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8/10/2019 Archives of Pharmacal Research Volume 25 Issue 6 2002 [Doi 10.1007_bf02976991] Ki -Jun Hwang; Kyung -Ho Par
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Arch Pharm Res Vo l 25, No 6 , 781-785, 2002
~r~Oi~es of
barmatal ~e~eard
ht tp: / /apr.psk.or.kr
Nove l Benzoy lu rea Der iva t i ves as Po ten t i a l An t i tum or Agents ;
Syn thes is Ac t iv i ti es and S t ruc tu re -Ac t iv i ty Re la t ionsh ips
K i -J u n H w a n g K y u n g - H o P a r k 1 C h o n g - O c k L e e 2 a n d B e o m - T a e K i m
Depar tment o f Chem ist ry a nd R esearch Center o f B ioac t ive Ma ter ia ls , Co l lege o f Natura l S c ience , Chonbuk
Nat ional Univers ity , Dukj indong 66 4-14 Ch onju 561-756, Ko rea , lDup on t CR D, Experimental S tat ion, Wi lmington,
DE 198 80-0328, US A, and 2Screening Toxicology Research C enter, Korea Research Inst itute of Chem ical Tech-
no logy, P .O. Box 107, Yusun g, Tae jeon 305-606, Korea.
(Received Sep temb er 1, 2002 )
A ser ies o f pyrazo loxyphenyl benzoy l urea der ivat ives w as des igned a nd synthes ized for cy to-
tox ic eva luat ion as potent ia l ant itumor a gents . The synthet i c com pou nds we re eva luated for in
v i tro cy to tox ic i ty aga inst f ive hum an tum or ce l l l ines, inc lud ing A-549, SKO V-3, S K-ME L-2, X F-
498 and H CT-15 . Am o ng o t he rs , com pou nd 11 exh ib i ted 50 -10 0 t i m es g rea t e r an ti tum or
act ivi t ies than the commercial product , Cisplat in.
Key words : Benzoyl Urea, Ant icancer, Cisplat in, Cytotoxici ty
I N T R O D U C T I O N
A v a r i e t y o f p h e n y l b e n z o y l u r e a d e r i v a t i v e s a r e w e l l
k n o w n a s i n s e c t i c i d e s w h i c h i n h i b i t t h e c h i t i n s y n t h e s i s o f
i n s e c t s , a n d s o m e o f t h e m a r e c o m m e r c i a l l y a v a i l a b le .
W r i g h t et a l . , 1 9 8 7 ) . C h l o r f l u a z u r o n 1 ) i s a r e p r e s e n -
t a t iv e c o m m e r c i a l p r o d u c t w h i c h i s w i d e l y u s e d a s
i n s e c t i c i d e , W h i l e c h l o r f l u a z u r o n i t s e l f h a d n o a n t i t u m o r
a c t i v i t y , s i m i l a r b e n z o y l u r e a c o m p o u n d 2 w a s r e p o r t e d t o
p o s s e s s a n t it u m o r a c ti vi ty a g a i n s t p 3 8 8 l e u k e m i a O k a d a
et a l . ,
1 9 9 1 ) . T h e r e a r e a l s o s e v e r a l r e l e v a n t r e p o r t s
H o w b e r t et a l . , 1 9 9 0 , C h e r n e t a l . , 1 9 9 7 ) a b o u t t h e
d i a r y ls u l fo n y l u r e a c o m p o u n d s 3 w h i c h w e r e r e p o r te d t o
b e e f f e c ti v e a g a i n s t s o l i d t u m o r s .
A f t e r t h e r e p o r t b y O k a d a et a l . , v a r i o u s b e n z o y l u r e a
c o m p o u n d s w e r e f u r t h e r i n v e s t i g a t e d i n t h e s e a r c h o f
p o t e n t i a l a n t i c a n c e r d e r i v a t i v e s t o c o m e u p w i t h H O - 2 2 1
4 ) b y I sh i h a ra S h n g y o K a i s h a , L T D . K o n d o et al . , 1 9 9 3 ) .
