Tổng hợp và thử tác dụng sinh học một số dẫn chất Benzensulflonamid mang khung...

B Y T

TRNG I HC DC H NI

NGUYN HUY PHONG

TNG HP V TH TC DNG SINH

HC MT S DN CHT

BENZENSULFONAMID MANG

KHUNG THIAZOLIDIN-2,4-DION

KHA LUN TT NGHIP DC S

H NI-2014

B Y T

TRNG I HC DC H NI

NGUYN HUY PHONG

TNG HP V TH TC DNG SINH

HC MT S DN CHT

BENZENSULFONAMID MANG

KHUNG THIAZOLIDIN-2,4-DION

KHA LUN TT NGHIP DC S

Ngi hng dn:

1. TS. Phan Th Phng Dung

2. DS. Th Mai Dung

Ni thc hin:

B mn Ha Dc

Trng i hc Dc H Ni

LI CM N

Trong thi gian nghin cu v lm kha lun, em xin chn thnh cm

n TS. Phan Th Phng Dung, PGS.TS Nguyn Hi Nam, Dc s

Th Mai Dung gip em hon thnh tt ti kha lun tt nghip.

Bn cnh , em cng xin cm n cc anh ch k thut vin b mn Ha

Dc, Trng i hc Dc H Ni gip v to iu kin tt nht cho

em trong thi gian thc hin kha lun. Em xin cm n s gip ca cc

cn b phng Phn tch hu c - Vin Hp cht thin nhin - Vin Hn lm

Khoa hc v Cng ngh Vit Nam v Phng Ha vt liu - Khoa Ha -

Trng i hc Khoa hc t nhin - i hc Quc gia.

Em cng xin chn thnh cm n cc thy c gio trong trng i hc

Dc H Ni ging dy v trang b cho em nhng kin thc c bn trong

hc tp nghin cu kho lun cng nh trong cng vic sau ny.

Nhng li ng vin, khch l t gia nh, s chia s, hc hi t bn b

cng gp phn rt nhiu cho kha lun tt nghip ca em t kt qu tt

hn.

H Ni, ngy 11 thng 5 nm 2014

Ngi vit

Nguyn Huy Phong

MC LC

DANH MC CC K HIU,CC CH VIT TT

DANH MC CC BNG

DANH MC CC HNH V

DANH MC CC S

T VN

CHNG 1.TNG QUAN

1.1. MT S MC TIU PHN T CA DN CHT THIAZOLIDIN-

2,4-DION ............................................................................................................. 2

1.1.1. Tc dng c ch enzym histon deacetylase (HDAC) ................................... 2

1.1.2. Tc dng hot ha PPAR- ca TZD trong iu tr i tho ng ............. 5

1.1.3. Tc dng c ch PTP1B ............................................................................... 7

1.2. MT S TC DNG KHC CA CC DN CHT THIAZOLIDIN-

2,4-DION ............................................................................................................... 9

1.2.1. c tnh t bo ............................................................................................. 9

1.2.2. Tc dng khng khun, khng nm ............................................................. 11

CHNG 2. NGUYN LIU, THIT B, NI DUNG V PHNG

PHP NGHIN CU ........................................................................................ 15

2.1. NGUYN VT LIU, THIT B ................................................................. 15

2.1.1. Ha cht ..................................................................................................... 15

2.1.2. Thit b, dng c ......................................................................................... 15

2.2. NI DUNG NGHIN CU .......................................................................... 16

2.2.1. Tng hp ha hc ....................................................................................... 16

2.2.2. Th c t nh t b o in vitro v nh gi s b t nh ging thuc ca mt

s n cht tng hp c .................................................................................... 16

2.3. PHNG PHP NGHIN CU.................................................................. 16

2.3.1. Tng hp ha hc v kim tra tinh khit ................................................ 16

2.3.2. Xc nh cu trc ........................................................................................ 17

2.3.3. Th tc dng c t nh t b o in vitro .......................................................... 17

2.3. . nh gi mc ging thuc ca cc n cht tng hp c .................. 18

CHNG 3. THC NGHIM, KT QU V BN LUN .......................... 20

3.1. HA HC ..................................................................................................... 20

3.1.1. Tng hp ha hc ....................................................................................... 20

3.1.2. Kim tra tinh khit ................................................................................. 28

3.1.3. Xc nh cu trc ........................................................................................ 29

3.2. TH HOT TNH SINH HC ..................................................................... 34

3.3. BN LUN .................................................................................................. 34

3.3.1. Tng hp ha hc ....................................................................................... 35

3.3.2. Tc dng sinh hc ....................................................................................... 38

KT LUN V KIN NGH ............................................................................ 40

Kt lun ................................................................................................................ 40

Kin ngh.............................................................................................................. 40

TI LIU THAM KHO

PH LC

DANH MC CC K HIU,CC CH VIT TT

13C-NMR Ph cng hng t ht nhn

13C (

13C nuclear magnetic resonance

)

DCM Dicloromethan

DMF N,N-dimethylformamid

DMSO Dimethyl sunfoxid

EtOH Ethanol

HAT Histon acetyltranferas

HDAC Histon deacetylase

HepG2 T b o ung th gan

1H-NMR Ph cng hng t ht nhn proton (

1H nuclear magnetic

resonance)

IR Ph hng ngoi (Infrared spectroscopy)

MeOH Methanol

MIC Minium inhibitory concentration

MS Ph khi lng (Mass spectroscopy)

