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Arch Pharm Res Vol 25, No 6, 781-785, 2002

~r~Oi~es of
barmatal ~e~eard)
http://apr.psk.or.kr
Novel Benzoylurea Derivatives as Potential Antitumor Agents;
Synthesis, Activities and Structure-Activity Relationships
Ki - Jun Hwang, Ky u n g - Ho Par k 1, Ch o n g - Oc k Lee 2, and Beom- Tae Ki m
Department of Chemistry and Research Center of Bioactive Materials, College of Natural Sci ence, Chonbuk
National University, Dukjindong 664-14 Chonju 561-756, Korea, lDupont CR&D, Experimental Station, Wilmington,
DE 19880-0328, USA, and 2Screening & Toxicology Research Center, Korea Research Institute of Chemical Tech-
nology, P.O. Box 107, Yusung, Taejeon 305-606, Korea.
(Received September 1, 2002)
A series of pyrazoloxyphenyl benzoyl urea derivatives was designed and synthesized for cyto-
toxic evaluation as potential antitumor agents. The synthetic compounds wer e evaluated for in
vitro cytotoxicity agai nst five human tumor cell lines, including A-549, SKOV-3, SK-MEL-2, XF-
498 and HCT-15. Among others, compound 11 exhibited 50- 100 times greater antitumor
activities than the commercial product, Cisplatin.
Key words: Benzoyl Urea, Anticancer, Cisplatin, Cytotoxicity
I NT RODUCT I ON
A var i et y of p h e n y l b e n z o y l u r e a der i vat i ves ar e wel l
k n o wn as i nsect i ci des wh i c h i nhi bi t t he chi t i n s y nt hes i s of
i nsect s, a n d s o me o f t hem ar e commer ci al l y avai l abl e.
( Wr i ght et al ., 1987) . Chl or f l uazur on (1) is a r epr es en-
t at i ve commer ci al pr oduc t whi c h i s wi del y us ed as
i nsect i ci de, Whi l e chl or f l uazur on i t sel f had no ant i t umor
activity, si mi l ar benz oy l ur ea c o mp o u n d 2 w a s r epor t ed t o
p o s s e s s ant i t umor act i vi t y agai ns t p 3 8 8 l eukemi a ( Ok ada
et al . , 1991). Th e r e ar e al so sever al r el evant r epor t s
( Ho wb e r t et al . , 1990, Cher n et al . , 1997) a b o u t t he
di ar yl sul f onyl ur ea c o mp o u n d s 3 wh i c h we r e r epor t ed t o
be ef f ect i ve agai ns t sol i d t umor s.
Af t er t he r epor t by Ok ada et al ., var i ous benzoyl ur ea
c o mp o u n d s we r e f ur t her i nvest i gat ed in t he sear ch of
pot ent i al ant i cancer der i vat i ves t o c o me up wi t h HO- 221
(4) by I shi har a Sh n g y o Kai sha, LTD. ( Kondo et al., 1993).
Al t hough HO- 221 wa s f ound t o act as a st r ong i nhi bi t or of
DNA pol y mer as e al pha acti vi ty and sel ect i ed as a can-
di dat e c o mp o u n d t o be devel oped, its i nher ent sol ubi l i t y
pr oper t y has c aus ed it t o be vi ewed as i nappr opr i at e f or
us e in medi ci nal dr ug. Th e caref ul scr ut i ni t y of HO- 221 by
Correspondence to: Ki -Jun Hwang, Department of Chemistry,
College of Natural Science, Chonbuk National University, Dukjin-
dong 664-2, Chonju 561-756, Korea
E-mail: kijun@moak.chonbuk.ac.kr
compar i ng wi t h t he ear l i er l ead c o mp o u n d 2 r eveal ed t hat
t he het er ocycl cl i c g r o u p s at t ached t o phenyl ri ng af f ect t he
ant i cancer acti vi ty dramat i cal l y.