A l t h o u g h H O - 2 2 1 w a s f o u n d t o a c t a s a s t r o n g i n h i b i t o r o f
D N A p o l y m e r a s e a l p h a a c t i v i t y a n d s e l e c t i e d a s a c a n -
d i d a t e c o m p o u n d t o b e d e v e l o p e d , i t s i n h e r e n t s o l u b i l i t y
p r o p e r t y h a s c a u s e d i t t o b e v i e w e d a s i n a p p r o p r i a t e f o r
u s e i n m e d i c i n a l d r u g . T h e c a r e f u l s c r u ti n it y o f H O - 2 2 1 b y
Correspondence to: Ki -Jun Hwang, Department o f Chemist ry ,
Col lege of Natura l Scienc e, Chonbu k Na t ional Universi ty, Dukj in-
dong 664-2, Chonju 561-756, Korea
E-mai l : k i jun@ moak.chonbuk.ac.kr
c o m p a r i n g w i t h t h e e a r l i e r l e a d c o m p o u n d 2 r e v e a l e d t h a t
t h e h e t e r o c y c l c l ic g r o u p s a t t a c h e d t o p h e n y l r i n g a f fe c t t h e
an t i cance r ac t i v i t y d ram at i ca l l y .
In c o n ti n u a ti o n o f o u r w o r k o n b e n z o y l u r e a c o m p o u n d s
H w a n g
et aL,
1 9 9 5 a n d 1 9 9 7 ) a n d in v ie w o f a b o v e m e n -
t io n e d l it e r a tu r e p r e c e d e n c e , i t w a s p l a n n e d t o u n d e r t a k e
t h e s y n t h e s is o f b e n z o y l u r e a c o m p o u n d s c o n t a in i n g n o v e l
p y r a z o l e h e t e r o c y l i c m o i e t y t o s e c u r e c o m p o u n d s o f e n -
h a n c e d a n t i t u m o r a c tiv it ie s . T h e p r e s e n t p a p e r d e s c r i b e s
s y n t h e s i s a n d b i o l o g i c a l e v a l u a t i o n o f t h e b e n z o y l u r e a
d e r i v a ti v e s c o n t a i n i n g n o v e l p y r a z o l e m o i e ti e s .
M T E R I L N D M E T H O D S
S y n t h e s i s
M e l t i n g p o i n t s w e r e r e c o r d e d o n e l e c t r o t h e r m a l m e l t i n g
p o i n t a p p a r a t u s a n d a r e u n c o r r e c t e d . M a s s s p e c t r a w e r e
r e c o r d e d o n a S h i m a d z u Q P - 1 0 0 0 s p e c t r o m e t e r 2 0 e V ) .
1 H - N M R a n d I ~ C - N M R d a t a w e r e o b t a i n e d f r o m J e o l 4 0 0
M H z s p e c t r o m e t e r a n d c h e m i c a l s h if ts 5 ) w e r e r e p o r te d
i n ppm i n re l a t ion t o t e t ram et hy l s i l ane 8 0 . 00 ) and C DCI 3
8 77 . 0 ) f o r 1H and ~ 3C NM R, respec t i ve l y . Th i n l aye r ch ro -
m a t o g r a p h y w e r e p e r f o rm e d o n p r e - c o a t e d s i li ca g e l 6 0 F -
2 5 4 l a y e r t h i c k n e s s 0 .2 m m , M e r c k) . T h e F l a s h C o l u m n
C h r o m a t o g r a p h y w a s p e r f o r m e d o n M e r c k s i l i c a g e l t y p e
6 0 2 3 0 - 4 0 0 m e s h ) . T h e o r g a n i c s o l v e n ts a n d c h e m i c a l s
w e r e o b t a i n e d f r o m A l d d c h . C o . a n d p u r i fi e d b y t h e a p p r o -
p r i a t e m e t h o d s b e f o r e u s e .
