd 9; h owe ve r,
i n c r e as e in a c ti v ity t owa rd s t he M CF- 7 ca nc er c el l li ne
wa s n o t s e le c ti v e , an d hF B wer e al s o af f ect e d. The
re s u lt s h ig h l ig h t t he ne ed t o i nv es ti ga te ce l l de a th
m e ch a n i s ms in d u c e d by di o sg en in de ri v at iv es , in or de r
t o i m p ro v e th e c h em ic al d esi g n o f d io sg en in pr od ru gs.
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