In cont i nuat i on of our wo r k on benzoyl ur ea c o mp o u n d s
( Hwang et aL, 1995 and 1997) and in vi ew of abov e men-
t i oned l i t erat ure pr ecedence, it wa s pl anned t o under t ake
t he synt hesi s of benzoyl ur ea c o mp o u n d s cont ai ni ng novel
pyr azol e het er ocyl i c moi et y t o s ec ur e c o mp o u n d s of en-
hanced ant i t umor activities. Th e pr es ent paper des c r i bes
s y nt hes i s and bi ol ogi cal eval uat i on of t he benzoyl ur ea
der i vat i ves cont ai ni ng novel pyr azol e moi et i es.
MAT E RI AL A N D ME T H OD S
Sy nt he s i s
Mel t i ng poi nt s we r e r ecor ded on el ect r ot her mal mel t i ng
poi nt appar at us and ar e uncor r ect ed. Ma s s spect r a we r e
r ecor ded on a Shi madzu QP- 1 0 0 0 s pec t r omet er (20 eV).
1H- NMR and I ~C- NMR dat a we r e obt ai ned f r om Jeol 4 0 0
MHz s pec t r omet er and chemi cal shi f t s (5) we r e r epor t ed
in ppm in rel at i on t o t et r amet hyl si l ane (8 0. 00) and CDCI3
(8 77. 0) f or 1H and ~3C NMR, respecti vel y. Thi n l ayer chr o-
mat ogr aphy we r e per f or med on pr e- coat ed si l i ca gel 60 F-
254 (l ayer t hi ckness 0. 2 mm, Merck). The Fl ash Col umn
Ch r o ma t o g r a p h y w a s per f or med on Mer c k si l i ca gel t ype
60 ( 2 3 0 - 4 0 0 mesh) . Th e or gani c sol vent s and chemi cal s
we r e obt ai ned f r om Al ddch. Co. and puri f i ed b y t he appr o-
pri at e met hods bef or e use.
781
782 K.-J. Hwang et al.
Gener al pr ocedur e f o r t h e p r e p a r a t i o n o f c o m-
p o u n d 7
To a stirred solution of commerci al l y available chloroni-
t robenzene (5, 10mmol) and pyrazol e (6, 10mr nol ) in
di methyl formami de (10 m L ) w a s added potassi um car-
bonat e (15 mmol). The reaction mixture was stirred at
90~176 f or 3 h. Af t er stirring t he whol e mixture at t he
reaction mixture at 90~176 for 3 h, the reaction mixture
was diluted with wat er (30 mL), and t hen extracted with
ethyl acetate (15 mL x 3). The combined ethylacetate solution
was washed with brine, dried over MgSO4 and concent -
rated in vacuo to provide crude products as solid. The crude
products wer e washed with hexane to give essenti al l y
pure materials. Anal yti cal sampl e can be prepared by
flash column chromat ography upon needed.
3,5-Dichloro-4-(1-methyl-3-trifluoromethyl-5-pyrazoyl)
o x y - n i t r o b e n z e n e (7a). Yeld 70%; mp 138-140~ ~H
NMR (CDCI3) ~ 3 . 9 (s, 3H), 5.6 (s, l H) , 8.3 (s,2H); MS : m/
z 354 (M+).
3- Chl or o- 4- ( 1- met hy l - 3- t r i f l uor omet hy l - 5- py r az oy l ) ox y -
nitrobenzene (7c). Yield 73%; mp 120-123~ ~H NMR
(CDCI3) *53.9 (s, 3H), 6.2 (s, 1H), 7.3 (d, 1H), 8.0-8.3 (m,
2H); MS : m/z 321 (M
3 - T r i f l u o r o m e t h y l - 4 - ( 1 - p h e n y l - 3 - t r i f l u o r o m e t h y l - 5 -
p y r a z o y l ) o x y - n i t r o b e n z e n e (7e). Yield 65%; mp 134-
136~ 1H NMR (CDCI3) *56. 4 (s, 1H), 7.1-7.8 (m, 6H),
8. 5-8. 7 (m, 2H); MS : m/z 417 (M+).