781
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Novel Benzoy lurea Der ivat ives as Potent ia l Ant i tumor Agents 783
Table I . Che mical Structures and Physical Properties of Compound 8
No. W X Formula Y mp, yie ld,% ~H NMR(acetone-d6,
11a 4H CH3 C19H12CI2FsN3Os 3,5 -C l2 225-2 26
11b 4H t-bu tyl C22H~sCI2F3N~Os 3,5 -C l2 228-22 g
11c 4H CH3 Cl~H13ClF~NsO~ 3- C l 20 5-20 6
11d 4H t-bu tyl C22H19ClF3NsQ 3- C l 195-1 97
11e
4H P h e n y l C2sH~sF6NsO5 3-CF3 153-154
11f 4H CH~ C19H12CI2F~N~O~ 2, 5- C l2 20 8-20 9
1g 4H P h e n y l C24H~sCIF3N~O~ 3- C l 212-21 4
11h
5H CH~ C~gH12CI2F~N~O~ 3,5 -C I2 25 3-25 4
11i 5H CH3 C19H~CIF3N~Os 3- C l 20 1-20 2
70 3.9(s ,3H ), .8(s,lH), 7.8-8.3(m,6H), 10.5(s,1H), 10.7(s,lH)
65 1.8(s , H), 5.8(s,1H),7.8-8.3(m,7H), 10.5(s,1H), 10.7(s, 1H)
64 3.9(s ,3H ), .9(s,1H),7.4-8.3(m,7H), 10.4(s,1H), 10.6(s,1H)
66 1.8(s , H), 5.9(s,1H),7.4-8.3(m,7H),10.4(s,1H), 10.6(s,1H)
62 6.3 (s,1 H ), .4-8.3(m,12H), 10.4(s,1H), 10.7(s,1H)
70 3.9(s ,3H ), .1(s,1H),7.7-8.7(m,6H),10.6(s,1H),11.2(s,1H)
74 6.1 (s,1 H ), .5-8.3(m,12H), 10.4(s,1H), 10.6(s,1H)
73 3.8(s,3 H), .3(s,1H),7.8-8.3(m,7H),10.4(s,1H),10.6(s,1H)
71 3.9(s,3H),7.1-8 .3(m,8H ), 0.4(s,1H), 10.5(s,1H)
in 6 2 - 7 5 % y i e ld s .
2 - n i t r o - N - [ [ [ 3 , 5 - d i c h l o r o - 4 - ( 1 - m e t y l - 3 - t r i f l o r o m e t h y l -
5 - p y r a z o y l ) o x y p h e n y l ] a m i n o ] c a r b o n y l ] b e n z d m i d e ( 1 1 a ) .
Y i e ld 7 0 % ; m p 2 2 5 ; 1 H N M R ( a c e t o n -d 6 ) ~ 3 . 9 ( s , 3 H ) , 5 . 8
(s , 1H ) , 7 . 8 -8 . 3 (m , 6H ) , 10 . 5 (s , 1H ), 10 . 7 (s , l h ) ; M S : m /
z 5 1 8 ( M + ) .
T h e c h e m i c a l s t r u c t u r e s a n d t h e i r p h y s i c a l p r o p e r t ie s f o r
o t h e r c o m p o u n d s 1 1 a r e s u m m a r i z e d i n T a b l e I .
A n t i c a n c e r a c t iv i ty t e s t i n v i t r o )
A n t i c a n c e r a s s a y w a s p e r f o rm e d b y P h a r m a c e u t i c a l
S c r e e n i n g L a b o r a t o r y i n K o r e a R e s e a r c h I n s t i t u t e o f
C h e m i c a l T e c h n o l o g y u s i n g f i v e d i f f e r e n t h u m a n t u m o r
c e l l l i n e s , A - 5 4 9 ( h u m a n l u n g ) , S K - O V - 3 ( h u m a n o v a r i a n ) ,
S K - M E L - 2 ( h u m a n m e l a n o m a ) , H C T - 1 5 ( h u m a n c o l o n ) ,
X F - 4 9 8 ( h u m a n C N S ) w h i c h w e r e p u r c h a s e d f r o m t h e
Na t i ona l Cance r I ns t i t u t e (NC I ) i n U . S . A .
