Nghiên cứu tổng hợp và thử tác dụng sinh học của một số dẫn chất thiazolidindion

 













THIAZOLIDINDION































THIAZOLIDINDION






CH

MÃ S: 60720402









và . Các t
 Tôi

- 
ki
cô  
 
  
 












 Error! Bookmark not defined.
 10
1.1.   10
1.1.1.  10

1.1.2.  17
1.1.3.  24
1.2. -2,4- 24
1.2.1. -2,4-dion 24
1.2.2. -arylidenthiazolidin-2,4-dion 25

 27
 27
 27
 27
 27
 28
 28
2.3.2.   . 28
2.3.3.  28
 29
 29
 29
 29
 33
3.1.  33
3.1.1.  33
3.1.2.  42
3.1.3.  43
3.2.  48
3.2.1.  48
3.2.2.  49
3.2.3.  50
 52
4.1.  52

4.2.  54
 54
 55
 56
 57
4.3.  57
 58
 58
 58
KT LUN VÀ KIN NGH 60
I. KT LUN 60
II.  60




1
H-NMR
13
C-NMR
BSLA
CV-1
DCM
DMF
DMSO
ED
50
GAPDH
H3, H4
HDAC

HepG2
IC
50
IGF1R
IR
IR5
MS
PPAR- 
PPRE
PTP1B
RXR
SW620
SRR1
SRR2
TEA
TLC
TZD




Diclomethan
N,N-dimethylformamid
Dimethyl sulfoxid

Glyceraldehyde 3-phosphate dehydrogenase
Histon 3, Histon 4
Histon deacetylase (enzym histon deacetylase)

Inhi

Insulin-like growth factor 1 receptor



Peroxisom proliferator gamma 
Proli
Protein tyrosin phosphatase 1B (enzym protein tyrosin phosphatase 1B)


N-(6-(2,4-dioxothiazolidin-3-yl)hexyl)benzamid
N-(6-(2,4-dioxothiazolidin-3-yl)hexyl)benzenesulfonamid
Triethanolamin

Thiazolidindion





IIa và IIb .11
Bảng 3.1. Bảng tổng hợp các thông số của các dẫn chất 4a-f 35
 4a-f 36
 4a-f 37

1
H-NMR  4a-f 37
 3.5
13
C-NMR

4a-f. 39
SW620 41
 42



Hình 1.1 2
Hình 1.2 4
Hình 1.3.  6
Hình 1.4: C 7
Hình 1.5. Cấu trúc chung của một số dãy chất ức chế HDAC được thực hiện tại bộ
môn Hóa Dược…………………………………………………………………………….8
Hình 1.6
Hình 1.7. SRR1 và SRR2 9
 9
Hình 1.9 nay 10
Hình 1.10 11
Hình 1.11peroxisom proliferator gamma 12
Hình 1.12. Cấu trúc của các dẫn chất TZD liên quan đến tác dụng hoạt hóa PPARγ
Hình 1.13 insulin. 14
Hình 1.14 15
Hình 1.15 15
Hình 1.16 17
Hình 3.14a-f. 24
Hình 3.24a-f. 40
Hình 4.14e. 47
Hình 4.2 4b. 47
Hình 4.3. Phổ
1
H-NMR của chất 4c 48

Hình 4.4
13
C-4d 49




thu 


                 




proliferator gamma (PPAR-     rotein tyrosin phosphatase 1B
c



-(6-(2,4-dioxothiazolidin-3-yl)hexyl)benzensulfonamid và N-
(6-(2,4-dioxothiazolidin-3-       

g tác







1.   -(2-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)ethyl)
benzensulfonamid và 
2. 




1.1. 
 


ng bì [1, 6, 8, 12, 


1.1.1. 



N
S
O
O
COOH
H
Ar
I


Ia Ib Ic Id Ie If Ig Ih Ii
Hình 1.1

in vitro 
-
-

50
(µM).
Ia) và
methyl benzen (Id
50
-100 µM. Khi
vòng benzen có thêm các nhóIbIc

50
-
-trimethoxyl (Ie
50
-36

Ig, Ih) và Oxy (Ii
IC
50
-
-


S
NH
O
O
R

O

-5-(4-
((E)-3-oxo-3-(thiophen-2-yl)prop-1-enyl)benzyliden)-1,3-thiazolidin-2,4-dion) có

50
là 4.00 ± 0.25 
        
50
là 3.61 ± 0.17 g/ml. Trong


  -2,4-          

- 

-  

- 
- 
-2-, ) [8].


               -nitro
furfural và thiazolidin-2,4-



            


in vitro 
   -2,4-      


PPAR  [8, 18].
1.1.1.1. AR














Hình 1.2


Ghi chú
-  

-2 /BCL-x và survivin) và
bào (p53, BAD, phosphatase và PTEN).
- 


TZD
+ PPAR


theo


B
(p21,p27)


(cd1,cd2 )





TZD
+ PPAR
RXR

 cyclin có vai

               

 



gamma [18, 26, 29, 34].

-             -benzyliden
thiazolidin-2,4-dion và 5-(furan-2-ylmethylen)thiazolidin-2,4-dion là   
             -1 (IGF-1R).
IGF-   

-

-
50
=57nM.
-  

3-



 


- 





. 


  







hóa có t

   -N-         





Hình 1.3. 





21].