2,6-Dichloro-,4-(1-methyl-3-trifluoromethyl-5-pyrazoyl)
ox y - ni t r obenz ene (7f). Yeld 40%; mp 144-145~ ~H NMR
(CDCI3) *53.9 (s, 3H), 6.1 (s, 1H), 7.3 (s, 1H) , 8.3 (s, 1H);
MS: m/z 354 (M+).
3- Chl or o- 4- ( 1- pheny l - 3- t r i f l uor omet hy l - 5- py r az oy l ) ox y -
nitrobenzene (7g). Yield 76%; mp 164-166~ ~H NMR
(CDCI3) ,56.3 (s, 1H) , 7.2-7.7 (m,6H), 8.4-8.9 (m,2H); MS :
m/z 383 (M+).
3 , 5 - Di c h l o r o - 4 - ( 1 - me t h y l - 3 - t r i f l u o r o me t h y l - 4 - p y r a z o y l )
o x y - n i t r o b e n z e n e (7h). Yeld 71%; mp 163-164~ ~H
NMR (CDCI3) *53.9 (s, 3H), 7.0 ( s, l H) , 8. 2 (s,2H); MS : m/
z 354 (M+).
3 - C h l o r o - ( 4 - 1 - m e t h y l - 3 - t r i f l u o r o m e t h y l - 4 - p y r a z o y i )
o x y - n i t r o b e n z e n e (7i). Yield 76%; mp 144-146~ 1H
NMR (CDCl3) *53. 9 (s,3H), 7. 0 (s, l H) , 7.3 ( d, l H) , 8. 0-8. 3
(m,2H); MS : m/z 321 (M*).
Gener al Pr oc e dur e f o r t he Pr epar at i on o f C o m-
p o u n d 8
A fl ask contai ni ng compound 7 (3 mmol), methanol (30
mL) and Raney nickel (0.05 g) was equipped with a
rubber balloon inflated with hydrogen gas. The reaction
mixture was heat ed to 90~ f or 4 h, cool ed to rt, filtered to
remove Raney nickel and t han concent rat ed to give crude
product as a solid, whi ch was purified by flash col umn
chromat ography with Et OAc/ Hexane (1/5) as el uent to
provide pure product.
3, 5- Di chl or o- 4- ( 1 - me t h y l - 3 - t r i f l u o r o me t h y l - 5 - p y r a z o y l )
oxy- ani l i ne( 8a) . Yeld 92%; mp 125-126~ ~H NMR
(CDCl3) *5 3.8 (s, 2H), 3.9 (s, 3H), 5.5 (s, 1H), 6.7 (s, 2H);
MS : m/z 324 (M+).
3- Chl or o- 4- ( 1- met hy l - 3- t r i f l uor omet hy l - 5- py r az oy l ) ox y -
aniline (8c). Yield 90%; mp 110-112~ IH NMR (CDCI3)
*53.8 (s, 2H), 3.9 (s,3H), 5.7 (s, l H) , 6.7-7.1 (m, 3H); MS :
m/z 291 (M+).
3.Trifluoromethyl,4-(1-phenyl-3-trifluoromethyl-5-pyrazoyl)
o x y - a n i l i n e (8e). Yield 58%; mp 120-123~ ~H NMR
(CDCI3) *53.8 (s, 2H), 5.8 (s, 1H) , 6.5-8.1(m, 8H); M S : m /
z 387 (M+).
2,6-Dichloro-4-(1 -methyl-3-trifl uoromethyi -5-pyrazoyl )
oxy- ani l i ne (8f ). Yel d 92%; mp 130-131~ 1H NMR (CDCI3)
*5 3.8 (s, 2H), 3.9 (s, 3H), 5.7 (s, 1H), 6.4 (s, 1H); MS : m/z
324 (M+).