T h e c e l ls w e r e g r o w n a t 3 7 ~ in R P M I 1 6 4 0 m e d i u m
s u p p l e m e n t e d w i t h 1 0 % F B S a n d s e p a r a t e d u s i n g P B S
con t a i n i ng 0 . 25% t ryps i n and 3 m M EDTA. 5103-2104 ce l l s
w e r e a d d e d t o e a c h w e l l o f 9 6 w e l l p l a t e a n d i n c u b a t e d a t
3 7 ~ f o r 2 4 h . E a c h c o m p o u n d w a s d is s o l v e d in D M S O
a n d d i lu t e d w i t h th e a b o v e m e d i u m a t f iv e d i f fe r e n t c o n -
c e n t r a t i o n s w i t h t h e r a n g e o f 0 . 1 - 3 0 t ~ g / m L . T h e D M S O
c o n c e n t r a t i o n w a s s e t t o b e b e l o w 0 . 5 % a n d f i l t r a t e d
u s i n g 0 . 2 2 m g f il te r . A f te r r e m o v i n g t h e w e l l m e d i u m b y
a s p i r a ti o n , a 2 0 0 t.[ L p o r t io n o f t h e s o l u t io n w a s a d d e d t o
a b o v e w e l l p l a t e s w h i c h w e r e p l a c e d i n 5 % C O 2 i n c u b a t o r
f o r 4 8 h . T h e p r o t e in s t a i n a s s a y w a s p e r f o r m e d a c c o r d i n g
t o S R B m e t h o d ( S k e h a n
e t a l .
1990) .
R E S U L TS N D D I S C U S S I O N
C h e m i s t r y
T h e s y n t h e s i s o f t a r g e t c o m p o u n d s 1 1 w a s s t a r te d f r o m
t h e p r e p a r a t i o n o f p y r a z o y l o x y n i t r o b e n z e n e 7 b y c o n d e n s -
i n g c o m m e r c i a l ly a v a i la b l e c h l o r o n i t r o b e n z e n e 5 w i t h
p y r a z o l e s 6 u n d e r b a s i c c o n d i t io n a t 9 0 ~ 1 7 6 f o r 3 h
i n 6 5 - 7 5 % y ie l d ( S c h e m e 1 ). T h e r e q u ir e d 5 - h y d r o x y - 3 -
t r if iu o r o m e t h y l p y r a z o l e a n d 4 - h y d r o x y - 3 - t r if lu o r o m e t h y l -
p y r a z o l e w a s p r e p a r e d u t i l i z i n g t h e p r e v i o u s l y d e s c r i b e d
m e t h o d s b y B r u c e e t a l . 1 9 9 3 a n d I w a t a e t a l . 1 9 9 1 ,
respec t i ve l y .
T h e n i t r o c o m p o u n d s 7 w e r e t h e n r e d u c e d t o a n i l i n e
a n a l o g u e s b y tr e a ti n g th e m u n d e r n o r m a l h y d r o g e n a t io n
cond i t i on . Wi t h t he key i n t e r r r i ed i a t es 8 i n hand , t he f i na l
CI CI
Ch l o r f l uazu ron (1 )
, -R2
R I ~ ~ J H H
Fig. 1. Structuresof som e biologically active urea com pounds
C l 0 0 O
2
N O 2 0 0 > - -/ y O ~ l ~ Nx--~
I I I |
HO-221 (4)
B r
8/10/2019 Archives of Pharmacal Research Volume 25 Issue 6 2002 [Doi 10.1007_bf02976991] Ki -Jun Hwang; Kyung -Ho Par
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784 K. -J . Hwan g e t a l
W \ .C F 3
,,., I .. , II
4 . . . N
O 2N . - ' ' ~ . \ ~ N
O 2 N . ~ C I a b
Y Y X Y
5 7
W C F 3
R e a g e n t s a ) H o . ~ .~ [ , ( 6 ), D M F , K 2 C O 3 , 9 0 - 1 0 0 ~ 3 h
< N . N
X
b) Ran ey N i , H2 , 90~ 4h
Schem e 1. Synthesisof Ke y Intermediates Pyrazo yloxyanilines8
W
O \ C F 3
H 2 N ' ~ \ N
X
NO
a ~ [ ~ ~ NO2 C~..O
N H 2 ~ . . N ~
O O
9 10
Re age nts : a) oxa ly l ch lor ide, CICH2CH2C I , 100~ 2h
b)
H 2 N ~ W . .~. t~I /CF3
- -N~'~\'~L'O~h- N (8 ), rt, l h
Y
X
Scheme 2. Synthesisof Benzoyl Ure a Derivatives 11
N O 2
H H 2 W
N -.rr. N 1 -.~ ~3 \ /C F3
II II I
4 \-~Trj
O O U \ / .L4 I I
11 X
p r o d u c t s 1 1 w e r e p r e p a r e d w i t h n o i n c i d e n c e b y r e a c t i n g
8 w i t h n i t r o b e n z o y l i s o c y a n a t e 9 w h i c h w a s f o r m e d i n s i t u
f r o m n i t r o b e n z a m i d e a n d o x a l y l c h l o r i d e ( S c h e m e 2 ) .