MTT Thuc nhum 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl

tetrazolium bromid

PPAR- Peroxisom proliferator activated receptor gamma

PTP1B Protein tyrosin phosphatase 1B

SAHA Acid suberoylanilid

SWL68 T b o gan bnh thng

SW620 T b o ung th i trng

TLC Sc k lp mng (Thin Layer Chromatography)

TZD Thiazolidin-2,4-dion

DANH MC CC BNG

STT Tn bng Trang

1 Bng 3.1: Hiu sut v cc ch s ha l ca cc sn phm

c tng hp

28

2 Bng 3.2: Gi tr Rf v tonc ca cc sn phm cui 4a-4d 29

3 Bng 3.3: Kt qu phn tch ph hng ngoi ca cc cht 29

4 Bng 3.4: Kt qu phn tch ph khi lng ca cc cht sn

phm cui

30

5 Bng 3.5: Kt qu phn tch ph 1H-NMR ca cc sn phm

cui

31

6 Bng 3.6: Kt qu phn tch ph 13

C-NMR ca cc sn phm

cui

32

7 Bng 3.7: Tc ng hng t b o ung th i tr ng (SW620) 34

8 Bng 3.8: nh gi mc ging thuc theo quy tc

Lipinsky

38

DANH MC CC HNH

STT Tn hnh Trang

1 Hnh 1.1: Vai tr ca HDAC 2

2 Hnh 1.2: Cu trc khung ca SAHA 3

3 H nh 1.3: Cu trc 2 hp cht c ch HD C 4

4 Hnh 1.4: Kt qu c ch HDAC ca cc cht sau 8h 5

5 Hnh 1.5: S c ch hot ng ca th th PPAR 6

6 Hnh 1.6: Cc d n cht TZD vi tc dng h ng huyt 7

7 Hnh 1.7: Cc TZD c ch PTP1B mi c nghin cu 8

8 Hnh 1.8: Cc d n cht TZD theo nghin cu ca Vijay Patil 9

9 Hnh 1.9: Cc d n cht c tng hp trong nghin cu ca

Avupati

10

10 Hnh 1.10: Cc d n cht TZD theo nghin cu ca Alegaon

Shankar

11

11 Hnh 1.11: Cc d n cht 3-benzyl-5-(4-cloro-2-piperidin-1-

yl-thiazon-5-yl-methylen) thiazol-2,4-dion

12

12 Hnh 1.12: Cc d n cht ca pyrazolyl-2, 4-thiazolidindion 12

13 Hnh 1.13: Dy cht A1, A2, A3, A4, A5, B1, B2, C1, C2,

D1

13

14 Hnh 3.1: C ch phn ng tng hp cc cht 2a-d 35

15 Hnh 3.2: C ch phn ng tng hp cc cht 3a-d 36

16 Hnh 3.3: Giai on cng hp 37

17 Hnh 3.4: Giai on ngng t 38

DANH MC CC S

STT Tn s Trang

1 S 3.1: Quy trnh tng hp chung 20

2 S 3.2: Quy trnh tng hp thiazolidin-2,4-dion 20

3 S 3.3: Quy trnh tng hp cht 2a 22



1

T VN

Cc d n cht ca thiazolidindion (TZD) c bit n vi rt nhiu tc

dng [9,11,13,18], trong ni bt nht l tc dng h ng huyt nh hot

ha th th peroxisom proliferator activated receptor gamma (PPAR-). T

TZD thc y s sao chp iu ha gen, gip tng hp mt s protein cn

cho cc t b o p ng vi insulin nn l m tng hiu nng insulin. Mt trong

nhng d n cht TZD in hnh c s dng trong i tho ng typ II l

Pioglitazon [28].

Bn cnh , trong thi gian gn y, TZD c cc nh khoa hc

tip cn theo hng nghin cu khc, l h nng c ch cc dng t bo

ung th [20,22]. Nm 2011, trong cng b ca Jung M., cc TZD c

chng minh l nhng cht c kh nng c ch enzym histon deacetylase

(HDAC), l mt enzym c s biu hin qu mc trong qu trnh hnh thnh

cc t b o ung th [20]. Hng nghin cu n y c cc nh khoa hc rt

quan tm v ch . Nhm nghin cu tng hp ha c, b mn Ha c,

trong thi gian 3 nm tr li y cng thit k 1 s dy d n cht ca TZD

v th hot tnh ca chng theo hng tip cn ny [4]. Tuy nhin kt qu th

c ch HDAC v c tnh t bo trn cc t b o ung th li cha my kh

quan, trn c s thay i mch cacbon s d n n thay i tng tc ca cht

vi mc tiu phn t , nhm mc ch tm im cc d n cht thiazolidindion

trin vng trong tng lai, chng ti thc hin t i Tng hp v th tc

dng sinh hc mt s dn cht benzensulfonamid mang khung

thiazolidin-2,4-dion vi cc mc tiu sau:

1. Tng hp N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)

propyl)benzensulfonamid v mt s d n cht.

2. Th c t nh t b o ca cc cht tng hp c.

2

CHNG 1. TNG U N

1.1. MT S MC TIU PHN T CA DN CHT THIAZOLIDIN -

2,4-DION

1.1.1. Tc dng c ch enzyme histon deacetylase (HDAC)

1.1.1.1. Khi nim v vai tr ca enzym histon deacetylase trong s to ung

th

Histon deacetylase (HDAC) l mt nhm cc enzym xc tc qu trnh

loi b nhm acetyl t -N-acetyl lysin amino acid ca phn histon [10,19].

u amin ca histon mang in ng nn tng tc mnh vi phn

phosphat mang in m trn phn t ADN to nn cu trc nucleosom v cu

trc bc cao hn ca nhim sc th. HDAC xc tc cho qu trnh deacetyl ha

l m tng s t ch in ng trn u N ca histon d n n lin kt cht hn

vi u phosphat ca ND gy ng xon NST c ch qu trnh phin m.

