Design and synthesis of novel tetrahydrofuran cyclic urea derivatives as androgen receptor antagonists

Article abstract of DOI:10.1007/s12039-020-01833-x

Abstract: In order to improve the antiproliferative activity of androgen receptor (AR) antagonists, which used clinically for the treatment of prostate cancer that is a major cause of male death in worldwide, we report the design and synthesis of a series of tetrahydrofuran cyclic urea-based non-steroidal small molecule AR antagonists and exhibit potent AR antagonistic activity. These molecules with higher stereochemical aspects have been achieved by changing the hydantoin analogue antiandrogens to 4-(2-oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2-(trifluoromethyl)benzonitrile analogues. Here, the thio-hydantoin pharmacophore of the recently reported antagonists is replaced by tetrahydrofuran cyclic urea. The antiproliferative properties of these molecules have been evaluated against androgen-dependent (LNCaP) cell line. Among the reported molecules, 4-(2-oxohexahydro-1H-furo[3,4-d]imidazol-1-yl)-2-(trifluoromethyl)benzonitrile (AR04) showed significantly improved in vitro activity, IC₅₀ = 3.926 μM. Molecular structure-activity relationship studies confirm that the oxetane analogue AR04 is distinct from other synthesized AR antagonists. These results have suggested that AR04 exhibiting their potential as a lead compound for the alternative treatment of prostate cancer. Graphic abstract: To improve the antiproliferative activity of androgen receptor (AR) antagonists, various compounds with tetrahydrofuran cyclic urea ring system were designed and synthesized. Among the synthesized compounds, AR04 showed significantly improved in vitro activity, IC₅₀ = 3.926 μmol, which is almost equal to the commercially available drug, enzalutamide.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-020-01833-x

J. Chem. Sci. ( 2 0 2 0 )1 3 2 : 1 3 6
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REGULAR ARTICLE
Design and synthesis of novel tetrahydrofuran cyclic urea derivatives
as androgen receptor antagonists
a
M U R A L I K RI SH N A Y A RA G A N I , P RA S A D Y A D L A P A L L I , S RI R A M R A G H A V A N ,
b
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N I R A IK U L A M A Y Y A D U RA I , S A RA V A NA N C H IN N U SA M Y
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*
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V E NK A T A B A S A V E S W A R A R A O M A N DA V A a n d
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R A J A S E K H A R A P R A S A D K O T T A P AL L I
a
D e p a r t m e n t o f C h e m i s t r y , K o n e r u L a k s h m a i a h E d u c a t i o n F o u n d a t io n , G u n tu r , A n d h r a P r a d e s h 5 2 2 5 02 ,
I n d i a
b
G V K B i o s c i e n c e s P v t . L t d , H y d e r a b a d , T e l a n g a n a 5 0 0 0 7 6 , I n d ia
C A S i n C r y st a l l o g r a p h y a n d B i o p h y s i c s , U n iv e r s i ty o f M a d r a s , G u i n d y C a m p u s , C h e n n a i,
c
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d
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A d y a r , C h e n n a i 6 0 0 0 2 0 , T a m i l N a d u , I n d i a
e
D e p a r t m e n t o f C h e m i s t r y , C e n t e r f o r A d v a n c e d O r g a n i c M a t e r i a l s ( S o n a - A R O M A ) , S o n a C o l l e g e o f
T e ch n o l o g y , S a l e m , T a m i l N a d u 6 3 6 0 0 5 , I n d i a
f
D e p a rt m e n t o f C h e m i s t ry , K ri s h n a U n i v e r s i ty , K r is h n a , A n d h r a P r a d e s h 5 2 1 0 0 1 , I n d i a
E - m a i l : s a r a v a n a n c @ s o n a t e c h . a c . i n ; k r s p r a s a d _ f e d @ k l u n i v e r s i ty .i n
M S r e c e i v e d 3 D e c e m b e r 2 01 9 ; r e v i s e d 2 7 M a y 2 0 2 0; a c c e p t e d 2 4 J u l y 2 0 2 0
Abstract. I n o r d e r t o i m p ro v e t h e a n t i p r o l i f e r a ti v e a c t i v i t y o f a n d r o g e n r e c e p t o r ( A R) a n t a g o n i s t s , w h i ch
u s ed c l i n i c a l l y f o r t h e t r e a t m e n t o f p r o s t a t e c a n c e r t h a t i s a m a j o r c a u s e o f m a l e d e a th i n w o r l d w i d e , w e r ep or t
t h e d e s i g n a n d s y n t h e s i s o f a s e r i e s o f t e t r a h y d r o f u r a n c y c li c u r e a - b a s e d n o n - s t e r o i d a l s m a l l m o l e c u l e A R
a n ta g o n i s t s a n d e x h i b i t p o t e n t A R a n t a g o n i s t ic a c t i v i t y . T h e s e m o l e c u l e s w i t h h i g h e r s t e r e o c h e m i c a l a s p ec t s
h a ve b e e n a c h i e v e d b y c h a n g i n g t h e h y d a n t o i n a n a lo g u e a n t i a n d r o g e n s t o 4 - ( 2 - o x o h e x a h y d r o - 1 H - f u r o [3 , 4- d ]
i m i da z o l - 1 - y l ) - 2 - ( t r i fl u o r o me t h y l ) b e n z o n i tr il e a n a lo g u e s . H e r e , t h e t h i o - h y d a n to in p h a r m a c o p h o r e o f t he
r e ce n t l y r e p o rt e d a n t a g o n i s t s i s r e p l a c e d b y t e t r a h y d r o f u r a n c y c li c u r e a . T h e a n t i p r o l i f e r a ti v e p r o p er t i es o f
t h es e m o l e c u l e s h a v e b e e n e v a l u a t e d a g a in s t a n d r o g e n - d e p e n d e n t ( L N C a P ) c e l l l in e . A m o n g t h e r ep or t ed
m o l ec u l e s , 4 - ( 2 - o x o h e x a h y d r o - 1 H - fu r o [ 3 ,4 - d ] i m i d a z o l - 1 - y l ) - 2 - ( t r i fl u o r o m e t h y l ) b e n z o n i tr il e ( AR04) s h o w ed
s i g ni fi c a n t l y i m p ro v e d i n v i t r o a c t i v i ty , I C = 3 . 9 2 6 lM . M o l e c u la r s t r u c t u r e - a c ti v i t y r e l a t i o n s h i p s t u d i es
5 0
c o nfi r m t h a t t h e o x e t a n e a n a l o g u e AR04 i s d i s t i n c t f r o m o t h e r s y n t h e si z e d A R a n t a g o n i s t s . T h e s e r e s u l t s h av e
s u g g e s t e d t h a t AR04 e x h i b i t i n g t h e i r p o t e n ti a l a s a l e a d c o m p o u n d f o r t h e a l t e r n a t i v e t r e a t m e n t o f p ro s t a t e
c an c e r.
Keywords. P ro s t a t e c a n c e r; t e t r a h y d r o f u r a n c y c li c u r e a ; a n d r o g e n r e c e p t o r a n t a g o n i s t ; o x e t a n e ; h y da n to i n .
1. Introduction
r ad i a t i o n t h er a p y , a n d r o g en d e p r i v at i o n i s o n e o f t h e
m ai n a p p r o a c h e s t o t r e a t i t a t t h e v a r i o u s s t ag e s o f i t s
d e v e l o p me n t , w h i ch f a l l s u n d er t h e a n d r o g e n b l o c k -
P r o s t a t e c a n c er ( P C ) i s c o ns id e r e d a s o n e o f t h e
l e ad i n g c a u s es o f a l l c a nc e r d e a t h s i n m o s t d e v e l o p ed
1
c o u n t r i e s. A n d i t i s o n e o f t he m o s t c o m m o n c an ce r
5, 6
a d e t h er a p y ( A BT ). T h e r at i o o f t h e r a t e o f c e l l
p r o l i f e ra t i o n t o t h e r a t e o f c el l d e a t h d e t e r mi n e s t h e
g r o w t h o f P C c el l s . T h e r a t e o f c el l p r o l i f er a t i o n i s
h i g h e r t h an t h at o f c el l d e a t h l e d t o c o n t i n u o u s n e t
g r o w t h r es u l t i n g i n P C. I mp o r t a n t l y , t h i s r a t i o i s
m ai n l y r e g u l a t e d b y a n d r o g e n s a n d a n d r o g e n
a m o n g m en i n t h e U S A a n d t he s e c o n d m o s t d a n -
g e r o u s c a u s e o f m a le d e a t h w o rl d w i d e , a f t e r l u n g
2
–
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c an c e r . E v e n t ho u g h s e v e ra l t re a t m e nt m e t h o d s
e x i s t f o r P C , i n cl ud i ng c a s t r a t i o n , c h e m o t he ra p y a n d
* F o r c o r re s p o n d e n c e
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-01833-x) contains supple-
mentary material, which is available to authorized users.

1 3 6 P a g e 2 o f 1 2
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 1 3 6
Figure 1. C h e m i c a l s t r u c t u r e s o f n o n - s t e r o i d a l A R a n t a g o n i s t s a p p r o v e d b y F D A .