A n t i c a n c e r a s s a y
T h e a n t i t u m o r a c t i v it ie s o f th e c o m p o u n d 1 1 to w a r d f iv e
d i f f e r e n t h u m a n t u m o r c e l l s w a s d e t e r m i n e d f r o m t h e T z
( n u m b e r o f c e ll s b e f o r e t h e a d d i t io n o f th e t e s t c o m p o u n d s ) ,
C ( n u m b e r o f c e l ls a f t e r 4 8 h i n c u b a t i o n w i t h o u t t e s t
c o m p o u n d s ) , a n d T ( n u m b e r o f c e l l s a f t e r 4 8 h i n c u b a t i o n
w i t h t e s t c o m p o u n d s ) b y t h e f o ll o w i n g e q u a t i o n ( 1 ) o r ( 2) .
~ - ( T - T z ) ~
I f T z > T , , ( C _ - - ~ z ) j X 1 0 0 ( 1 )
If T z < T , [ ~ ] x l 0 0 ( 2 )
T h e v a l u e t h u s o b t a i n e d w e r e a p p l i e d t o L o t u s p r o g r a m
u s i n g d a t a r e g r e s s i o n t o f iv e E D s o o f e a c h c o m p o u n d . T h e
r e s u l t o f t h e i n v i tr o a n t i c a n c e r d a t a a r e c o m p a r e d t o c o m -
m e r c i a l p r o d u c t c i s p l a t i n ( S i g m a T a u C o , I t a l y ) a n d s u m -
m adzed i n Tab l e I I .
T h e r e s u l t s i n d ic a t e e x c e l l e n t a n t i t u m e r a c t i v it ie s t o w a r d
t he f i ve d i f f e ren t ce l l l i nes , A -549 ( l ung ca rc i nom a) , SK-
O V - 3 ( o v a r y m a l i g n a n t a s c i t e s ) , S K - M E L - 2 ( m a l i g n a n t
m e l a n o m a ) , X F - 4 9 8 ( C N S t u m o r ) a n d H C T - 1 5 ( c o l o n a d -
e n o c a r c i n o m a ) . A d d i t i o n a l ly c o m p o u n d 1 1 g e x h ib i ts 5 0 -
1 0 0 t i m e s m o r e p o t e n t t h a n c o m m e r c i a l p r o d u c t c i s p l a t i n
Tab le I1. Antitumu or Activites of targ et com pou nd 11
Compound EDs0 l~g/mL)
N~ A -549 SK-O V-3 SK-M EL-2 XF 498 HCT 15
Cisplatinb 0.7 75 0.460 0,460 0.638 1.100
11a 0.281 0.332 0.242 0.494 0.202
11b 4.7 95 24 .31 4 7.245 7.225 7.489
11c 0.256 0.281 0.139 0.129 0.022
11d 2.611 4.284 2.386 4.431 2.701
11e 1.137 1.597 0.640 1,763 0.880
11f 0.614 1.212 0.429 2.059 0.383
11g 0.916 3.301 1.059 2.282 0.951
11h 2.993 3.041 1.960 3.644 1.929
11i 0.011 0.023 0.022 0.029 0,013
refer to Table I.
b taly, Sigm a Tau
t o w a r d t h e f i v e h u m a n c a n c e r c e l l l i n e s . N o w i t c a n b e
c l e a r l y s t a t e d t h a t b e n z o y l u r e a d e r i v a t i v e s c o n t a i n i n g
h e t e r o c y c l i c p y r a z o l g r o u p p o s s e s s e x c e l l e n t a n t i t u m o r
ac t i v i ti es i n v it ro , a nd f u r t he r s t udy i nc l ud i ng i n v i vo ex pe r i -
m e n t s a n d m o l e c u l a r m o d i f i c a t i o n s i s w a r r a n t e d .
R E F E R E N E S
Chern, J . W . , Leu , Y. , W ang , S. , Jou, R. , Lee , C.F. , Tsou, P.C. ,
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Nove l Benzoy lu rea De r iva t ives as Poten t ia l An t i tum or Age nts 785
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