3-Chi oro-4-(1 - p h e n y l - 3 - t r i f l u o r o me t h y l - 5 - p y r a z o y l ) o x y -
ani l i ne (8g). Yield 88%; rnp 150-151~ ~H NMR (CDCl3)
,5 3.8 (s, 2H), 5.7 (s, 1H), 6. 5-7. 8 (m,8 H); MS : m/z 353
(M*).
3,5-Dichloro-4-(1 -methyl-3-trifluoromethyl-4-pyrazoyl)
o x y - a n i l i n e (8h). Yeld 94%; mp 136-138~ ~H NMR
(CDCI3) .5 3.9 (s, 3H), 5.2 (s, 2H), 6.9 (s, 2H), 7.2 (s, 1H);
MS : m/z 324 (M+).
3- Chl or o- 4- ( 1- met hy l - 3- t r i f l uor omet hy l - 4- py r az oy l ) ox y-
ani l i ne (8i). Yield 91%; mp 128-130~ ~H NMR (CDCI3)
5 3.8 (s, 2H), 3.9 (s, 3H), 6.4-7.0 (m, 4H); MS : m/z 291
(M+).
Gener al Pr ocedur e f o r t he Pr epar at i on o f C o m-
pound 11
A solution of 2-nitrobenzamide (2 retool) and oxazol yl
chloride (2 retool) in 1,2-di chl oroethane (8 mL) was heat-
ed at 100~ f or 2 h under argon atmosphere. To t he re-
suiting i socyanat e solution was added compounds 8 at rt.
Af t er stirring f or 1 h, the reaction mixture was concent -
rated under vacuo and t he residue was chromat ographed
with EtOAc/Hexane (1/5) as eluent to provide pure product
Novel Benzoylurea Derivatives as Potential Antitumor Agents 783
Table I. Chemical Structures and Physical Properties of Compound 8
No. W X Formula Y mp, yi el d,% ~H NMR(acetone-d6, )
11a 4H CH3 C19H12CI2FsN3Os 3, 5- Cl 2 225-226
11b 4H t-butyl C22H~sCI2F3N~Os 3, 5- Cl 2 228-22g
11c 4H CH3 Cl~H13ClF~NsO~ 3- Cl 205-206
11d 4H t-butyl C22H19ClF3NsQ 3- Cl 195-197
11e 4H P h e n y l C2sH~sF6NsO5 3-CF3 153-154
11f 4H CH~ C19H12CI2F~N~O~ 2, 5- Cl 2 208-209
!1g 4H P h e n y l C24H~sCIF3N~O~ 3- Cl 212-214
11h 5H CH~ C~gH12CI2F~N~O~ 3, 5-CI 2 253-254
11i 5H CH3 C19H~CIF3N~Os 3- Cl 201-202
70 3.9(s,3H), 5.8(s,lH), 7.8-8.3(m,6H), 10.5(s,1H), 10.7(s,lH)
65 1.8(s, 9H), 5.8(s,1H), 7.8-8.3(m,7H), 10.5(s,1H), 10.7(s, 1H)
64 3.9(s,3H), 5.9(s,1H), 7.4-8.3(m,7H), 10.4(s,1H), 10.6(s,1H)
66 1.8(s, 9H), 5.9(s,1H), 7.4-8.3(m,7H), 10.4(s,1H), 10.6(s,1H)
62 6.3(s,1H), 7.4-8.3(m,12H), 10.4(s,1H), 10.7(s,1H)
70 3.9(s,3H), 6.1(s,1H), 7.7-8.7(m,6H), 10.6(s,1H), 11.2(s,1H)
74 6.1(s,1H), 7.5-8.3(m,12H), 10.4(s,1H), 10.6(s,1H)
73 3.8(s,3H), 7.3(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), 10.4(s,1H), 10.5(s,1H)
in 62- 75% yi el ds.