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r e c e p t o r s ( A R s ) . S i n c e A R p la y s a n i m p o rt an t r o l e u n i t p l ac e d b e t w e e n t h e a ro ma t i c r i n g r e s u l t i n g h i g h l y
i n t h e g r o w t h o f P C , A R a n t a g o n is t s a r e u s e d f o r t h e r i g i d i fi e d s t ru ct u r al f u t u r es . R ec e n t l y , I v a ch t ch e n k o
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a n t a go n i st s c o m m o n ly c a te g o r iz e d i n t o s t e r o ida l a nd n o n - l a r a ct i v i t y . T h e y c l a i m ed t h at t h e k e y r ea s o n f o r t h i s
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o i d a l A R a n t ag on is ts ( F i gu r e 1) fo r t he tr e a t m e nt o f P C a r e o s p ec i fi c s p i r o - mo i et y a n d fl u o r i d e a t t h e p a r a -p o si t i o n
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a f t e r s e v e r a l y e a r s o f t r eat m en t t h ey b ec am e i n ef f e ct i v e m u t a n t , w h e r e as t h e a mi d e g r o u p i s p l a c ed i n
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I n g e n e r a l , n o n -s te ro id a l a n t ia nd r o g e n s h a v i n g t h e g o o d a ct i v i t y . W h i l e c o n s i d e r i n g t h e c h e mi ca l s t r u c -
s t r u c t u r a l f e a t u r e s t h a t t w o d if fe re n t l y s u b s t i t u t e d t u re o f e f fe c t i v e A R i n h i b i t o r , t h e s u b s t i t u t i o n o f t r i -
a r o ma t i c r i n g s c o nn e c t e d t hr ou g h l in e a r ( b i c a l u - fl u o r o m e t h y l g r o u p t o o n e o f t h e b e n z e n e r i n g i s a
t a m i d e - l i k e c o m p ou n d s (2 o r 3) ) o r c y c l i c ( en za l u - c ri t i ca l f a ct o r f o r b i o l o g i c a l a ct i v i t y a n d t h e i n t r o -
1
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t a m i d e - l i k e c o m p o u nd s (5 o r ARN-509) ) l in k e r s . I n d u ct i o n o f fl u o r i n e a l s o i m p r o v es a n t i -p ro l i f er a t i v e
t h e f o r m e r c a s e, t he a m id e l in k a g e i s p l a c e d i n a ct i v i t y a n d p h ar m ac o l o g i ca l p r o p e r t i es o f t h e c o m -
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p o s i t i o n o f t h e a r o m a ti c r in g s i m u l ta ne ou s l y h y d a n t o i n a n d ‘ o p e n ’ c o n f o r m at i o ns o f A R -H 1 2 h e l i x , e v e n

J. Chem. Sci. ( 2 0 2 0 )1 3 2 : 1 3 6
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s t an d a rd . T h e c h e mi ca l s h i f t s ( d ) f o r H a n d C a r e
g i v e n i n p p m r el a t i v e t o r es i d u al s i g n a l s o f t h e s o l v en t .
C o u p l i n g c o n s t an t s a r e g i v e n i n H z . T h e f o l l o w i n g
a b b r e v i a t i o n s a re u s e d t o i n d i c a t e t h e m u l t i p l ic i t y : s ,
s i n g l e t ; d , d o u b l e t ; t , t r i p l e t ; q , q u ar t e t ; m , m ul t i p l e t ;
b r s , b r o a d s i n g l e t . M a s s s p e c t r a w e re r ec o r d e d o n
P O L A R IS Q ( T h e r mo S ci e n t i fi c ) . S p e ci fic r o t a t i o n s
w e re t a k e n o n R u d o l p h A u t o p o l I V I n s t ru me n t a n d
H R M S s p e c t r a w e re r ec o r d e d o n B ru k e r M a x i s T O F.
T h e f o l l o w i n g c o m me r ci a l g r a d e r e ag en t s a n d s o l v e n t s
w e re p u r c h a s e d f r o m A l d ri ch c h e mi ca l s , B e n g a l u r u
a n d u s e d w i t h o u t f u r t h e r p u r i fic a t i o n : m- Ch l o r o p e r -
o x y b e n z o i c a ci d ( m- C P BA ) , N H C l , N a N , P d - C ,
Figure 3. C h e m i c a l s t r u c t u r e s o f n o n - s t e ro i d a l A R a n t a g -
o n i s ts i n c li n i c al d e v e l o p m e n t f o r t h e t r e a t m e n t o f P C .
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( Bo C) O , T r i e t h y l a mi n e ( T E A ) , S w er n o x i d a t i o n ,
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s l i g h t m o di fi c at i on s i n t he c h e m ic a l s t r uc t u r e o f A R
l i g a n d c a n l e a d t o d ra m a t ic a l t e r a t i on s i n t h e r e ce p t o r -
l i g a n d i n t e r a c t i on t h e re by p r o vi d i ng o p p o s i t e p h a r -
b o r o h y d r i d e ( N a BH C N ), t r i flu o ro ac e t i c a ci d ( T F A) ,
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W i t h t h e a i m t o d e v e lo p n o v e l A R a n t a g o n i s t s , w e
d e s i g n e d a n d s y n t h e s iz e d s e ri e s o f n o v e l t e t r a h y d r o -
f u r a n c y c l i c u r e a d e r iv a t i v e s ( F i g u re 3) , w h ic h i s d i s -
t i n c t f r o m F l u t a m i de (1) a n d E n z a lu t a m i d e ( 5 o r ARN
509) a n a l o gu es , a n d t h e ir p o t e n ti a l o f a n t i P C a ct i v i t y
w a s e v a l u at ed a g a i ns t t h e a n dr o g e n - s e n s i t ive h u ma n
p r o s t at e a d e n o c ar c i n o m a L N C a P c e l l l in e . H e r e, w e
h a v e i n t r o d u c e d t w o s t e re os p e c i fi c c a rb o n a t o ms i n
c y c l i c u r e a s k e l e t o n . A m o ng t h e r e p o r te d c o m p o u n d s ,
ARO4 s h o w e d s i g n i fi c a n tl y i m p r o v e d in vitro a ct i v i t y ,
d i n i u m 3 - o x i d h e x a fl u o r o p h o s p h a t e ) ( H A T U ) , N , N-
d i i s o p r o p y l et h y l am i n e ( D I PE A) , N a N O , K I , H Cl ,
2
d i ch l o r o m e t h a n e ( D CM ) ( Ra n k em ) , m e t h a n o l
( M e O H ) , e t h a n o l ( E t O H ) , T o l u e n e ( Sp ec t ro c h e m) ,
T H F ( Fi n a r ). T h e c o m p o u n d 12 w a s r ea c h e d f r o m 2 , 5 -
d i h y d r o fu ra n t h ro u g h t h e r ep o r t e d s y n t h e t i c
m et h o d o l o g i e s .
2
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3 D - m ol ec u l ar d o c k i n g a p p r o a c h t o e s t im a t e p o s s i -
b l e b i n di n g m o d e s a n d d i v e r s e p o i n t s o f t h e
c o mp o un d.
2 . 2 a Model selection (protein and ligand): T h e
l i g a n d s w e re m i n i mi ze d t o a l o ca l e n e r g y m in i m u m
u s i n g h y b ri d b a s e d s t ee p e s t d e s c e n t t i l l 5 0 0 0 i t e r a t i v e
2 7
s t ep s u s i n g L B FG S a l g o ri t h m
t a u t o m er i c a n d i o n i z e d s t at e u s i n g E P I K .
w i t h d e f a u l t
2 8
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h
e
2. Experimental
2 9
A n d ro g e n r ec e p t o r ( N R3 C4 ) P D B i D : 1 E 3 G w as
s t ru ct u r a l l y o p t i m i z e d u s i n g p r o t ei n p r e p a r a t i o n
w i z a r d S ch ro d i n g er . H y d ro g e n i s n o t v i s i b l e i n X -r a y
d i ff r a ct i o n t h u s h y d r o g e n w a s fi x e d a l o n g w i t h b o n d
2 . 1 Materials
1
1 3
T h e H a n d C N M R s p e c t ra w e r e r e c o r d e d a t
4 0 0 M H z B r u k e r A d v a n c e D P X 4 0 0 /3 00 s p e c t ro me t er
i n C D C l a n d ( C D ) S O u s i n g T M S a s t h e i n t e rn al
o r d e r w i t h s t an d a rd s a m p l i n g u s i n g P ro t As si g n
3 0
m o d u l e .
P ro t e i n m i n i mi za t i o n w a s d o n e u s i n g
3
3
2

1
3
6
P
a
g
e
4
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2
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 1 3 6
1 3
I m p e r f w h e r e b y a l l r ot a t a b le h y d ro g e n b o n d w a s 9 H ) . C N M R ( 4 0 0 M H z , D M S O - d , p p m ) : d 1 5 8 . 8 5 ,
6
m i n i m i z e d w i t h t h e r e m o va l o f t or s i o na l p o t e n t i a l . T h e 1 5 5 . 8 7 , 1 2 9 . 3 5 , 1 1 3 . 8 7 , 1 1 3 . 7 8 , 7 9 . 4 8 , 7 3 . 3 1 , 7 1 . 4 4 ,
˚
m i n i m i z a t i o n i s c a r r ie d u n t i l R M S D c u t -o ff o f 0 . 3 0 A 5 8 . 6 1 , 5 5 . 2 4 , 5 2 . 0 6 , 5 1 . 7 8 , 2 9 . 6 5 , 2 8 . 4 3 , 2 8 . 3 6 , 2 8 . 3 1 ;
f o r t h e h e a v y a t o m s . A l t o g e th e r t h e p ro to na ti o n s t at e H R M S ( E S I- T O F ) : C al cd f o r C H N O [ M ? H ]?:
1
7
2
6
2
4
a n d h y d r o g e n b o n d o f t he s t r u c tu re a r e fi x e d w i t h r e- 3 2 3 . 1 9 7 1 ; f o u n d : 3 2 3 . 1 9 9 7 .
o r i e n t e d c l a s h p e na l ty s c or e . G r id - b a s e d l i g a n d
d o c k i n g w i t h e n e r g e ti c s ( G L ID E ) w a s u s e d t o fi n d
f a v o u r a b l e i n t e r a c t io ns b e t w e e n l ig a n d a n d t h e
r e c e p t o r s w i t h fl e x ib l e c o nf o rm a t i o n s o f t he l i g a n d .
G l i d e s c o r i ng f u n c t io n i s g i v e n b y t he e q u a ti o n b e l o w :
2
.
