B Y T
I HI
 TRN TH THANH

TNG H HOC
MT S DN CHT
N-HYDROXYPROPENAMID MANG KHUNG
3-METHOXYIMINO-2-OXOINDOLIN N TT NGHI
I - 2015
3-METHOXYIMINO-2-OXOINDOLIN

N TT NGHI

ng dn:
1. GS.TS. Nguyn Hi Nam
2. 
c hin:
1. B c
I - 2015
i, 13  

Trn Th Thanh

MC LC
Trang
DANH M VIT TT
DANH MNG
DANH M
DANH M
T V
C1. TNG QUAN
1.1. HISTON DEACETYLASE (HDAC)
histon deacetylase (HDAC)
1.1.2.
T C CH HDAC
1.2.1t c ch HDAC
1.2.1
1.2.1
1.2.1
1.2.2t c ch  nghi


1.2.3.2. Li
1.3. MT S U TNG HC CH
 GI
n din b mt PXD101

U
T LIU, THIT B
t
2.1.2. Thit b, dng c
2.2. NU
2.2.1. Tng hc
2.2.2. Th ng sinh hc ct tng hc
U
2.3.1. Tng h hc
2.3.2. Th ng sinh hc
 ging thuc ct tng hc
3. THC NGHIM, KT QU N
C
3.1.1. Tng hc
3.1.2. Ki tinh khit
nh c
3.2. TH HOHC
3.2.1. Th hoc
 ging thuc
N
3.3.1. Tng hc
3.3.2. Ho sinh hc
KT LUN NGH
U THAM KHO
PH LC

16

APL
ch cu
APAF1
: Yu t ho
CBHA
: Carboxy cinnamic acid bis-hydroxamic
CD
t t i ti
DCM
: Dicloromethan
DMF
: Dimethylformamid
MeOH
: Methanol
MHC
: Phc h 
ROS
: Gc oxy t do hong

: Receptor ca acid retinoic
SPB
: SulforhodamineB
SAHA
: Acid suberoylanilid hydroxamic
T
O
nc
: Nhi y
VEGF
: Yu t ch

5

t ester
29
6

f

o
nc
4a-d
30
7
Bng 3.3: 4a-d
31
8
Bng 3.4: t 4a-d
32
9
Bng 3.5:  ph
1
H-NMR ct 4a-d
33
10
Bng 3.6: 
13
C-NMR ct 4a-d
34
11


3
3
: 
8
4
H: S t ca cn thit acid hydroxamic
c ch  nghisng
9
5
: Cn cht acid indol - hydroxamic 
11
6
   c t   n cht N-hydroxy-3-(4-(5-
aryl/arylalkyl-1,3,4-oxadiazol-2-yl)phenyl)acrylamidN-hydroxy-3-
(4-(5-aryl/arylalkyl-1,3,4-oxadiazol-2-yl)methyl)benzamid
12
7

 Kt qu th ng c ch HDAC cn cht 4a-d

37
1 





        Acid suberoylanilid hydroxamic (Zolinza

,
2006), depsipeptid (Romidepsin

, 2009), belinostat (Beleodaq


[19,24,33] nh 1.1).

: Cca nucleosom
u amin ca histon mang nhinh vi
 ADN t 
c     a nhim sc th     u hin gen. Khi
n nhim sc th 
c ch ng hc ch s biu hic
l  u, nhim sc th  ng hp
protein diu hing. M n
 a histon ph thu     u amin  pha
n hot ng ca 2 en
acetyltransferase (HAT).
1.1.1.iston deacetylase (HDAC)
Histon deacetylase           
acetyl t -N-acetyl lysin amino acid ca histon. i lp vi histon
acetyltransferase (HAT)- enzym n chuy acetyl coenzym

histon
(147bp ADN)
Cu ni ADN

3   -amino ca lysin  u N ca histon      
acetyl c h
 [33] (h).

:    HAT

 .
 


1.2.1




1,20,23].

in vitroin vivoa
-RAR
              
PLZF-RAR

--


 [22].
5 
            -  

 -  - 


-


) [1,20].


CD95 (CD95L). 
butyrat


-


sin - 





                
SAHA.
1.2.1

      
               



7 

Tc, NSCLC

Acid valproic

I, II

Tc, 

Phenyl butyrate
II
Tc, AML/MDS
Acid
hydroxamic
Vorinostat
(SAHA)
I, II

T       

CTCL, u lympho Hodgkin
8 Practinostat
(SB-939)
I
T
Belinostat
(PXD101)
II

Tng 
Entinostat
(MS275)
II
T

Romidepsin
I, II
T     
Hodgkin
 ch cu tp; MDS: hi chng lon sn ty; CTCL: u
lympho da t ch cu cp.

1.2.3.