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- pyr az oyl ) oxyphenyl ] ami no] car bonyl ] b e n z d mi d e (11a).
Yi el d 70%; mp 225; 1H NMR (aceton-d6) ~ 3. 9 (s, 3H), 5. 8
(s, 1H), 7. 8- 8. 3 (m, 6H), 10.5 (s, 1H), 10.7 (s, l h ) ; MS : m/
z 518 (M+).
Th e chemi cal st r uct ur es and t hei r physi cal pr oper t i es f or
ot her c o mp o u n d s 11 ar e summar i zed in Tabl e I.
A n t i c a n c e r a c t i v i t y t e s t ( i n v i t r o )
Ant i c anc er a s s a y wa s per f or med by Phar maceut i cal
Scr eeni ng Labor at or y in Kor ea Res ear c h I nst i t ut e of
Chemi cal Technol ogy usi ng five di f f erent human t u mo r
cell l i nes, A- 549 ( human l ung), SK- OV- 3 ( human ovari an),
SK- MEL- 2 ( human mel anoma) , HCT- 15 ( human col on),
XF- 4 9 8 ( human CNS) whi ch we r e pur c has ed f r om t he
Nat i onal Ca n c e r I nst i t ut e ( NCI ) in U. S. A.
Th e cel l s we r e gr own at 37~ in RPMI 1640 medi um
s uppl ement ed wi t h 10% FBS and s epar at ed usi ng PBS
cont ai ni ng 0. 25% t rypsi n and 3 mM EDTA. 5103-2104 cells
we r e a d d e d t o eac h wel l of 96 wel l pl at e and i ncubat ed at
37~ f or 24 h. Each c o mp o u n d wa s di ssol ved in DMS O
and di l ut ed wi t h t he above medi um at fi ve di f f erent con-
cent r at i ons wi t h t he r ange of 0. 1- 30t ~g/ mL. The DMS O
concent r at i on wa s set t o be bel ow 0. 5% and fi l trated
usi ng 0. 22 mg filter. Af t er r emovi ng t he wel l medi um by
aspi r at i on, a 200 t.[L port i on of t he sol ut i on wa s added t o
above wel l pl at es whi ch we r e pl aced in 5 % CO2 i ncubat or
f or 48 h. Th e prot ei n st ai n a s s a y wa s per f or med accor di ng
t o SRB met hod ( Skehan e t a l . , 1990).
RESULTS AND DISCUSSION
C h e m i s t r y
The synt hesi s of t ar get c o mp o u n d s 11 wa s st ar t ed f r om
t he preparat i on of pyr azoyl oxyni t r obenzene 7 by condens-
ing commer ci al l y avai l abl e chl or oni t r obenzene 5 wi t h
pyr azol es 6 under basi c condi t i on at 90~176 f or 3 h
in 6 5 - 7 5 % yi el d ( Sc heme 1). Th e r equi r ed 5- hydr oxy- 3-
t r i f i uor omet hyl pyr azol e and 4- hydr oxy- 3- t r i f l uor omet hyl -
pyr azol e wa s pr epar ed utilizing t he pr evi ousl y descr i bed
met hods by Br uce e t a l . , 1993 and I wat a e t a l . , 1991,
respecti vel y.
The ni t r oc ompounds 7 we r e t hen r educed t o ani l i ne
anal ogues by t r eat i ng t hem under nor mal hydr ogenat i on
condi t i on. Wi th t he key i nt er r r i edi at es 8 in hand, t he final
CI CI
o o
Chl orf l uazuron (1)
,-R2
R I ~ . ~ J H H
3
Fig. 1. Structures of some biologically active urea compounds
Cl 0 0 O
2
NO 2 0 0 ">" " " " - - K / y O " ~ l ~ Nx--~
I H I I |
HO-221 (4)