Phiên mã gen
Đóng vòng
Mở vòng

             

- Ion Zn
2+
 



2+


- Kênh enzym: là 


[19].


               rinostat,
Zolina®) - - 
  Chromobacterium violaceum         

1.4)
H
N
O
N
H
O
OH
SAHA

Romidepsin



N

H
3
C
CH
3
O
CH
3
CH
3
NHOH
O

H
3
C
CH
3
OH
O

TSA
Acid valproic
Hình 1.4: 





R

H
N
O
H
N
O
NHOH
O
n
1
n
2


n
1
: 1-3, n
2
: 1-2
n: 1-6
Hình 1.5. Cấu trúc chung của một số dãy chất ức chế HDAC được thực hiện tại bộ
môn Hóa Dược
               
chính [11,14,18] (hình 1.6).
- Nhóm C: nhóm 
2+


- 
-           


H
N
O O
H
N
OH
n


Hình 1.6
-2,4-


N-6-(2,4-dioxothiazolidin-3-yl)hexyl)benzamid (SRR1) và N-(6-(2,4-dioxo
thiazolidin-3-yl)hexyl)benzenesulfonamid (SRR2      

A
B
C


SRR1 SRR2
Hình 1.7. SRR1 và SRR2 


SRR1 

SRR2 
SAHA:


1.1.2. 


cholesterol 
             
       


            


           


 darglitazon

O
S
NH
CH
3
CH
3
CH
3
CH
3
O

O
CH
3

N O
S
NH
O
O
CH
3

Troglitazon Pioglitazon
N N
CH
3
O
S
NH
O
O

N
O
S
NH
O
CH
3
O

O

Rosiglitazon Darglitazon
O
O
S
NH
O
O

O
CH
3
O
S
NH
O
O

Englitazon Ciglitazon
Hình 1.9
-
arylidenthiazolidin-2,4-          
            (Z)-5-(2-(4-((2,4-
dioxothiazolidin-5-yliden)methyl)-phenoxy)acetyl)-2-hydroxybenzamid (IIa) và (Z)
-2-(4-((2,4dioxothiazolidin-5-yliden)methyl)phenoxy)-N(5-nitro-thiazol-2-yl)
acetamid (IIb)          

 


IIa và IIb .


[glucose]
máu
(%)

[TG] (%)

[CHL] (%)
IIa
64.43 ± 1.26 N.S.
74.18 ± 4.64*
89.70 ± 0.77**
IIb
56.08 ± 2.04 N.S
78.11 ± 1.46**
92.46 ± 0.54**
Pioglitazon HCl
51.57 ± 3.15**
78.38 ± 1.80*
86.83 ± 3.24**
Ghi chú

PPAR PTP1B.
1.1.2.1. 
a. 
 



 receptor

9-

(hình 1.11).
Tác nhân PPAR 9-cis retionic acid


Hình 1.10
Quá trình phiên mã


- 

- 






PPAR               


b. 

 F [17] (hình 1.11).
- 
2


- Vùng C (DBD -        

- 
- Vùng E (LBD - ligand binding d


A/B C D E/F
Hình 1.11peroxisom proliferator gamma

c. -2,4-



S
NH
O
O
O

  
Hình 1.12. Cấu trúc của các dẫn chất TZD liên quan đến tác dụng hoạt hóa PPARγ
- 
inding domain) trên PPAR-



-
- 





- 
                 

1.1.2.2. 
a. Varotein tyrosin phosphatase 1B
Protein tyrosin phosphatase 1B (PTP1B) 
           
t hóa insulin và
leptin). 




Hình 1.13
             

              

          

b. PTP1B



- 

- C             
cysteinyl-phosphat.

-  

phosphotyrosin.
Phiên mã gen
quy định leptin

Chuyển hóa
glucose
Tổng hợp
glucogen


Hình 1.14
Ghi chú: 
(màu cam) và Q loop (màu xanh)).
c. 


- -

 


 IIIa và IIIb (hình 1.15).
H
3
C S O
Br
S
NH

O
CF
3
O
O
O
O
IIIa

O
F
3
C CF
3
S
NH
O
O
Br
IIIb

Hình 1.15
in vitro  
--
1
     IIIa  
50
=1.3    
50
=1.4 

IIIb 
50
=5
IIIa 
-
Trên in vivo, IIIa và IIIb 
 
             
triglycerid. 

           

1.1.3. 
- 
- 
- 






 

1.2. -2,4-
1.2.1. -2,4-dion
Nhân thiazolidindion- 

a

-126
o
C [25].




[25].
HN
C
SH
NH
2
+
ClCH
2
COOH
-NH
4
Cl
S
NH
O
O


-imino-thiazolidin-4-on:
HN
C
SH

NH
2
+
ClCH
2
COOH
-HCl
H
2
O
S
NH
O
NH

2-imino-thiazolidin-4-

S
NH
O
NH
+HCl; +H
2
O
-NH
4
Cl
S
NH
O

O

1.2.2. -arylidenthiazolidin-2,4-dion
1.2.2.1. -2,4-dion
Nhân thizolidin-2,4-dion có nhóm imid (       
methylen (-CH
2


              CH
2
và

-2,4-dion.
1.2.2.2. 
      -arylidenthiazolidin-2,4- g cách
-2,4--CHO) [3]:
S
NH
S
NH
CHO
O
O
+
O
O
-H
2
O

AcOH; AcONa
R
R