2
e
C
i
s
1-(4-methoxybenzyl)
tetrahydro-1H-
furo[3,4-d] imidazol-2(3H)-one (9): T F A ( 6 0 m L )
w a s a d d e d t o t h e s o l u t i o n o f 8 ( 6 g , 1 8 . 6 1 m m o l ) i n
D C M ( 6 0 m L ) a t 0 °C a n d a l l o w ed t o s t i r a t r o o m
t e m p e ra t u r e f o r 1 2 h . A f t e r c o m p l e t i o n o f t h e r e a c t i o n ,
t h e c o n c e n t r a t i o n o f t h e s o l v e n t w a s r e d u c ed u n d e r
v a c u u m , d i l u t ed w i t h a 1 0 % a q . N a O H s o l u t i o n a n d
e x t r a c t e d w i t h e t h y l a ce t a t e. T h e o r g a n i c l a y e r w as
GScore ¼ 0 :0 5 Â vdW þ 0:1 5 Â Coul þ Lipo
þ Hbond þ Reward þ RorB þ Site
þ hydrophobicity
w a s h e d w i t h b r i n e, d r i e d o v er a n h y d r o u s M g S O a n d
4
G l i d e s c o r i n g w i th X P d e s c ri p to r w i th I n d u ce d F i t
d o c k i n g ( I F D ) r e w a r d s h y d ro p h o b ic i nt e r a c ti o n s i n -
b e t w e e n l i g a n d a nd t he r e c e pt o r s . I F D a l s o r ed u c es
f a l s e p o s i t i v e o f t ru e l ig a n d b i n d e r w h e re b y I FD
t h e s o l v e n t w a s r e mo v ed u n d e r v a c u u m t o g i v e a p a l e -
y e l l o w
c o l o u r ed
l i q u i d
c o m p o u n d
N -3 -( 4 -
m et h o x y b e n z y l) t e t r a h y d ro fu r an - 3 , 4 - d i am i n e ( 3 . 5 g
c ru d e ). T h e c r u d e p r o d u c t w a s u s e d f o r t h e n e x t s t e p
w i t h o u t a n y f u r t h e r p u r i fic a t i o n . I t w a s d i ss o l v e d
i n T H F a n d c o o l ed t o 0 °C . T h e n , T E A ( 6 . 6 m L ,
4 7 . 2 2 m mo l ) a n d C D I ( 2 . 8 0 g , 1 7 . 3 1 m mo l ) w er e
a d d e d u n d e r n i t r o g e n a t m o s p h er e a n d a l l o w ed t o s t i r a t
r o o m t e m p e ra t u r e f o r 1 2 h . T h e m i x t u r e w a s p o u r e d
i n t o a b r i n e s o l u t i o n a n d e x t r a c t e d b y e t h y l a c e t a t e ,
3 1
i n d u c es s i d e c h a i n fl e xi b i l it y i n t h e r e c e p t o rs .
2 . 2 b General procedure for the synthesis
of compound 7 and 8: S y nt h e s is b e gi n s w i t h
c o mm er ci a l l y a v a i la b l e 2 , 5 - d i h y d r o fu ra n a n d r e ac h e s
i n t e r m ed i a t e t e r t - b u t yl ( S )- ( 4 - o x ot e tra h y d ro fu ra n - 3 - y l )
c ar b a m a t e (6) t hr ou g h t he r e p o r te d o p t i mi ze d
c o n d i t i o n s . R e d u c t iv e a m in a t i on o f 6 w i th p -m e t h o x y
w a s h e d w i t h w a t e r a n d d r i e d o v e r a n h y d r o u s M g S O .
4
T h e s o l v e n t w a s r e mo v ed u n d er v a c u u m a n d p u r i fi e d
b y s i l i c a g e l c o l u mn c h r o m at o g r a p h y ( D CM – M e OH )
t o g i v e 9 ( 3 . 0 g , 7 7 % ) a s a w h i t e p o w d e r ( M . p .
b e n z y l a mi n e ( P M B N H ) i n t he p re s e n c e o f A C O H
2
a n d N a B H C N i n E T O H y ie ld s trans-t e r t- b u t y l ( 4 - ( (4 -
3
met ho xyb en zy l) ami no )t et rah ydr of ur an -3 -y l) ca rb ama te
1
9 9 – 1 0 3 °C ). H N M R ( 4 0 0 M H z , D M SO - d 6 , p p m ) : d
(7)
an d
cis-te rt- bu ty l
a mi no )t et ra hy dr of ur an -3 -y l) ca rb ama te (8) wi th t he
(4 -( (4 -me th ox yb en zyl )
7 . 1 6 ( d , J = 8 . 4 H z , 2 H ) , 6 . 8 9 ( d , J = 8 . 7 H z , 2 H ) , 6 . 6 9
( s , 1 H ) , 4 . 4 1 ( d , J = 1 5 . 3 H z , 1 H ) , 4 . 0 9 – 3 . 9 5 ( m , 3 H ) ,
3 . 8 1 – 3 . 7 8 ( m, 1 H ) , 3 . 7 3 ( s , 3 H ) , 3 . 7 0 – 3 . 6 6 ( m , 1 H ) ,
3 . 4 1 – 3 . 3 7 ( m, 1 H ) , 3 . 4 4 – 3 . 4 2 ( m, 1 H ) , 3 . 2 2 – 3 . 1 7 ( m ,
y ie ld o f 42 % a nd 38 %, re sp ec tiv ely. B oth t he i so mer s
3 2
a re c le ar ly s ep ar at ed b y p re pa ra ti ve H PLC . T he ra tio
o f ( 7) a nd ( 8) i s 1. 1:0 .9 .
1 3
1 H ) . C N M R ( 4 0 0 M H z , D M S O - d 6 , p p m) : d 1 6 0 . 3 1 ,
1 5 8 . 4 0 , 1 2 9 . 7 3 , 1 2 9 . 0 2 , 1 1 3 . 8 6 , 7 4 . 8 9 , 7 0 . 6 3 , 5 9 . 7 2 ,
5 5 . 0 0 , 5 3 . 4 0 , 4 4 . 0 3 ; H R M S ( E S I- T O F ) : C a l c d f o r
2 . 2 c Trans tert-butyl (4-((4-methoxybenzyl) amino)
1
tetrahydrofuran-3-yl) carbamate (7): H N M R ( 4 0 0
?
C H N O [ M ? H ] : 2 4 9 . 1 2 3 9 ; f o u n d : 2 4 9 . 1 2 2 7 .
1
2
1
8
2 2
M H z , C D C l ) : d 7 . 2 6- 7. 2 3 ( m , 2 H ), 6 . 86 -6 . 8 4 ( m, 2 H ) ,
3
4 . 6 9 ( s , 1 H ) , 4 . 04 -4 . 0 0 ( m , 3 H ) , 3 . 8 4 -3 . 7 4 ( m, 5 H ) ,
3 . 6 2 -3 . 6 1 ( m , 1 H ) , 3 . 50 -3 . 4 7 ( m , 1 H ), 3 . 1 9 -3 . 1 7 ( m,
1 H ) , 1 . 4 5 ( s , 9 H ) . C N M R ( 40 0 M H z , D M S O - d 6 ): d
1 5 8 . 65 , 1 5 5 . 26 , 1 3 1 . 92 , 1 2 9 . 35 , 1 1 3 . 75 , 7 9 . 6 0 , 7 3 . 1 0 ,
2 . 2 f Cis-4-(3-(4-methoxybenzyl)-2-oxohexahydro-
1H-furo[3,4-d] imidazol-1-yl)-2-(trifluoromethyl)
benzonitrile (10): A m i x t u r e o f c o m p o u n d 9 ( 1 . 1 g ,
4 . 4 3 m mo l ) , 4 - i o d o - 2 - ( t r i flu o r o me t h y l ) b e n z o n i t r i l e
( 1 . 5 7 g , 5 . 3 1 m mo l ) , C u l ( 0 . 0 8 4 g , 0 . 4 4 3 m m o l ) ,
1
3
7 2 . 1 7, 6 4 . 8 2, 6 0 . 3 1 , 5 7 . 1 1, 5 5 . 1 8, 5 1 . 3 5 , 2 8 . 3 1 ; H R M S
?
( E S I - T O F) : C a l c d f o r C H N O [ M ? H ]
1 7 2 6
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3 2 3 . 19 71 ; f o u n d : 3 2 3 . 19 6 4 .
0 . 4 4 3 m mo l ) a n d t r i -p o t a s s i u m p h o s p h a t e ( 2 . 8 2 g ,
1 3 . 2 9 m mo l ) i n t o l u e n e ( 2 0 m L ) w a s d e g a s s e d w i t h
n i t r o g e n f o r 1 0 m i n i n a s e a l e d t u b e a n d k e p t i n a
p r e h e at e d o i l b a t h a t 1 1 0 °C a n d a l l o w ed t o s t i r f o r
1 2 h . T h e r ea c t i o n m i x t u r e w a s c o o l ed t o R T a n d
fi l t e r e d t h ro u g h a p a d o f c el i t e. A n d t h e fi l t r a t e w as
c o n c e n t r a t e d u n d er r e d u c ed p r e s s u r e t o g i v e a r e si d u e ,
w h i ch w a s p u r i fie d b y s i l i c a g e l c o l u m n
2 . 2 d Cis tert-butyl (4-((4-methoxybenzyl) amino)
1
tetrahydrofuran-3-yl) carbamate (8): H N M R ( 4 0 0
M H z , C D C l ) : d 7 . 2 6- 7. 2 2 ( m , 2 H ), 6 . 87 -6 . 8 5 ( m, 2 H ) ,
3
5 . 5 0 ( d , J = 6 . 4 H z , 1 H ), 4 . 1 4 -4 . 1 1 ( m , 1 H ), 4 . 0 0 - 3 . 9 6
( m , 1 H ) 3 . 92 -3 . 9 0 ( m , 1 H ) , 3 . 8 0 ( s , 3 H ), 3 . 73 -3 . 6 6 ( m,
3 H ) , 3 . 54 -3 . 5 1 ( m , 1 H ), 3 . 3 8 -3 . 3 6 ( m , 1 H ), 1 . 4 5 ( s ,

J. Chem. Sci. ( 2 0 2 0 )1 3 2 : 1 3 6
P
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c h r o ma t og r a ph y y i e ld s c o m p o u nd 10 a s w h i t e s o l i d 1 H ) , 8 . 1 7 ( d , J = 9 H z , 1 H ) , 7 . 9 4 – 7 . 8 5 ( m, 2 H ) , 7 . 7 4
1
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C D C l , p p m ) : d 8 . 1 9 ( s , 1 H ) , 7 . 7 7 –7 . 7 0 ( m, 2 H ) , 8 . 7 H z , 1 H ) , 5 . 2 5 – 5 . 1 4 ( m 2 H ) , 4 . 3 0 ( q , J = 7 . 2 H z,
3
1 3
7 . 2 6 – 7. 1 9 ( m , 2 H ), 7 . 87 ( d , J = 8 . 7 H z , 2 H ) , 4 . 7 8 ( d , 2 H ) , 3 . 9 8 – 3 . 8 3 ( m, 4 H ) , 1 . 3 1 ( t , J = 6 . 9 H z , 3 H) .