Cc sai lch trong qu trnh phin m l mt trong nhng nguyn nhn d n

n s hnh thnh khi u [19].

Trong khi enzym histon acetyltranferase (HAT) xc tc qu trnh acetyl

ha c tc dng ngc li. H T v HD C l 2 enzym iu ha qu trnh

acetyl ha t quyt nh s biu hin gen.

Hnh1.1: Vai tr ca HDAC v HAT

Mt s thng k gn y cho thy cc HD C c lin quan n nhiu

giai on iu ha c bn ca qu trnh sinh hc trong t b o ung th nh chu

Ngng t cc nhim sc th

ngn cn phin m

Ko dn cc nhim sc th

kch thch phin m

3

trnh t bo, s bit ha, s cht t b o theo chng trnh, c s di chuyn,

s xm ln v s to mch. V vy, c ch hot ng ca enzym HDAC l

ch tc ng ca nhiu thuc chng ung th ang c nghin cu trong giai

on hin nay [10,20,31,32].

1.1.1.2. Cu trc ca cc cht c ch HDAC

Hiu qu tc dng ca cc cht c ch HDAC da trn s c mt ca 3

yu t chnh [15] :

- Nhm kt thc (zinc-binding group-ZBD): l nhm lin kt vi Zn2+

ti trung tm hot ng ca cc enzym HD C, thng c cu trc acid

hydroxamic, thiol, benzamid, mecaptoceton...

- Cu ni (lin er): thng l cc mch hydrocarbon, nm trong lng

enzym.

- Nhm kho hot ng (capping group): thng l vng thm hoc

pepti vng, thng nm trn b mt ca enzym.

Hin nay, c nhiu ti liu cng b v hot tnh c ch HDAC ca

nhiu d n cht vi cc cu trc khc nhau [31,32]. c bit n nhiu l

SAHA (Vorinostat, Zolina), mt c cht c cu trc amid-alkyl-

hydroxamic, c FDA cp php lu h nh trn th trng c tc dng iu tr

u lympho t b o T i da [10,19]. Mc d cc cht c ch HDAC c cu

trc hc nhau, nhng c bn gm 3 phn chnh: nhm kha hot ng lin

quan n hiu lc v t nh c hiu (thng l aryl), phn cu ni (akyl) v

nhm kt thc gn kt vi ion Zn2+ (acid hydroxamic) [15] (hnh 1.2).

Hnh 1.2: Cu trc khung ca SAHA

Nhm kha hot ng Cu ni Nhm kt thc

4

Cho n nay c nhiu cng trnh trn th gii khi nghin cu lin quan

cu trc tc dng ca cc cht c ch HD C tp trung vo vic thay i

cu ni [33,34] hoc thay i nhm kha hot ng [35].

1.1.1.3.Kh nng c ch HDAC ca TZD

Thi gian gn y, trong mt s nghin cu v TZD c t i liu cng

b v hot tnh c ch HDAC ca chng. Nm 2011, Rhea Mohan v cng s

thit k 2 hp cht ca thiazolidindion l : N-(6-(2,4-dioxothiazolidin-3-

yl)hexyl)benzamid (SRR1) v N-(6-(2,4-dioxothiazolidin-3-y)hexyl) benzen

sulfonamid (SSR2) vi nh hng c ch HD C trn ng t b o ung th

gan (hnh 1.3). y, tc gi s dng khung TZD l nhm to phc vi ion

Zn2+

ti trung tm hot ng ca enzym [22].

C

O

N

NS

O

O

H

N

NS

O

O

H

S

OO

SSR1 SSR2

H nh 1.3:

nh gi c tnh t bo ca hai hp cht c tng hp c tin

hnh trn 2 dng: t b o ung th gan (HepG2) v t bo gan bnh thng

(WRL68). Hai tiu ch c nh gi l tc ng ph thuc vo liu v tc

dng ph thuc vo thi gian. Nghin cu chng minh kh nng gy c

ca 2 hp cht ny trn 2 dng t bo, tuy nhin v n c s chn lc hn trn

t b o ung th (HepG2). Bn cnh cht SSR1 cho thy hot tnh c ch

mnh hn theo thi gian so vi cht SSR2. Tuy nhin li c im hn ch khi

tc dng trn dng t b o bnh thng (WRL68) li mnh hn trn ng t

b o ung th (HepG2).

5

Tip tc nh gi h nng c ch HDAC invitro ca cc cht c

tng hp trn dng t b o ung th gan (HepG2), i chiu v so snh kt qu

vi hai cht c ch HDAC mnh l SB (sodium butyrat) v SAHA (hnh1.4).

Hnh 1.4: K t qu c ch HDAC ca cc cht sau 8h

Cht SSR2 lc ny cho kt qu c ch HDAC tt hn so vi cht SSR1

(42,11%), cht so snh SB (52,32%) v c hot tnh gn tng ng vi

SAHA (57,89%).