Br
784 K.-J. Hwang et al.
W \ . CF 3
,,., I . . , II ' 4 . . . N
O 2 N . - ' ' ~ . \ ,~ N
O 2 N . ~ CI a b
Y Y X Y
5 7
W CF 3
R e a g e n t s a ) Ho , . ~. ~[ , (6), DMF, K2CO3, 90-100~ 3h
<N. N
X
b) Raney Ni, H2, 90~ 4h
Scheme 1. Synthesis of Key Intermediates Pyrazoyloxyanilines 8
W
O \ " CF3
H 2 N ' ~ \ " N"
8 X
NO2
a ~ [ ~ " ~ NO2 C~..O
NH2 ~ . . N ~"
O O
9 10
Reagents: a) oxalyl chloride, CICH2CH2CI, 100~ 2h
b) H 2 N ~ W I..~.t~I/CF 3
- - " "N~'~\'~L'O~h-" N (8), rt, l h
Y
X
Scheme 2. Synthesis of Benzoyl Urea Derivatives 11
NO2
H H 2 W
N "-.rr." N 1"-.~"~3 \ / CF3
II II I 4 ~\-~Trj 3
O O U \ /.L4 II "
11 X
pr oduct s 11 we r e pr epar ed wi t h no i nci dence by r eact i ng
8 wi t h ni t r obenzoyl i socyanat e 9 whi ch wa s f or med in si tu
f rom ni t r obenzami de and oxal yl chl or i de ( Sc heme 2).
An t i c a n c e r a s s a y
The ant i t umor acti vi ti es of t he c o mp o u n d 11 t owar d five
di f f erent human t u mo r cel l s w a s det er mi ned f rom t he Tz
( number of cells bef ore t he addi ti on of t he t est compounds) ,
C ( number of cel l s af t er 4 8 h i ncubat i on wi t hout t est
c ompounds ) , and T ( number of cel l s af t er 48h i ncubat i on
wi t h t est c o mp o u n d s ) by t he f ol l owi ng equat i on (1) or (2).
~ - ( T - T z ) ~
If Tz>T, , ( C_ - - ~ z ) j X 1 0 0 (1)
If Tz<T, [ ~ ] x l 0 0 (2)
The val ue t hus obt ai ned we r e appl i ed t o Lot us pr ogr am
usi ng dat a r egr essi on t o five EDso of each c ompound. The
r esul t of t he in vitro ant i cancer dat a ar e c ompar ed t o c om-
merci al pr oduct ci spl at i n ( Si gma Tau Co, Italy) and s um-
madzed in Tabl e II.
The r esul t s i ndi cat e excel l ent ant i t umer acti vi ti es t owar d
t he fi ve di f f erent cell l i nes, A- 5 4 9 (l ung car ci noma) , SK-
OV- 3 ( ovar y mal i gnant asci t es) , SK- MEL- 2 ( mal i gnant
mel anoma) , XF- 4 9 8 ( CNS t umor ) and HCT- 15 ( col on ad-
enocar ci noma) . Addi t i onal l y c o mp o u n d 11 g exhi bi t s 5 0 -
100 t i mes mor e pot ent t han commer ci al pr oduct ci spl at i n
Table I1. Antitumuor Activites of target compound 11
Compound EDs0 (l~g/mL)
N~ A-549 SK-OV-3 SK-MEL-2 XF 498 HCT15
Cisplatin b 0.775 0.460 0,460 0.638 1.100
11a 0.281 0.332 0.242 0.494 0.202
11b 4. 795 24. 314 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 Italy, Sigma Tau
t owar d t he five human c anc er cell lines. No w it can be
cl ear l y st at ed t hat benzoyl ur ea der i vat i ves cont ai ni ng
het er ocycl i c pyr azol gr oup p o s s e s s excel l ent ant i t umor
act i vi t i es in vitro, and f ur t her s t udy i ncl udi ng in vivo exper i -
ment s and mol ecul ar modi f i cat i ons is war r ant ed.
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