C
J = 1 5 H z , 1 H ) , 4 . 21 – 4 . 1 4 ( m , 2 H ) , 4 . 01 ( d , J = 1 0 . 8 N M R ( 4 0 0 M H z , D M S O - d 6 , p p m) : d 1 6 2 . 9 7 , 1 5 9 . 8 3 ,
H z , 1 H ) , 3 . 84 –3 . 8 2 ( m , 1 H ) , 3 . 80 ( s , 3 H ), 3 . 5 1 ( d d , J1 1 5 3 . 0 6 , 1 4 3 . 5 4 , 1 4 2 . 7 6 , 1 3 6 . 3 9 , 1 3 2 . 4 9 , 1 3 1 . 8 7 ,
1 3
= 4 . 2 , J2 = 1 0 . 5 H z , 1 H ) . C N M R ( 4 0 0 M H z , C D Cl , 1 2 1 . 0 8 , 1 1 5 . 9 2 , 1 1 5 . 6 9 , 1 1 3 . 8 8 , 1 1 2 . 3 7 , 1 0 6 . 5 0 ,
3
p p m ) : d 1 5 5 . 51 , 1 4 3 . 3 7 , 1 4 3 . 37 , 1 3 5 . 63 , 1 3 4 . 1 0 , 1 0 6 . 1 3 , 1 0 1 . 3 7 , 7 1 . 9 0 , 6 0 . 7 6 , 5 7 . 4 2 , 5 7 . 2 0 ,
1 3 3 . 6 7, 1 2 9 . 59 , 1 2 7 . 3 7 , 1 2 4 . 0 8 , 1 2 0 . 44 , 1 1 8 . 9 1 , 1 4 . 0 8 ; H R M S ( E S I- T O F ) : C al cd f o r C H F N O
?
1 1 5 . 8 2, 1 1 4 . 91 , 1 1 4 . 7 8 , 1 0 2 . 01 , 7 2 . 3 7 , 7 1 . 3 8 , 5 7 . 9 3 , [ M ? H ] : 4 6 4 . 1 2 3 3 ; f o u n d : 4 6 4 . 1 2 5 8 .
2 2 1 7 4
3
4
5 7 . 1 0 , 5 5 . 28 , 4 5 . 8 2 ; H R M S ( E S I - T O F ) : c a l cd f o r
C H F N O [ M ? H ]?: 4 1 8 . 13 7 9 ; f ou n d : 4 1 8 . 1 3 9 5 .
2 . 2 i Cis 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-2-
oxohexahydro-1H-furo[3,4-d]imidazol-1-yl)-2-
fluorobenzoic acid (AR01): T o a s o l u t i o n o f
2 1 1 8 3
3 3
2 . 2 g Cis-4-(2-oxohexahydro-1H-furo[3,4-d]
imidazol-1-yl)-2-(trifluoromethyl)
(11): A m i x t ur e o f c o m p o u nd 10 ( 1 . 2 g , 2 . 87 m mo l ) M e O H ( 1 0 m L ) a n d H O ( 5 m L ) , l i t h i u m h y d r o x i d e
benzonitrile c o m p o u n d 12 ( 0 . 7 g , 1 . 5 1 m mo l ) , T H F ( 1 0 m L ) ,
2
a n d T FA ( 2 0 m L) w e r e h e a t e d t o r e fl u x f o r 6 h . A f t e r m o n o h y d r a t e ( 0 . 3 1 6 g , 7 . 5 5 m mo l ) w a s a d d e d a t r o o m
c o m p l e t i o n o f t h e r e a c t io n, t he m i x t u re w a s c o o l ed t o t e m p e ra t u r e a n d a l l o w ed t o s t i r f o r a n o t h e r 6 h . T h e
r o o m t e m p e r at u r e a n d s o l v e n t w a s r e m o ve d b y v a c u u m . r e ac t i o n m i x t u r e w a s c o n c e n t r a t e d u n d e r r e d u c e d
T h e m i x t ur e w a s d i l u t e d w i t h a q ue ou s s o d i u m p r e s s u r e , p o u r ed i n t o w a t e r ( 1 0 m L ) a n d e xt r ac t e d
b i c a r bo na te s o l u t i o n a n d e x t ra c t e d w i t h e t h y l a ce t a t e. w i t h d i et h y l e t h e r . T h e p H o f a q u e o u s l a y e r w as
T h e o r g a n i c l a y e r w a s w a s he d w i t h b r i ne , d ri e d o v e r a d j u s t e d t o 2 u s i n g c o n e . H C I, w h i t e p r e ci p i t a t e i s
a n h y d r o u s M g S O a n d c o n c e n tr a ted i n v a c u um y i el d s g e n e r at e d , w h i ch w a s fi l t e r e d a n d d r i e d t o g i v e
4
c o mp o un d 1 2 ( 0 . 8 g c r u d e ) a s a n o ff w h it e s o l id , w h i ch c o m p o u n d AR01 ( 0 . 5 5 0 g , 8 3 % ) a s w h i t e s o l i d . M . p .
1
w a s u s e d f o r t h e n e x t s t e p w i th o u t a n y f u r t h er 2 9 6 – 3 0 0 °C ; H N M R ( 3 0 0 M H z , D M S O - d 6 , p p m ) : d
1
p u r i fic a t io n. M . p . 2 4 0 – 2 4 4 °C ; H N M R ( 40 0 M H z , 1 3 . 0 5 ( s , 1 H ) , 8 . 5 7 ( d , J = 1 . 8 H z , 1 H ) , 8 . 1 8 ( d , J = 8 . 4
D M S O - d 6 , p p m ) : d 8 . 57 ( d , J = 2 . 4 H z , 1 H ) , 8 . 06 ( d , J = H z , 1 H ) , 7 . 9 4 – 7 . 8 5 ( m, 2 H ) , 7 . 7 2 ( d d , J1 = 1 . 8 , J2 =
8 . 7 H z , 1 H ) , 7 . 92 ( s , 1 H ) , 7 . 6 7 ( d d , J1 = 2 . 1, J2 = 8 . 7 H z , 1 3 . 8 H z , 1 H ) , 7 . 5 7 ( d d , J1 = 2 . 4 , J2 = 9 . 3 H z, 1 H ) ,
1 3
1 H ) 5 . 0 2 ( q , J = 4 . 2 H z , 1 H ) , 4 . 3 3 ( q , J = 4 . 2 H z , 1 H ) , 5 . 2 5 – 5 . 1 4 ( m, 2 H ) , 3 . 9 8 – 3 . 8 3 ( m, 4 H ) . C N M R ( 3 0 0
3 . 8 9 –3 . 7 9 ( m , 2 H ) , 3 . 72 – 3 . 6 7 ( m , 1 H ), 3 . 5 8–3 . 5 4 ( m, M H z, D M S O - d 6 , p p m ) : d 1 6 4 . 4 7 , 1 6 0 . 0 1 , 1 5 3 . 1 2 ,
1 3
1 H ) . C N M R ( 4 0 0 M H z , D M S O - d 6 , p p m ) : d 1 5 6 . 9 6 , 1 4 3 . 4 0 , 1 4 2 . 8 3 , 1 3 6 . 4 1 , 1 3 2 . 8 1 , 1 2 1 . 0 9 , 1 1 5 . 9 3 ,
1 4 4 . 00 , 1 3 6 . 2 6, 1 3 1 . 7 5 , 1 1 9 . 2 7 , 1 1 6 . 0 2 , 1 1 4 . 4 1 , 1 1 4 . 3 4 , 1 1 5 . 7 2 , 1 1 3 . 8 0 , 1 1 3 . 3 1 , 1 0 9 . 5 0 , 1 0 6 . 5 5 , 1 0 6 . 1 7 ,
9 9 . 3 1, 7 4 . 2 7, 7 1 . 6 3, 5 9 . 8 1, 5 3 . 0 2 ; H R M S ( E S I - T O F ) : 1 0 1 . 3 3 , 7 1 . 9 3 , 7 1 . 7 6 , 5 7 . 4 5 , 5 7 . 2 1 ; H R M S ( E S I -
C al c d f o r C H F N O [ M ? H ]?: 2 9 7 . 2 3 26 ; f o u n d : T O F ) : C al cd f o r C H F N O [ M ? H ]?: 4 3 6 . 0 9 6 1 ;
1
3
1
0
3
3
2
2
0
1
3
4
3
4
2 9 7 . 23 42 .
f o u n d : 4 3 6 . 0 9 7 7 7
2 . 2 h Cis ethyl 4-(3-(4-cyano-3-(trifluoromethyl) 2 . 2 j Cis 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-2-
imidazol-1-yl)-2-
phenyl)-2-oxohexahydro-1H-furo[3,4-d] imidazol-1- oxohexahydro-1H-furo[3,4-d]
yl)-2-fluorobenzoate (12): A m i x tu re o f c o m p o u n d fluorobenzamide (AR02): T o
a
s o l u t i o n o f
11 ( 0 . 8 g , 2 . 6 9 m m o l ), e t h yl -2 -fl uo r o - 4 - i o d ob e n z o a t e c o m p o u n d AR01 ( 0 . 1 0 0 g , 0 . 2 2 9 m mo l ) a n d N H C l
4
( 0 .9 4 9 g , 3 . 2 2 m m o l ), C u l ( 0 . 0 51 g , 0 . 2 6 9 m mo l ) , ( 0 . 0 3 6 g , 0 . 6 8 7 m mo l ) i n D M F ( 2 m L ) , D I PE A ( 0 . 1 1 9
t r a n s - 1 , 2- d i a m in o c y c l o h e x a n e
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4
t h r o u g h a p a d o f c e l it e a n d t he fi l t ra t e w a s u n d er v a c u u m . T h e c ru d e p r o d u c t w a s p u r i fi e d b y
c o n c e n t r a t ed u n d e r r e d u c e d p r e s s u re t o g i v e a s i l i c a g e l c o l u mn c h r o m at o g ra p h y ( D CM – M e OH ) t o
r e s i d u e. T h e r e s i d u e w a s p u r ifi e d b y s i l i c a g e l g i v e AR02 ( 0 . 0 7 0 g , 7 0 % ) a s w h i t e s o l i d . M . p .