T t qu nghin cu ca nhm tc gi Rhea Mohan, c th thy rng

cc hp cht ca thiazoli in-2, - ion c tim nng ln trong vic c ch

enzym HD C. Nhm thiazoli in-2, - ion ng vai tr l nhm tc ng, c

ch trung tm hot ng ca enzym.

1.1.2. Tc dng hot ha PPAR- ca TZD trong iu tr i tho ng

1.1.2.1. Tc dng ca cc dn cht TZD ln th th PPAR-

Peroxisom proliferator (PPAR) gm 3 loi: PPAR-, PPAR- v PP R-

. Trong peroxisom proliferator activate gamma (PP R-) l mt th th

mng nhn t bo, c chc nng nh nhng yu t phin m iu chnh s

biu hin ca gen. PPAR- c mt trong cc t bo ni m v cc t b o c

trn mch mu [24].

Khi c gn vi cc cht ch vn (nh cc TZD), PP R- chuyn

thnh dng hot ng. PPAR- hot ng to dimer vi receptor X

% HDAC ca HepG2 b c ch sau 8h

6

retinoid alpha (RXR-) ( c gn vi cht ch vn ni sinh 9-cis retinoic

acid) to thnh phc hp proliferator proxisom (PPRE).

Hnh 1.5: S ho ng ca th th PPAR

Phc hp ny gn vi ND l m iu ha qu trnh phin m, dch m

ca gen trong nhn t bo, lm cho kch thch d tr v s dng acid bo,

triglycerid t bo m, kch thch s dng glucose v c ch oxi ha acid bo

c, c ch s tng hp glucose gan, ngo i ra cn tng cng s oxi ha

cc LDL i thc bo, t ci thin s nhy cm vi insulin ca t bo,

gim nng glucose trong mu, gim acid bo trong mu, chng x va

ng mch v cao huyt p [8,13].

1.1.2.2. V tr ca cc dn cht TZD trong iu tr i tho ng hin nay

Thiazolidindion c dng trong iu tr i tho ng type 2 k t

cui nhng nm 1990. Tuy nhin troglitazon b rt khi th trng mt vi

nm sau o nhim c gan.Tip , nm 2010, o tng nguy c bin c

tim mch, c quan y t chu u ngh tm nh ch s dng rosiglitazon. Do

ch cn pioglitazon l thiazolidindion v n c s dng iu tr i tho

ng type 2, nhng vic s dng pioglitazon phi c kim sot cht ch

do gp mt s tc dng ph trn gan, xng, tim v c th gy ung th b ng

quang. iu ny, cng vi s pht trin ca cc chin lc iu tr c ph

7

duyt trong vi nm qua, t ra cu hi l c nn s dng thiazolidindion

(c th l pioglitazon) trong iu tr i tho ng type 2 hay khng [28]?.

V o nm 2009, Pattan Shashikant R v cng s tng hp 1 lot cc

d n cht thiazolidin-2,4-dion c cu trc nh sau [25,26]:

S

O

O

RS

NH

O

O

Hnh 1.6: Cc dn cht TZD vi tc dng h ng huy t

Cc cht n y c em th nghim trn chut bch, o nng ng

huyt trong mu cc thi im 0 gi, 1 gi, 3 gi, 6 gi, dng Glibenclamid

lm cht chun so snh. Kt qu thu c 6 cht c tc dng h ng

huyt ng .

Gn y nht, nm 2011, Mehen ale-Munj v cng s [36] tin hnh

tng hp cc d n cht 5-arylidenthiazolidin-2,4-dion, t th nghim tc

dng h ng huyt v kim sot m mu. Kt qu l c 2 d n cht (Z)-5-(2-

4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)acetyl)-2-hydroxy

benzamid (IIIa) v (Z)-2-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)-

N-(5-nitro-thiazol-2-yl)acetami (IIIb) u cho tc dng kim sot ng

huyt, cholesterol (CHL) v triglyceride (TG) trn chut c Sprague

Dawley c ch n giu m sau 14 ngy s dng.

Nh vy, c th thy rng TZD v n cn cha ng nhiu tim nng

trong iu tr i tho ng type 2.

1.1.3. Tc dng c ch PTP1B

1.1.3.1. Khi nim v tc dng ca PTP1B

Protein tyrosin phosphatase 1B (PTP1B) l mt phosphotyrosin

phosphatase, enzym thy phn nhm phosphat gn trn acid amin tyrosin.

8

PTP1B tham gia phn ng dephosphoryl ha phosphotyrosin ca enzym

kinase hot ha insulin v leptin. PTP1B lm gim thng tin d n truyn ca

th th insulin v th th leptin m m, gan, c. c ch PTP1B l m tng

nhy cm, p ng ca insulin v leptin ti th th, d n n gim nng

glucose, lipid trong mu [14,17].

V vy, c ch PTP1B s l mt chin lc hiu qu iu tr bnh

tiu ng loi II v bnh bo ph.

1.1.3.2. Tc dng c ch PTP1B ca cc dn cht TZD

Trong mt s nghin cu gn y, cc n cht TZD cn c chng

minh c tc dng c ch enzym PTP1B. Mt s d n cht ca TZD, c th l

benzyliden-2,4-thiazolidindion vi cc nhm th v tr ortho v para

c tng hp v nghin cu tc dng trn ch PTP1B [14,29]. Kt qu

tm c hai d n cht c hot tnh sinh hc mnh nht l a v b (hnh 1.7).