 1.3: Cn c cht c ch HDAC
C [23] .3):
- n din b mt (surface
recognition group) (A)ng nm  mt
enzym.
9 -  u n  c (B)      u mch
th  no ho tt Van der Waals vi

- n vi km (Zinc binding group - ZBG) (C)i
ion Zn
2+

2+
(C):  thi 
ng c ch HDAC.
         


 ng tng h dn cht acid indol - hydroxamic:
u Nht Bt k thay th n din b
mt ca PXD 101, tng hp  dn cht acid indol - hydroxamic 
b 20. 11
. Cn cht acid indol - 
Kt qu th ng c ch H

Cht
1
IC
50

HDAC
2
KB
a
H460
b


0,56 0,11
1,11 0,06

Ie
0,56  0,04

1,67 0,34
1,97 0,29

If
0,10  0,05
0,23
0,57 0,01
1,63 0,41

Ig
0,24  0,11

0,91 0,06
1,24 0,18

Ih
0,60  0,09

1,82 0,01
4,11 0,43

Ik
0,85  0,11

ACY-c th nghing. Cht If c th 
chu   t qu kh quan vi sinh kh d ng ung 33% trong khi
SAHA 8,33t 7-azaindolylsulfonylcinnamic hydroxamat
(If) y ti n thuc chi kh c ch chn l
12 
PXD
 ng tng h-oxadiazol:

m N-hydroxy-3-(4-(5-aryl/arylalkyl-1,3,4-
oxadiazol-2-yl)phenyl)acrylamid  N-hydroxy-3-(4-(5-aryl/arylalkyl-1,3,4-
oxadiazol-2-yl)methyl)benzamid d PXD101, vi cu n
-oxadiazo  [30]c
t6.

 6:  c t   dn cht N-hydroxy-3-(4-(5-aryl/arylalkyl-
1,3,4-oxadiazol-2-yl)phenyl)acrylamid  -hydroxy-3-(4-(5-aryl/arylalkyl-1,3,4-
oxadiazol-2-yl)methyl)benzamid.

mt s dn cht IIa, IIb, IIc, IId

R
n
1
IC
50
+ 
HDAC1

:
1
N c ch 50% s trin ca t t qu c ly
n th nghim v sai l


C6c bit cht IIb, IId
vi vithgn vi cu nng tn
cht IIa, IIc. 

      N-hydroxy-4-((5-(naphtalen-1-ylmethyl)-1,3,4-
13 oxadiazol-2-yl)methyl)bezamid (IIb)     
 
methyl gu ni phenylmethyl ca PXD101.
1.3.2. t c ch u b ng
i hi thit k u.

g 3-methoxyimino-2-oxoindolin 
th Tho [4]. Kt qu c
ch   -n tin lit
y AsPC-i NCI-H460 c (bng 1.4) ht sc kh
quan, c 7 chu c ch t SW620 u rt tt vi khong
IC
50
thp ch t 0,26-1,35 M.

Bng 1.4 c

1,15
0,97
0,97
3
5-Cl
0,49
1,56
2,33
0,49
0,76
4
5-Br
2,32
7,79
8,91
1,68
2,90
5
5-NO
2
1,35
0,94
1,69
0,84
14,27
6
5-CH
3
1,07
16,67


n din b mt  ng kh 
acid amin  ming thi ng tt
 ng t
 [4].
ng thit k
so vi PXD 101 ng tng hp dn cht hydroxamic 
khung 3-methoxyimino-2-oxoindolin n din b mt u c cht
c ch HDAC ttng thi c  
y, trong kn tt nghi
da tr cPXD101  ng 
khung 3-methoxyimino-2-oxoindolin vi m
 v mi
 . Nh c ch
c ch s n ca t 

1.4.1. T
Ta hay s dng KCN hophn ng acid hydroxamic t
n  [6, 7, 9, 16]:

Vu ki
kha ch ti
phn    :
15
: 
.


t
 c nghi
tng hc nhp t c Sigma-c
s dng trc ti m:
 
- Isatin
- 5-Methylisatin
- 5-Methoxyisatin
- 5-Bromoisatin
 Methyl 3-[4-(bromomethyl)phenyl]prop-2-enoat
 Hydroxylamin hydroclorid
 Methoxyamin hydroclorid
       N,N-dimethylformamid (DMF), aceton,
c ct, FeCl
3
.
2.1.2. Thit b, dng c
- Dng c th
u thy sp mng (TLC).
- y t gia nhit, m-200.
-   thut Shimazu.
- T lnh, t s u nhit.
- Bn mng silicagel Merck 70   chy sp mng.
-  y nhin (Melting point Apparatus Smp3)  
nh nhi y.
-  nh ph IR.
- Mi ph Agilent 6310 Ion Trap  ghi ph MS
- Mng t Bruker AV- ghi ph
1
H-