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J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 1 3 6
7 . 5 8 ( s , 2 H ) , 7 . 51 ( dd , J1 = 2 . 1 , J2 = 8 . 7 H z , 1 H ) , H z , 1 H ) , 8 . 1 7 ( d , J = 8 . 8 H z , 1 H ) , 7 . 8 6 ( d d , J1 = 2 . 0 , J2
1 3
5 . 2 5 –5 . 1 4 ( m , 2 H ) , 3 . 98 – 3 . 8 3 ( m , 4 H ) . C N M R ( 4 0 0 = 8 . 4 H z , 1 H ) , 7 . 7 1 ( d d , J1 = 1 . 6 , J2 = 1 3 . 2 H z , 1 H ) ,
M H z , D M S O - d 6 , p p m ) : d 1 6 4 . 4 1 , 1 6 0 . 8 0 , 1 5 3 . 1 7 , 7 . 6 3 ( t , J = 8 . 4 H z , 1 H ) , 7 . 5 0 ( d d , J1 = 2 . 0 , J2 = 8 . 8 H z,
1 4 2 . 94 , 1 4 1 . 6 1, 1 4 1 . 4 4 , 1 3 6 . 4 0 , 1 3 1 . 19 , 1 2 0 . 9 6 , 1 H ) , 5 . 2 4 – 5 . 1 5 ( m, 2 H ) , 3 . 9 9 – 3 . 8 2 ( m, 7 H ) , 3 . 4 1 – 3 . 3 2
1 1 7 . 78 , 1 1 5 . 8 9, 1 1 5 . 7 6 , 1 1 4 . 1 4 , 1 0 6 . 28 , 1 0 5 . 9 0 , ( m, 2 H ) , 1 . 7 7 ( d d , J1 = 2 . 4 , J2 = 1 2 . 4 H z , 2 H ) ,
1
3
1 0 1 . 15 , 7 1 . 9 0, 7 1 . 8 0 , 5 7 . 4 7, 5 7 . 1 8 ; H R M S ( E S I- 1 . 5 9 – 1 . 4 9 ( m, 2 H ) . C N M R ( 4 0 0 M H z, D M S O- d 6 ,
?
T O F ) : C a l c d f o r C H F N O [ M ? H ] : 4 3 5 . 0 7 1 6 ; p p m) : d 1 6 2 . 4 7 , 1 6 0 . 6 0 , 1 5 8 . 1 4 , 1 5 3 . 1 8 , 1 4 2 . 9 6 ,
2 0 1 4 4
3 4
f o u n d : 4 3 5 . 06 88 .
1 4 1 . 1 3 , 1 4 1 . 0 3 , 1 3 6 . 4 1 , 1 3 1 . 8 3 , 1 3 1 . 5 1 , 1 3 0 . 7 2 ,
1 2 3 . 8 5 , 1 2 1 . 1 2 , 1 2 0 . 9 4 , 1 1 9 . 0 4 , 1 1 8 . 9 0 , 1 1 5 . 7 5 ,
2 . 2 k Cis 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 1 1 4 . 1 8 , 1 0 6 . 3 2 , 1 0 6 . 0 4 , 1 0 1 . 1 4 , 7 1 . 8 5 , 6 5 . 9 3 , 5 7 . 4 7 ,
2-oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2- 5 7 . 1 8 , 4 5 . 6 4 , 3 2 . 2 2 ; H R M S ( E S I- T O F ) : C a l c d f o r
fluoro-N-methylbenzamide (AR03): T h i s c o m p o u n d C H F N O [ M ? H ] ?: 5 1 9 . 1 6 5 5 ; f o u n d :
w a s a l s o p r e p a r e d b y a d o p t in g t h e s a m e p r o c e d u r e a s 5 1 9 . 1 6 1 0 .
2 5 2 2 4
4 4
c o m p ou nd AR02 u s i ng m e th a n a m i n e i ns t e a d o f
1
N H C l . Y i el d ( 0 . 0 6 0 g , 5 8 % ) M . p . 2 7 4 – 2 7 8 °C ; H
2 . 2 n Cis 4-(3-benzyl-2-oxohexahydro-1H-furo[3,4-
d] imidazol-1-yl)-2-(trifluoromethyl) benzonitrile
(AR06): T h e s o l u t i o n o f c o m p o u n d 12 ( 0 . 3 0 g ,
1 . 0 0 8 m mo l ) i n D M F ( 2 m L ) w a s a d d e d t o t h e i c e
c o o l ed s u s p e n s i o n o f N a H ( 0 . 0 7 8 g , 2 . 0 1 6 m mo l , 6 0 %
i n o i l , w a s h e d w i t h h e x a n e ) i n D M F ( 5 m L) . T h e
r e s u l t i n g m i x t u r e w a s v i g o r o u s l y s t i r r ed f o r 0 . 5 h
u n d er t h e s a m e i c e b a t h f o l l o w e d b y b e n z y l b r o m i d e
( 0 . 2 5 8 g , 1 . 5 1 2 m mo l ) w a s a d d e d a n d a l l o w ed t o s t i r
o v e r n i g h t a t t h e a mb i e n t t e m p e ra t u r e. A f t er t h e
r e ac t i o n w a s c o m p l e t e d , t h e m i x t u r e w a s p o u r e d i n t o
w a t e r ( 2 0 m L ) a n d t h e e x t r a c t e d w i t h e t h y l a c e t a t e ,
4
N M R ( 4 0 0 M H z , D M S O - d 6 , p p m ) : d 8 . 5 8 ( s , 1 H ) ,
8 . 1 9 –8 . 1 3 ( m , 2 H ) , 7 . 86 ( d , J = 8 . 7 H z , 1 H ) , 7 . 7 4 – 7 . 6 8
( m , 2 H ) , 7 . 52 ( d , J = 8 . 4 H z , 1 H ), 5 . 2 2 –5 . 1 5 ( m, 2 H ) ,
1 3
3 . 9 8 – 3. 8 3 ( m , 4 H ) , 2 . 78 ( d , J = 4 . 8 H z , 3 H ). C N M R
( 3 0 0 M H z , D M S O -d 6 , p p m ) : d 1 6 3 . 32 , 1 6 1 . 1 6 ,
1 5 7 . 88 , 1 5 3 . 1 7, 1 4 2 . 94 , 1 4 1 . 3 7 , 1 4 1 . 22 , 1 3 6 . 4 0 ,
1 3 0 . 87 , 1 2 0 . 9 3, 1 1 8 . 22 , 1 1 8 . 0 3 , 1 1 5 . 76 , 1 1 4 . 2 0 ,
1 0 6 . 30 , 1 0 5 . 9 2, 1 0 1 . 14 , 7 1 . 9 0 , 7 1 . 8 1 , 5 7 . 4 7 , 5 7 . 1 8 ;
H R MS ( E S I - T OF ) : C a lc d f or C H F N O [ M ? H ]
2 1 1 6 4
4 3
?: 4 49 . 1 4 7 7 ; f o u n d : 4 4 9 . 14 6 6 .
2 . 2 l Cis 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-2- w a s h e d w i t h w a t e r a n d b r i n e s o l u t i o n , d r i e d o v e r
oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2-fluoro- a n h y d ro u s M g SO a n d t h e s o l v e n t w a s r e mo v e d u n d e r
4
N-(oxetan-3-yl)benzamide (AR04): T h i s c o m p o u n d v a c u u m . T h e c ru d e p r o d u ct w a s p u r i fie d b y s i l i c a g e l
w a s p r e p a r e d b y a d o p t in g t he s i m i l a r p r o c e d u r e a s c o l u mn c h r o m at o g r a p h y ( H e x a n e – et h y l a ce t a t e ) t o
c o m p ou nd AR02 u s i n g o x e t a n -3 - a m i n e i n s t ea d o f g i v e c o m p o u n d AR06 ( 0 . 1 2 0 g , 3 0 % ) a s o f f w h i t e
1
1
N H 4 C l . Y i el d ( 0 . 0 6 5 g , 5 8 % ) ; M . p . 2 4 0 – 2 4 4 °C . H s o l i d . M . p . 1 2 7 – 1 3 1°C . H N M R ( 4 0 0 M H z, C DC l ,
3
N M R ( 4 0 0 M H z , D M S O - d 6 , p p m ) : d 8 . 94 ( d , J = 6 . 3 p p m ) : d 8 . 1 5 ( s , 1 H ) , 7 . 7 7 ( s , 2 H ) , 7 . 3 8 – 7 . 2 8 ( m , 5 H ) ,
H z , 1 H ) , 8 . 58 ( s , 1 H ), 8 . 17 ( d, J = 8 . 7 H z , 1 H ) , 7 . 8 7 ( d , 4 . 8 6 ( d , J = 1 1 . 1 H z , 1 H ) , 4 . 7 1 ( q , J = 3 . 6 H z , 1 H ) ,
J = 8 . 7 H z , 1 H ) , 7 . 76 – 7 . 6 5 ( m , 2 H ) , 7 . 53 ( d , J = 8 . 7 4 . 2 4 ( d , J = 1 1 . 4 H z , 1 H ) , 4 . 1 7 ( q , J = 3 . 0 H z , 1 H ) ,
H z , 1 H ) , 5 . 25 –5 . 1 5 ( m , 2 H ) , 5 . 02 – 4 . 9 5 ( m , 1 H ) , 4 . 7 6 4 . 0 3 ( d , J = 7 . 5 H z , 1 H ) , 3 . 8 2 ( d d , J1 = 3 . 6 , J2 = 7 . 8
1 3
( t , J = 6 . 6 H z , 2 H ) , 4 . 56 ( t, J = 6 . 6 H z , 2 H ), 3 . 9 8 – 3 . 8 2 H z , 1 H ) , 3 . 5 1 ( d d , J1 = 2 . 7 , J2 = 7 . 8 H z , 1 H ) .