S

NH

O

O

O

CF3

Br

O

SO

O

CH3

a b

Hnh 1.7: Cc TZD c ch PTP1B mi c nghin c u

Th nghim invitro cho thy, cc d n cht n y ng thi c hai tc

dng: c ch enzym PTP1B v hot ha PPAR-. Hot tnh c ch PTP1B

ca b IC50 = 1.3m, cn a tc dng yu hn vi IC50 = 5m. S c mt ca

nhm sulfonyl ca hp cht b c vai tr quan trng trong vic to tng tc

vi c 2 th th PTP1B v PPAR-.

Trn invivo, a v b c tc dng nh l cht h ng huyt, ci thin

9

ng dung np glucose. Hai hp cht n y cng c ch ng s tng cn,

chng bo ph do c tc dng h triglicerid, cholesterol huyt [14].

Nghin cu ny m ra hng pht trin cc thiazolidindion mi vi tc

dng h ng huyt mnh ng thi c th ng nh nhng cht iu ha

lipid mu, chng bo ph v gim thiu cc bnh v tim mch trong tng lai.

1.2. MT S TC DNG KHC CA CC DN CHT THIAZOLIDIN-

2,4-DION

1.2.1. c tnh t bo

Nm 2010, Vijay Patil v cng s [16] tin hnh tng hp mt s d n

cht mang khung TZD (hnh 1.8).

SNH

O

O

OY

O

Y=R-NH-(1b,1c, 1d)

Y=R-(1a,1d)

Cht 1a 1b 1c 1d 1e

R

Hnh 1.8: Cc dn cht TZD theo nghin c u ca Vijay Patil

Sau th c tnh invitro trn 7 dng t b o ung th bao gm: ung

th phi (HOP62), ung th tuyn tin lit (PC3), ung th v (MCF7), ung

th gan (HEPG), ung th bch cu (K562), ung th ming (GUR V), ung th

vm hng (KB).

Kt qu nghin cu cho thy, hp cht 1e c tc dng c ch t bo ung

th mnh nht trong cc cht c tng hp. Cht ny c ch 5 trong s 7

10

dng t b o ung th c th nghim l K562, MCF7, PC3, GUARV v KB.

Cht 1c c ch c 4 trong s 7 dng t bo: K562, HOP62, PC3 v

GUARV. Hp cht 1a v 1d cng cho thy tc dng trn 3 dng t bo ung

th l MCF7, HOP62 v PC3. Ring cht 1b ch c ch c duy nht 1 dng

t bo l HOP62.

Tip , vupati v cng s [37] tng hp cc d n cht 5-aryl v th

tc dng c t bo. Cc d n cht c cng thc cu to i y:

S

NHO

OR

O

Hnh 1.9: Cc d n cht c tng hp trong nghin cu ca Avupati

Kt qu cho thy: trong cc d n cht tng hp c th hp cht ((Z)-5-

(4-((E)-3-oxo-3-(thiophen-2-yl)prop-1-enyl)benzyliden)-1,3-thiazolidin-2,4-

dion) c tc dng c t bo tt nht vi gi tr ED50 l 4.000.25g/ml.

Avupati cn phn tch mi lin quan gia cu trc v tc dng c t bo ca

cc d n cht TZD. Tc gi thy rng tc dng c ch t b o c lin quan n

nhn thiazolidin-2,4-dion v cc nhm th hc nhau l m tng cng hoc

gim bt tc dng c ch t bo, c th:

- Nhm th halogen ti v tr meta hoc para trn vng bn l m tng tc

dng c ch t bo.

- Tc dng c ch t bo b gim khi thay th phenyl bng naphatalen

hoc khi c thm nhm hot ng nh hy roxyl trn vng phenyl.

- V iu th v nht l hot ng c ch t b o tng rt mnh khi thay

th phenyl bng thiophen-2-yl (c 2 nhm carbonyl v tr , ).

Gn y nht v o thng 8 nm 2013, nhm tc gi Alegaon Shankar

cng c 1 bo co v cc d n cht TZD trn kh nng gy c tnh t bo

[12].

11

3a: Ar = 2-Cl C6H4 3f: Ar = 2-OH-5-NO2 C6H3

3b: Ar = 2,3-di-Cl C6H3 3g: Ar = 3,5-di-Br-4-OH C6H2

3c: Ar = 2-Cl-5-NO2 C6H3 3h: Ar = 4-Br-2-F C6H3

3d: Ar = 4-Cl-3-NO2 C6H3 3i: Ar = 4-Br-3-F C6H3

3e: Ar = 2,3-di-OH C6H3 3j: Ar = 2,4-di-NO2 C6H3

3k: Ar = 2-furyl 3m: Ar = 1-methylpyrol

3l: Ar = 2-thienyl

Hnh 1.10: Cc dn cht TZD theo nghin c u ca Alegaon Shankar

Cc cht n y c nh gi c tnh trn cc dng t b o ung th

ngi: ung th c t cung (HeLa), ung th i trc trng (HT-29), ung th

phi (A549), ung th v (MCF-7). Kt qu cho thy hu ht cc cht u c

kh nng chng li ung th phi ( 5 9) v ung th v (MCF-7). Cc cht 3a,

3c, 3e, 3f, 3g, 3j, 3l, v 3m cho thy tc dng ng vi IC50 nm trong

khong 40-50 M. Cc cht 3a, 3b, 3g, 3k, 3l c kh nng chng li A549

vi IC50 ln lt l 38, 37, 45, 36, 30 M.