1 3
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1 6 2 . 82 , 1 6 1 . 5, 1 5 8 . 0 , 1 5 3 . 1 7 , 1 4 2 . 9 2 , 1 4 1 . 5 8 , 1 4 1 . 4 1 , 1 3 6 . 6 1 , 1 3 6 . 3 3 , 1 3 6 . 3 3 , 1 3 1 . 7 4 , 1 3 1 . 4 9 , 1 2 8 . 6 2 ,
1 3 6 . 41 , 1 3 1 . 8 8, 1 3 0 . 8 4 , 1 2 0 . 9 7 , 1 1 7 . 90 , 1 1 5 . 7 6 , 1 2 7 . 4 5 , 1 2 3 . 6 5 , 1 2 1 . 4 7 , 1 1 9 . 4 1 , 1 1 5 . 9 8 , 1 1 4 . 5 6 ,
1 1 4 . 19 , 1 0 6 . 3 3, 1 0 5 . 9 6 , 1 0 1 . 2 0 , 7 6 . 8 3 , 7 1 . 8 7 , 7 1 . 8 1 , 1 1 4 . 5 2 , 9 9 . 6 2 , 7 1 . 7 6 , 7 0 . 7 2 , 5 7 . 6 7 , 5 7 . 4 6 , 4 5 . 2 0 ;
?
5 7 . 4 7, 5 7 . 1 8, 4 4 . 5 0 ; H R M S ( E S I -T O F ) : C a l c d f o r L C M S f o r C 2 0 H 1 6 F3 N3 O 2 [ M ? H ] : 3 8 8 . 1 2 .
C H F N O [ M ? H ] ?: 4 9 1 . 1 3 42 ; f o u n d :
2
3
1
8
4
4
4
4 9 1 . 13 55 .
2 . 2 o Cis 4-(3-benzyl-2-oxohexahydro-1H-furo[3,4-
d] imidazol-1-yl)-2-(trifluoromethyl) benzamide
2 . 2 m Cis 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- (AR07): A m i x t u r e o f c o m p o u n d AR06 ( 0 . 1 0 g ,
2-oxohexahydro-1H-furo[3,4-d]
fluoro-N-(tetrahydro-2H-pyran-4-yl)
imidazol-1-yl)-2- 0 . 2 5 8 m mo l ) , T F A ( 1 0 m L ) a n d t o l u e n e ( 1 0 m L ) i n a
benzamide s e a l e d t u b e w a s h e a t e d t o r efl u x f o r 3 d a y s . A ft er
(AR05): T h i s c om po u n d w a s a l s o p re p a r e d b y c o m p l e t i o n o f r ea c t i o n , t h e r ea c t i o n m i x t u r e w as
a d o p t i n g s i m i l a r p r o c e d u r e a s c o m p o u nd AR02 d i l u t ed w i t h a n a q u e o u s s o l u t i o n o f s o d i u m
u s i n g t e t r a h y d r o - 2 H - p yr a n -4 -a m in e i ns te a d o f b i ca r b o n at e, e x t r a c t e d w i t h e t h y l a ce t a t e, w as h e d
1
N H C l . Y i e l d ( 0 . 07 0 g , 7 0 % ) , M . p . 2 4 0 – 2 4 4 °C ; H w i t h b r i n e a n d d r i e d o v e r a n h y d r o u s M g SO . T h e
4
4
N M R ( 4 0 0 M H z , D M S O - d 6 , p p m ) : d 8 . 57 ( d , J = 2 . 0 s o l v e n t w a s r e mo v ed , a n d t h e c ru d e p r o d u c t w as

J. Chem. Sci. ( 2 0 2 0 )1 3 2 : 1 3 6
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p u r i fie d b y s i l i c a g e l c o l um n c h r o m a t o g r a p h y ( 7 0 %
e t hy l a c et a t e a n d h e x a n e ) y ie ld s c o m p o u nd AR07
( 0 . 0 05 g , 4 . 8% ) a s b r o w n s o l id . M . p . 1 1 8 – 1 2 2 °C ; H
u n d er s t a n d t h e e ff e c t o f p h ar m ac o p h o r e a s A R
a n t a g o n i s t s , t h er e a r e n o c h a n g e s i n t h e r em ai n i n g
s t ru ct u r a l f ea t u r es o f r ep o r t e d d r u g s . S ch em e 1 s h o ws
t h e o p t i m i z e d s y n t h e t i c p a t h w ay f o r t h e p r e p a r a t i o n o f
t h e n e w l y d e s i g n e d c o m p o u n d s AR01, AR02, AR03,
AR04 a n d AR05. S y n t h e s i s b e g i n s w i t h t h e c o m m er -
c i a l l y a v a i l a b l e 2 , 5 -d i h y d r o f u r an a n d r e ac h e s i n t e r -
1
N M R ( 4 0 0 M H z , D M S O - d 6 , p p m ) : d 8 . 34 ( d , J = 1 . 6
H z , 1 H ) , 7 . 85 ( s , 2 H ) , 7 . 58 – 7 . 5 0 ( m , 2 H ), 7 . 48 ( s , 1 H ) ,
7 . 3 8 –7 . 2 7 ( m , 5 H) , 4 . 9 9 ( q, J = 4 . 4 H z , 1 H ) , 4 . 6 2 ( d ,
J = 1 1 . 1 H z , 1 H ) , 4 . 71 ( q , J = 1 5 . 6 H z , 1 H ) , 4 . 3 5 ( d ,
J = 1 5 . 6 H z , 1 H ) , 4 . 22 ( q , J = 4 . 0 H z , 1 H ), 3 . 9 7 ( d . J =
1 0 . 0 H z , 1 H ) , 3 . 81 ( d , J = 1 0 . 4 H z , 1 H ) , 3 . 73 – 3 . 6 9 ( m,
m ed i a t e t e r t - b u t y l - ( 4 - o x o te t r a h y d r o f u r a n - 3 - y l )
3 2
c ar b am a t e (6) u s i n g t h e r e p o r t e d p r o c e d u r e s .
1 3
1 H ) , 3 . 42 ( d d , J1 = 4 . 0, J2 = 1 0 . 0 H z , 1 H ) . C N M R
T h e d e t a i l e d s y n t h e t i c s t ep s f r o m t h e c o m p o u n d 1 t o
a r e s h o w n i n t h e s u p p o r t i n g i n fo r m a t i o n
( 4 0 0 M H z , D M S O -d 6 , p p m ) : d 1 6 8 . 73 , 1 5 5 . 9 2 ,
1 4 0 . 27 , 1 3 6 . 9 8, 1 2 9 . 68 , 1 2 9 . 3 7 , 1 2 8 . 62 , 1 2 7 . 7 7 ,
1 2 7 . 39 , 1 1 9 . 35 , 1 1 4 . 5 8 , 7 1 . 8 5, 7 0 . 9 3 , 5 7 . 5 8, 5 7 . 3 6 ,
4 5 . 2 0; H R M S ( E S I -T O F ) : C a lc d f or C 2 0 H 1 8F 3 N3 O3
[ M ? H ]?: 4 0 6 . 1 3 79 ; f o u nd : 4 0 6 . 13 7 7 .
6
( Sc h e m e S 1 ) . R ed u c t i v e a mi n a t i o n o f 6 w i t h p - m e t h -
o x y b e n z y l a m i n e ( PM BN H ) i n t h e p r e s e n c e o f
2
A C O H a n d N a BH C N i n E T O H y i el d s trans-t e r t -
3
b u t y l - 4 - ( ( 4 - m e t h o xy b en z y l )a m i n o ) t e t ra h y d r o f u r a n - 3 -
y l )c a r b a ma t e ( 7) a n d cis-t e r t - b u t y l – ( 4 -( ( 4 - m e t h o x y -
b e n z y l ) a m i n o )te t r a h y d r o f u ra n -3 - y l ) c a r b a m a t e ( 8) w i t h
t h e y i el d o f 4 2 % a n d 3 8 % , r e s p e ct i v e l y . B o t h t h e
i s o me r s a r e c l e a rl y s e p a r at e d b y p r e p a ra t i v e H P L C . I n
o r d e r t o g e t c y c l i c u r e a d e r i v a t i v e o f c o m p o u n d 7 a n d
8, e ac h c o m p o u n d t r e a t e d w i t h t r i flu o ro ac e t i c a c i d
( T F A ) f o l l o w e d b y 1 , 10- Ca r b o n y l d i i m i d a zo l e ( C DI )
a n d t r i et h y l a mi n e ( T E A ) i n T H F ; cis i s o me r 8 o n l y
2 . 3 Screening against primary prostate cancer
cell lines (LNCaP) assay
L N C a P c e l l s ( A T C C , c a t a l og u e n o . C R L -1 7 4 0 ) w e re
p r o p a g a t e d i n R P MI - 1 6 4 0 ( In v i t ro g e n , c a t a l o g u e n o .
R 4 1 30 ) c o n t a i ni n g 1 0 % F B S ( F a t a l B o vi n e S er u m ,
G i b co , c a t a l og u e n o . 1 0 2 7 0 ) a n d 1 % A A S ( G i b c o ,
c at a l o g u e n o . 1 1 1 4 0 -0 5 0 ). L N C a P c e l ls w e r e s e e d e d a t
a d e n s i t y o f 1 0 0 0 c e l l p e r w e l l a n d i n c u b a t e d o v e r n i g h t
i n R P M - 1 6 4 0 h a vi n g 1 0 % C C S (C h a r c o l S t ri p p e d
S e r u m, G i bc o, c a t a lo gu e n o . 1 2 6 7 6 -0 2 9 ) 2 0 0 X c o m -
p o u n d s w e r e p r e p a re d i n 1 0 0 % D M S O H y b ri m ax
( S i g m a , C a t a l o g u e n o . D 2 65 0 ) , f o l l o w e d b y 3 f o l d
s e r i a l d i l u t i o n a n d i nt e r m e d i a t e s t o c k s o f 1 0 X c o m -
p o u n d w a s p r e p a r e d i n i n c o m p le t e R P M I m ed i u m .
C o m p o u n d s w e r e a d de d t o r e s p e c ti v e w e l l s , D M S O
fi n a l c o n c e n t r a t i on w a s 0 . 2% a n d i nc ub a t e d f o r 7 d a y s ,
a t t h e s a m e t i me f o r T - 0 p la te 5 0 lL C t g l o w a s a d d e d
a n d l u m i n e s c en ce w a s m e a s u r e d . F r e s h m e d i a a l o n g
w i t h c o m p ou nd s w a s r e p la c e d o n d a y 3 a n d 6 , o n 7 t h
d a y 5 0 lL C t g l o w a s a d de d t o p la te s a n d l um i n e s ce n c e
w a s m ea s u r e d , t h e v a l ue o f T - 0 w a s s u bt r a c t ed f o r
c al c u l a t i o n o f % g r o w th o r c o nt r o l .
g i v e s
1 - ( 4 - m et h o x y b e nz y l ) t et ra h y d r o - 1 H - f u ro [ 3 , 4 -
d ] i m i d az o l -2 ( 3 H )- o n e (9) w i t h t h e y i el d o f 5 4 % .