Cc kt qu nghin cu trn phn no cho thy cc d n cht mang

khung TZD c tc dng trong vic c ch s pht trin ca cc t bo ung

th, m ra hng mi trong pht trin cc thuc iu tr ung th trong tng

lai.

1.2.2. Tc dng khng khun, khng nm

Vi hot tnh khng khun, khng nm tim nng, cc n cht ca TZD

v ang thu ht c s ch ca cc nh tng hp ha c. Mt s d n

cht ca TZD c hot tnh sinh hc tt c cc nh khoa hc cng b trn

cc tp ch quc t [21,23].

Nm 2006, M.C.Unlusoy v cng s tng hp thnh cng d n cht

ca 3-benzyl-5-(4-cloro-2-piperidin-1-yl-thiazon-5-yl-methylen)thiazol-2,4-

dion.

Cu trc ca chng nh sau:

S

N

Ar- O

O

O

OH

12

N

S

S

N

O

O

Cl

R1

R2

N

R1= H, Cl

R2=H, Br, Cl, F, NO2

Hnh 1.11: Cc dn cht 3-benzyl-5-(4-cloro-2-piperidin-1-yl-thiazon-5-yl-

methylen)thiazol-2,4-dion.

Kt qu th hot tnh sinh hc cho thy chng c tc dng kh tt trn

cc chng vi khun Gram (+): Bacillus subtillis, Staphylococus aureus v vi

khun Gram (-): E.coli [30].

Nm 2011, trong mt bo co ca nhm tc gi Aneja D.K v hot tnh

khng khun, khng nm ca 24 d n cht pyrazolyl-2,4-thiazolidindion, mt

ln na cho thy tim nng ca cc d n cht TZD [38].

NN

S

NO

O

R2

R1

O

O

4a-h: R2=C2H5

5a-h: R2=CH3

6a-h: R2=H

4-5-6 a b c d e f g h

R1 H Me OMe Cl F Br OH NO2

Hnh 1.12: Cc dn cht ca pyrazolyl-2,4-thiazolidindion

24 cht n y c em th nghim hot tnh khng nm ca 2 loi nm

l: Aspergillus niger v Aspergillus flavus. Kt qu thu c rt kh quan khi

c 24 cht u c tc dng khng nm, c bit 2 cht mnh nht 4b v 4e c

tc dng khng nm A.niger (70%) v A.flavus (67,7%). 11 cht 4d, 4e, 4g,

5a, 5h, 6a, 6b, 6d, 6e, 6f, v 6h cho thy tc dng khng nm A.flavus trn

13

60% so vi 77,7% ca Fluconazol. Cn vi kh nng hng nm A.niger, cc

cht khng trn 60% l 4b, 4d, 4e, 4h, 5c, 5d, 6a, 6b, 6d, 6e, 6f.

Th kh nng hng hun: cht 4a, 4h, 5h, c tc dng khng

Staphylococus aureus mnh nht (MIC = 6 g/mL), 2 cht 6a v 6h c tc

dng khng Bacillus subtillis (MIC = 6 g/mL).

Vi mong mun tm ra thm cc cht khng khun, khng nm khc

mang hung TZD, nm 2012, Shital L. Nawale v Avinash S. Dhae tng

hp nn 10 d n cht khc nhau ca thiazolidin-2,4-dion: A1, A2, A3, A4,

A5, B1, B2, C1, C2, D1 [23] (hnh 1.13).

SNH

O

O

OEtO

O

B1

SNH

O

O

O

OCH3

EtO

O

A1

SNH

O

O

O

EtO

O

B2

SNH

O

O

O

OCH3

NH

O

NHS

NH2A2

SNH

O

O

NHNHH N

NH NH

2

C1

SNH

O

O

O

OCH3

NH

O

NHO

NH2A3

SNH

O

O

NH

NHH2N

SC2

SNH

O

O

O

OCH3

EtO

OA4

SNH

O

O

O

Cl

D1

SNH

O

O

HO

OCH3

NHNH

S

NH2

A5

Hnh 1.13: Dy cht A1, A2, A3, A4, A5, B1, B2, C1, C2, D1

10 cht c xc nh nng c ch ti thiu trn 3 chng vi sinh vt

l Bacillus subtilis, Pseudomonas aerugenosa v Staphylococcus aureus. Cht

chun c so snh l Streptomycin. Kt qu cho thy A2, A5 l c hot

tnh khng khun mnh vi gi tr MIC i vi c 3 vi khun u l 31.25(g)

14

T nhng nghin cu trn ta thy ngy nay vi s gia tng sc

khng ca vi khun, nm th vic pht trin cc d n xut 2,4-thiazolidindion

l cn thit tm ra cc cht mi trong vic khng vi khun v nm.

Vi cc kt qu nghin cu khoa hc c cng b trn y, cho

thy tip cn cc d n cht TZD l mt hng nghin cu y tim nng

thit k cc c cht c hot tnh sinh hc trn i tho ng, ung th cng

nh khng khun, khng nm. Chng ti hy vng, kha lun s gp phn lm

phong ph hn cc n cht TZD v tm ra c nhng c cht c tc dng

sinh hc tt c th ng dng c trong lm sng.