U n f o r t u n at e l y , t r a n s i s o m er 7 c o u l d n o t y i e l d t h e
c o m p o u n d 9. T h i s m ay b e b e c au s e t h e f o r ma t i o n o f
h i g h l y s t ra i n ed fi v e -m e mb er e d o x et an e r i n g i s n o t
p o s s i b l e f r o m t h e trans i s o me r (7) . T h e c y c l i c u r e a
t e t r a h y d ro fu r an d e r i v a t i v e ( 9) r ea c t e d w i t h 4 - i o d o - 2 -
( t r i fl u o ro me t h y l ) b e n z o n i t r i l e i n t h e p r e s e n c e o f
K P O , C u I a n d trans d i am i n e c y c l o h ex an e i n t o l u en e
3
4
a ff o r d s c o m p o u n d 10 w i t h t h e y i el d o f 5 5 % , w h i c h
t r e a t e d w i t h T F A g i v e s c o m p o u n d 11 w i t h t h e q u a n -
t i t a t i v e y i el d . I t r e ac t e d w i t h e t h y l 2 - fl u o r o -4 -
i o d o b e n z o a t e i n t h e p r e s e n c e o f K P O , C u I a nd trans
3
4
d i am i n e c y c l o h ex an e i n t o l u e n e y i el d s c o m p o u n d 12,
w h i ch w a s t r e a t e d w i t h L i O H . H O i n M e O H , T H F,
2
H O t o a f fo rd a ci d AR01 w i t h t h e y i el d o f 8 3 % . T h i s
2
a ci d w a s t r e a t e d w i t h v a r i o u s a mi n e s a s s h o wn i n
S ch em e 1 y i el d s t h e AR02, AR03, AR04 a n d AR05.
F i n a l l y , c o m p o u n d 11 w a s t r e a t e d w i t h B en z y l b r o -
m i d e i n t h e p r e s e n c e o f N a H i n D M F a ff o r d s c o m -
p o u n d AR06 t h at w a s t r e a t e d w i t h T F A y i e l d s
3. Results and Discussion
I n o r d e r t o d e v e l o p n o v e l A R a n t a g on is t s , w e f o c u s e d c o m p o u n d AR07 w i t h a q u a n t i t a t i v e y i el d a s s h o wn i n
o n t h e s t r u ct u r e o f e n z a lu t a m i d e ( 4) , A R N - 5 0 9 a n d S ch em e 2 .
R - 6 . W h i l e l o o ki n g a t t h e s e s t r u c tu re s , t h e m ai n
p h a r m a c o p h o r e i s t h i o -h y d a n t o i n u n i t l in k e d t o t h e t e s t i n g t h ei r c y t o t o x i ci t y e f fe c t . F o r t h i s p u rp o s e, w e
T h e a ct i v i t y o f t h es e c o m p o u n d s w a s d e fi n e d b y
3 3
t r i fl u o r o m e t h y l a n d c y a n op h e n y l g ro u p s t h a t i s t h e s e l e c t e d t h e A R -p o s i t i v e L N C a P c el l l i n e s , a c e l l
k e y s t r u c t u r a l f e a t ur e o f p o t e n t n o n s t e r o i d al A R s y s t e m w i d el y u s e d a s a m o d e l o f a n d r o g e n - r e s p o n s i v e
1 7 – 1 9
a n t a g on is t s. W i th t h e e x t e n s i o n o f t h e s e s t ru ct u r al g r o w t h . L N C aP c el l l i n e i n h i b i t i o n d a t a o f c o m p o u n d s ,
f e a t u r e s , w e d e v e l o p e d n o v e l A R a n t a g on is t s u s i n g AR01-AR07 ( T a b l e 1 ) , r e v e al s t h at , e x c ep t AR04, a l l
t e tr a h y d r o f u r an c y c l i c u r e a p h a r m a c o p h o r e . T o t h e d e r i v a t i v e s s h o w v e r y w e ak a ct i v i t y w i t h t h e h a l f -

1 3 6 P a g e 8 o f 1 2
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 1 3 6
PMB
HN
PMB
HN
NHBoc
NHBoc
+
O
NHBoc
a, b, c, d, e
f
O
O
8
O
O
1
7
6
g, h
CF3
O
O
CN
CN
I
N
N
N
NH
O
CF3
9
10
O
O
i
O
O
F
j
CF3
CN
O
I
F
O
O
CF3
O
HN
N
N
N
O
CN
11
12
l
k
O
O
CF3
F
HO
CN
CF3
F
O
O
O
H2N
NH4Cl
m
CN
N
N
N
N
O
NH2
AR02
AR01
O
O
O
m
CH3NH2
CF3
F
O
F
CF3
NH
O
O
CN
O
CN
N
N
O
N
H
N
N
AR04
AR03
O
O
N
F
O
F
HO
O
CF3
CF3
O
N
H
O
O
CN
CN
O
NH2
N
N
N
m
AR05
AR01
O
O
Scheme 1. S y n t h e s i s o f AR01, AR02, AR03, AR04 a n d AR05. R e a g e n ts a n d c o n d i t io n s : ( a ) m - C P B A / D C M , r t ;
( b) N H C l/ N aN / M e O H/ H O , r e fl u x ; ( c ) P d / C , E t O H , H y d r o g e n ; ( d ) ( B o c ) O , N a C O , A c e t o n e , w a t e r , R T ( e ) O x a l yl
4
3
2
2
2
3
c h l o r i d e , T H F , D M S O, T E A ; ( f) P M B NH / M e O H /A c O H / N a B H C N , r t ; ( g ) T F A , r t ; ( h ) C D I , T E A , T H F , r t ; ( i ) K P O ,
2
3
3
4
C
u
I
,
T
r
a
n
s
d
i
a
m
i
n
e
c
y
c
l
o
h
e
x
a
n
e
,
T
o
l
u
e
n
e
,
1
1
0
°
C
;
(
j
)
T
F
A
,
r
e
fl
u
x
;
(
k
)
K
P
O
,
C
u
I
,
T
r
a
n
s
d
i
a
m
i
n
e
c
y
c
l
o
h
e
x
a
n
e
,
T
o
l
u
e
n
e
,
3
4
1
1
0
°
C
;
(
l
)
L
i
O
H
.
H
O
,
M
e
O
H
,
T
H
F
,
H
O
,
r
t
;
(
m
)
H
A
T
U
,
D
I
P
E
A
,
D
M
F
,
r
t
.
2
2
Scheme 2. S y n t h e s i s o f AR06 a n d AR07. R e a g e n t s a n d c o n d i t io n s : ( n ) N a H / D M F / B e n z y l b r o m id e , r t . ; ( o ) T F A r efl ux .
m
a
x
i
m
a
l
i
n
h
i
b
i
t
o
r
y
c
o
n
c
e
n
t
r
a
t
i
o
n
(
I
C
)
v
a
l
u
e
o
f
l
M
.
)
;
P
C
c
y
t
o
t
o
x
i
c
i
t
y
o
f
A
R
0
4
t
e
s
t
e
d
a
g
a
i
n
s
t
t
h
e
5
0
a
r
o
u
n
d
3
0
.
0
0
2
l
M
.
E
v
e
n
t
h
o
u
g
h
a
l
l
t
h
e
d
e
r
i
v
a
t
i
v
e
s
L
N
C
a
P
c
e
l
l
l
i
n
e
a
n
d
t
h
e
I
C
v
a
l
u
e
e
s
t
i
m
a
t
e
d
t
o
b
e
5
0
h a v e s i m i l a r s t r u c t u r a l f e a t u re s , AR04 s h ow s r e m ar k - 3 . 9 2 6 lM ( Fi g u r e 4 ) . H e n c e, w e s t ro n g l y b e l i e v e t h a t
a b l e a c t i v i t y t o w a rd s t h e L N C a P c e l l l in e ( IC : 3 . 9 2 6 t h e b e n z a mi d e w i t h o x et an e r i n g p l ay s a m aj o r r o l e i n
5 0

J. Chem. Sci. ( 2 0 2 0 )1 3 2 : 1 3 6
P
a
g
e
9
o
f
1
2
1
3
6
Table 1. A R a n t a g o n i s t i c a c t i v i t y o f s y n t h e s i z e d c o m p o u n d s t o w a r d s h u m a n p r o s ta te c a n c e r
C el l L i n e ( L N C a P) .
a
C
o
m
p
o
u
n
d
T
y
p
e
A V G I C (lM )
5 0
C
L
o
g
P
K
S D ( n M )
N A
N A
N A
3 8 9 .6
N A
N A
N A
i
AR01
AR02
AR03
AR04
AR05
AR06
AR07
A n t a g o n i s t
A n t a g o n i s t
A n t a g o n i s t
A n t a g o n i s t
A n t a g o n i s t
A n t a g o n i s t
A n t a g o n i s t
[3 0 . 0 0 2
[3 0 . 0 0 3
[3 0 . 0 0 3
3 . 9 2 6
[3 0 . 0 0 3
[3 0 . 0 0 0
[3 0 . 0 0 1
3 . 1 2
1 . 9 1
2 . 1 5
2 . 3 0
1 . 7 8
3 . 4 0
1 . 5 6
NA n o t a c t i v e
a
C el l g r o wt h w a s p r o mo t e d b y 1 0 n M D H T a n d I C v a l u e s f o r a n d r o g e n - d e p e n d e n t c e l l
5 0
p
r
o
l
i
f
e
r
a
t
i
o
n
( b i c a l u t am i d e ( 0 . 5 0 9 lM ) a n d e n z al u t a m i d e
( 3 . 6 4 1 lm )) , AR04 s h o w s a l m o s t s i mi l a r a c t i v i t y
t o w ar d s t h e L N C a P c el l l i n e ( 3 . 9 2 6 lM ) . U p o n c o n -
s i d e ri n g t h e c h e mi ca l s t ru ct u r e o f r ep o r t e d h i g h l y
a ct i v e A R a n t a g o n i s t , p r e s e n c e o f t h e a mi d e g r o u p
e i t h er i n b e t w e e n t h e a ro ma t i c r i n g o r a t t h e t e r m i n al
p o s i t i o n o f a n y o n e o f t h e a r o ma t i c r i n g s d o e s n o t
s h o w a n y s i g n i fi c a n t d i ff e r en ce i n t h ei r a ct i v i t y . E v e n
t h o u g h t h e p y ra n r i n g i n AR05 i s m o r e s t ab l e t h a n t h e
o x et an e r i n g i n AR04, t h e AR04 s h o w s v e r y h i g h
a ct i v i t y t h an t h at o f t h e AR05 m ay b e d u e t o t h e f a c t
t h at t h e s t ra i n ed r i n g i s m o r e i m p o rt an t t o b i n d w i t h
t h e s u r f a ce r e ce p t o r o f t h e c el l s t h an t h e s t ab l e p y r a n
r i n g . I t i s i m p o r t an t t o n o t e t h at w h e n c o m p a r i n g t h e
s t ru ct u r a l f ea t u r es o f e n z al u t a m i d e a n d AR03, o n l y t h e
h y d an t o i n r i n g i n e n z al u t a m i d e i s r e p l a c ed b y t h e
t e t r a h y d ro fu r an c y c l i c u r e a, t h e AR03 s h o ws v e r y
p
o
o
r
a
c
t
i
v
i
t
y
.