15

CHNG 2. NGUYN LIU, THIT B, NI DUNG V

PHNG PHP NGHIN CU

2.1. NGUYN VT LIU, THIT B

2.1.1. Ha cht

Cc ha cht, dung mi dng trong qu trnh thc nghim l loi dng

trong tng hp c nhp t cng ty Merck hoc Sigma-Aldrich. Cc ha

cht ny c s dng trc tip khng qua tinh ch thm. Bao gm:

+) Benzensulfoclorid

+) 4-Clorobenzensulfoclorid

+) 4-Methylbenzensulfoclorid

+) 4-Methoxybenzensulfoclorid

+) 3-Bromopropanamin

+) 4-Hydroxybenzaldehyd

+) Acid cloroacetic

+) Thioure

+) Acid acetic bng

+) Piperazin

Cc ha cht v dung mi khc: DMF, aceton,dicloromethan, ethanol,

methanol, NaOH, HCl, nc ct, N,N-dimethylformamid.

2.1.2. Thit b, dng c

- Dng c thy tinh: bnh cu y trn ung t ch 50 ml c nt m i, sinh

hn hi lu, pipet, bnh chit, phu thy tinh, bnh chy sc k lp mng

(TLC).

- My khuy t gia nhit.

- My ct quay chn khng Buchi R-210.

- Phu lc Buchner

- Cn phn tch, cn k thut Shimazu.

16

- T lnh, t sy, my siu m.

- Bn mng silicagel Merck 70-230 mesh chy sc k lp mng.

- My o nhit nng chy nhit in (Electrothermal igital) xc

nh nhit nng chy.

- My Per in Elmer xc nh ph IR.

- My khi ph HP 5989B-MS ghi ph MS.

- My cng hng t Bruker AV-500 ghi ph 1H-NMR, 13C-NMR.

2.2. NI DUNG NGHIN CU

2.2.1. Tng hp ha hc:

Tng hp cc hp cht sau:

- N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)propyl)

benzensulfonamid (4a).

- N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)propyl)-4-

methylbenzensulfonamid (4b).


methoxy benzensulfonamid (4c).


chlorobenzensulfonamid (4d).

2.2.2. Th c t nh t o in itro nh gi s t nh ging thuc c

t s n cht tng h c

2.3. PHNG PHP NGHIN CU

2.3.1. Tng hp ha hc v ki tr tinh khit

- Nghin cu tng hp 4 cht trong mc tiu bng phng php ha

hc.

- Dng TLC theo di tin trnh ca phn ng.

- Kim tra tinh khit ca sn phm bng TLC v o nhit nng

chy.

17

2.3.2. Xc nh cu trc

Cc cht tng hp c xc nh cu trc bng cc loi ph sau: ph

hng ngoi (IR), ph hi lng (MS), ph cng hng t proton (1H-NMR),

ph cng hng t carbon (13C-NMR).

Ph hng ngoi (IR): ph hng ngoi c ghi ti Khoa Ha - Trng i

hc Khoa hc T nhin (KHTN) H Ni i hc Quc Gia H Ni, trn

my Per in Elmer vi thut vin nn KBr trong vng 4000-600cm-1. Cc

m u rn c phn tn trong KBr sy h vi t l 1:200 ri p i ng

film mng i p lc cao c ht chn hng loi b hi m.

Ph hi (MS): ph hi lng cc cht c ghi ti Khoa Ha, Trng

i hc KHTN H Ni vi ch o EI v Vin Ha hc cc hp cht thin

nhin Vin Hn lm Khoa hc v Cng ngh Vit Nam vi ch o ESI.

Ph cng hng t ht nhn (1H-NMR, 13C-NMR) c ghi trn my

Bru er V-500 ti Vin H n lm Khoa hc v Cng ngh Vit Nam ng

DMSO l m ung mi, cht chun ni l tetramethylsilan (TMS).

2.3.3. Th tc dng c t nh t o in itro

Th hot t nh hng t b o ung th (c t nh t b o) in vitro c thc

hin ti hoa Dc, Trng i hc uc gia Chungbu , Cheongju, H n

uc theo phng php MTT v gi tr IC50 c t nh trn phn mm

GraphPad Prism.

Dng t b o th nghim: t b o ung th i tr ng (SW620). Dng t

b o ung th c s dng t Ngn h ng t b o ung th ca Vin nghin cu

sinh hc v cng ngh sinh hc H n uc (KRIBB) v c nui cy trong

mi trng DMEM (Dulbecco s mo ifie ) hoc RPMI b sung 10 FBS

(huyt thanh b o thai b).

c t nh t b o ca cc cht c th bng phng php MTT theo cc

bc sau:

18

c hu n

Cc t b o pha logarit c tripsin ha v phn tn v o hn ch n

t b o trong mi trng DMEM hoc RPMI b sung 10 FBS. iu chnh

nng hong 1,5x104 n 3,5x104 t b o, sau chia u v o cc ging ca

a 96 ging, mi ging 200 L, cc a sau c 37oC trong iu in

5% CO2.

Sau 2 gi , cc m u th c chun b trong 20 L mi trng

DMEM/RPMI b sung 10 FBS t ung ch gc 10 mg/mL trong dimethyl

sulfoxid (DMSO) ri thm 2 L m u th v o cc ging nhiu nng hc

nhau. Cc a n y sau c thm 8 gi. Tt c cc m u c chun b

sau cho nng cui cng ca DMSO hng qu 0,1%.

c Tin h nh th

Sau 8 gi , thm v o mi ging 20 L thuc nhum MTT (nng

MTT 5 mg/ mL trong mui m phosphat PBS). Cc a c thm 3 gi

37oC trong iu in 5% CO2. Tip theo mi ging c cho 100 L dung

dch DMSO, 5 pht cho MTT formazan c ha tan. hp th c

c bc sng 510 nm.