I
n
c
o
n
t
r
a
s
t
,
A
R
0
4
s
h
o
w
s
a
l
m
o
s
t
s
i
m
i
l
a
r
Figure 4. T h e p e rc e n t a g e v i a b i l i t y o f L N C a P c e l l s w i t h
d i ff er en t c o nc e n t r a t i o n o f A R 0 4 .
a ct i v i t y a s e n z al u t a m i d e b u t h e r e, t h e m et h y l g r o u p i n
e n z al u t a m i d e i s r e p l a c ed b y a n o x e t an e r i n g i n AR04.
I t r ev ea l s t h at t h e a ct i v i t y i s h i g h l y d e p e n d i n g o n t h e
r e l a t i o n s h i p b e t w e e n t h e l i n k i n g g r o u p i n b e t w e e n t h e
t w o a r o ma t i c r i n g s a n d g r o u p s l i n k e d o u t s i d e o f e i t h e r
o f t h e a r o ma t i c r i n g . A l s o , i t i s c o n c l u d e d t h a t t h e
h i g h e s t a ct i v i t y o f AR04 m ai n l y d e p e n d s o n b o t h
o x e t an e r i n g a n d t e t r a h y d ro fu r an c y c l i c u r e a u n i t s , b u t
n o t o n l y b e c au s e o f o x e t an e r i n g .
M o l e c u l a r d o c k i n g s t u d i es w e r e p e r fo r m ed t o
e v a l u a t e t h e p r o p o s e d s t ru ct u r a l m o d i fic a t i o n s . S i n c e
t h e c o m p o u n d AR04 s h o w s t h e v e r y b e s t a c t i v i t y
c o m p a re d t o i t s c o u n t e rp ar t s , AR04 w a s c h o se n a s
r e p r es e n t at i v e f o r t h e n o v el s e r i e s o f c o m p o u n d s a n d
a t t e m p t e d t o p r e d i c t t h e r ea s o n f o r t h e a ct i v i t y . T h e
d o c k i n g p o s e o f AR04 i s s h o w n i n F i g u re 5 a n d t h e
i m a g e s o f t h e r e ma i n i n g c o m p o u n d s a re s h o w n i n t h e
S u p p l em e n t ar y I n f o r m at i o n . T h e d o ck i n g s co r e i s
g i v e n i n T a b l e S 1 ( Su p p l em e n t a r y I n f o r m a t i o n ) .
t h e a c t i v i t y . I n r e c e n t d r u g d is c o v e r y s y s t e ms , o x e -
t a ne s h a v e a c k n ow le d g e d e n or m o us i n t e r e s t a s a n
a d d i t i o n a l a n d / o r r e p l a c e m e nt g r o up s f or g e m - d i m e -
t h y l a n d c a r b o n y l g ro u p s w i th e n h a n c e d p h y s i co -
c h e m i ca l p r o p e r t ie s . H e n c e , t he o x e t a n e i nc or p o r at i o n
a s a p e n d a n t m o t if o f d ru g m o le c u le s i m p r o v e s t h e
‘ d r u gl i k e’ p r o p e r t i e s m a y b e d u e t o t he s m a l l a n d
3
4
h
i
g
h
l
y
s
t
r
a
i
n
e
d
p
o
l
a
r
n
a
t
u
r
e
.
A s a r e s u l t , t h e i n c o r p o ra t i o n o x e t a n e g r o up i n t h e
d r u g m ol e c ul e a s a n a d di t i o n a l o r r e p l a c e m e n t g r o u p s
h a v e b e e n w i de l y a c c e pt e d i n m e d i c i n a l c h e m i s t ry
r e s e a r c h i n r e c e n t y e a r s . I n t hi s r e g a r d , t he d i s t i n c t
a ct i v i t y o f AR04 c l a im e d t ha t t h e h i g h l y s t ra i n ed
o x e t a n e r i n g e a s i ly r e l a x e s t hr ou g h t he i n t e r a ct i o n s
w i t h t h e s u r f a c e r e c e pt o r o f t h e c e l l l in e u s e d i n t h i s
s t u d y . W h e n c o m p a r e d t o t h e A R a n t a g on is t s c u r r en t l y
e m p l o y ed c l i n i c a l ly f o r t h e t re a t m e n t o f P C a ct i v i t y

1
3
6
P
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1
2
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 1 3 6
Figure 5. 2 D L i g a n d i n t e ra c t i o n d i a g ra m o f c o m p o u n d A R 0 4 w i t h a n t i c a n c e r t a r g e t p r o te in A n d r o g e n R e c e p to r u s i n g
¨
M a e s t r o ( S ch r o d i n g e r) p r o g r a m w i t h t h e e s s e n t i a l a m i n o a c i d r e s i d u e s a t t h e b i n d i n g s i te a r e t a g g e d i n c i r c l e s .
T h e c y t o c h r o m e P 4 50 a c t iv e s i t e c o n s i s t s o f m ai n 7 5 2 . B o t h g a l e t e r o n e a n d e n z a l u t a m i d e h a v e c o n -
r e s i d u es s u c h a s A s p a r a g in e 7 0 5 , A r gi n i n e 7 5 2 a n d s e r v e d h y d r o g e n b o n d w i t h a r g i n i n e 7 5 2 . I m p o r t a n c e
T h r e o n i n e 8 7 7 w h ic h b in ds w i t h a n dr o g e n ic h o r mo n e s o f a r g i n i n e 7 5 2 r o l e s t o w a r d s l i g a n d b i n d i n g h a s a
l e ad i n g t o t r an sc r i pt i on f a c t o r a n d g e ne r e g u l a t i o n s . r o l e i n t h e c o n f o r m a t i o n a d a p t a t i o n o f l i g a n d
A n d r o g e n r e c e p t o r ( P D B i D : 1 E 3G ) w i t h b o u n d d r u g b i n d i n g .
m e t r i b o l on e, a s y n t h e t ic h i g h - a f fi n i ty a n a b o l i c -a n d ro -
g e n i c s t e r o i d , w a s t a k e n a s a t e m p l a t e m o d e l f o r
d o c k i n g a n a l y si s. A n d r o g e n r e c e pt o r t e n ds t o b i n d
w i t h m an y a n d r o g e n i c s t e ro i d s a n d a h i g h e r c o n c e n -
4. Conclusions
t r a t i on o f p r o g e s t i n s t e n d s t o i nh ib i t a n d r o g e n r ec e p t o r
( N R 3 C 4 ) . S u b s t r a t e m i m i c s w h i c h c a n h a l t t h e r e g u -
l a ti o n a n d h a s p r o fo un d i m p li c a ti o n i n t he t re a t m e n t .
N R 3C 4 a c t i v e s i t e i s i n b e t w e e n i nt e r -h e l i c a l r e g i o n o f
h e l i x H 2 , H 4 a n d H 9 . T h e c a vi t y c o nt a i n s 5
m e t h i o n i n e r e s i d ue s a l o n g w i t h t he h y d r o p h o b i c c av -
i t y , 4 p o l ar r e s i d u e s a n d o n e c h a r g e d a r g in in e 7 5 2 . A
s t r u ct u r a l a n t a g o ni s t w i th s i m i l a r b i n d i n g c o m p l e -
m e nt a t i o n m i g h t a l t e r t h e r e g u l a t i o n b y d i f f e r en t i a l
o r g a n i z a t i on a l t e r i ng o r h a l ti n g r e g u l a t io n . T h e s y n -
t h e s i z ed c o mp o un d t e n ds t o h a v e a s i m i l a r b i n d i n g
a f fi n i t y w i t h r e l e va n c e t o d o c k i ng s c o r e s h o w n i n
T a b l e 1 . T h e b i n d i n g p o s e o f t he c o m p ou n d s w i t h
r e s p ec t t o a c t i ve s i t e r e s i d u a l l in i n g i s s h ow n i n S u p -
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I n s u m m ar y , w e h a v e d e s i g n e d a n d s y n t h e s i ze d c y c l i c
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a n d r o g en -s e n s i t i ve L N C a P c el l l i n e . E v e n t h ou g h a l l
t h e c o m p o u n d s h a v e t h e s a m e s t ru ct u r al f e at u r e s, t h e
c o m p o u n d w i t h o x et an e r i n g l i n k e d a mi d e g r o u p
(AR04) s h o w s v e r y h i g h a ct i v i t y t h an t h at o f i t s
c o u n t er p a r t s c o n fi r ms t h e r o l e o f t h e o x et an e r i n g .
I mp o r t a n t l y , w e b e l i ev e t h at t h e a ct i v i t y m a i n l y
d e p e n d s o n b o t h t h e o x et an e r i n g a n d t e t r a h y d r o f u r a n
c y c l i c u r e a u n i t s , b u t n o t o n l y b e c au s e o f t h e o x e t a n e
r i n g . I t i n d i r e ct l y r ep re s en t s t h at i n t r o d u ct i o n o f t h e
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