Gi tr IC50 l nng ca m u th m , hp th gim i 50 so

vi nhm chng (trng m t nh l ging ch thm mi trng nui cy). Kt

qu cui cng l gi tr trung bnh ca ln o c lp vi gi tr hp th

khc nhau hng qu 5 . Gi tr IC50 c t nh a trn phn mm

GraphPa Prism. Trong phng php th n y, IC50 20 g/mL c coi l c

hot t nh.

2.3. . nh gi c ging thuc c cc n cht tng h c.

T nh gi tr logP ca cc n cht tng hp c bng phn mmEPIsuite.

uy trnh bao gm v cu trc 2D, to Smiles notation bng phn mm

Chems etch .0 ca CD labs sau a Smile notation v o phm mm

19

EPIsuite t nh cc gi tr logP.

nh gi mc ging thuc ca cc n cht a trn quy tc Lipins y

- Khi lng phn t ca cht phi nh hn 500 g/mol.

- S trung tm nhn lin t hy ro (N, O) phi nh hn 10.

- S trung tm cho lin t hy ro (NH, OH) phi nh hn 5.

- Cn bng gia t nh thn nc/ u: logP

20

CHNG 3: THC NGHIM, KT QU V BN LUN

3.1. HA HC

3.1.1. Tng hp ha hc

Qu trnh tng hp 4 cht trong kha lun n y c tin h nh theo s

3.1

OH

OCl

+NH2 NH2

S

iv

SNH

O

NH

H+

SNH

O

O

R

SCl

OO

i

R

SNH

OO

Br

R

SNH

OO

O

CHO

ii

R

SNH

OO

O

S

NH

O

Oiii

S 3.1: Quy trnh tng hp chung

Tc nhn v iu kin: i) 2-bromoethanamin, DMF, TEA, 25oC, 24h; ii) p-hydroxy

benzaldehyd, MeOH, K2CO3, 80oC, 24h; iii) thiazolidin-2,4-dion, EtOH, piperazin,

80oC, 24h; iv) HCl, H2O, 100

oC, 2h.

3.1.1.1. Tng hp thiazolidin-2,4-dion

S phn ng:

OH

OCl

+NH2 NH2

S

iv

SNH

O

NH

H+

SNH

O

O

S 3.2: Quy trnh tng hp thiazolidin-2,4-dion

Tc nhn v iu kin :iv) HCl, H2O, 100oC, 2h.

Tin hnh phn ng:

- Cho 9.45g (0.1 mol) acid monocloroacetic; 7.6g thioure (0.1 mol)

21

thioure vo bnh cu 500 ml. Thm tip 100 ml nc ct, lp sinh h n, un

hi lu bng bp in c o bc.

- Sau khi dung dch si khong 1h, rt tip 10 ml HCl 10% qua

sinh hn vo bnh cu. Tip tc hi lu thm 2h na.

- Kim tra phn ng bng TLC vi pha ng DCM:MeOH:AcOH

= 90:10:1.

X l hn h thu c:

- Rt hn hp phn ng vo cc c m, vo t lnh, s xut

hin cc tinh th.

- kt tinh lnh trong 24h.

- Lc ta qua phu lc Buchner, r a 2 ln vi 50ml nc ct

lnh.

- Ty mu: cht rn sau hi thu c, c ha tan trong 50ml

nc nng, thm 50 mg than hot, ng a thy tinh khy nng 10 pht. Lc

qua phu lc Buchner, r a 2 ln vi 10ml nc nng. Dch lc thu c

vo cc c m, vo t lnh trong 24h. Sn phm s kt tinh, mu trng nh

vng. Lc dung dch qua phu lc Buchner, r a ta 3 ln vi 10ml nc lnh.

Kt qu:

Hiu sut: 72% (8.4g).

Cm quan: tinh th mu trng .

Tonc: 124.5-126.2oC.

3.1.1.2.Tng hp (Z)-N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)

phenoxy) propyl)benzensulfonamid (4a)

tng hp cht 4a chng ti tin hnh quy trnh phn ng gm 4

giai on tng t trong s phng php chung.

a. Tng h p cht 2a

22

SCl

OO

SNH

OO

Br

NH2Br+

i

S 3.3: Quy trnh tng hp cht 2a

Tc nhn v iu kin : i) DMF, TEA, 25oC, 24h.

Tin hnh phn ng

- Cho 0.3ml d= 1.184g/ml (2mmol) benzensulfoclorid (1a), 2ml

DMF vo bnh cu dung tch 50ml, lm lnh dung dch bng nc .

- Thm 482 mg (2.2 mmol) 3-bromopropanamin hydrobromid vo

bnh cu.

- Tip tc thm t t 0.6ml TEA, lc u trong hn hp nc

sao cho mu ca dung dch hng c m ln.

- Phn ng c tin hnh trong nhit phng, kt hp khuy t,

thi gian 24h.

- Kim tra phn ng bng TLC vi pha ng DCM:MeOH = 40:1.

X l hn h thu c:

- Thm dn 10ml dung dch nc lnh, tip tc acid ha vi 10ml

dung dch HCl 5% (kim tra bng giy qu vn nng).

- Chit thu sn phm 3 ln bng dung mi dicloromethan , mi ln

5-10ml dung mi. Thu lp dung mi, lm khan bng Na2SO4. Gp dch chit

ca 3 ln.

- Ct quay thu hi dung mi bng my ct quay chn khng

40oC n hi thu c sn phm.

- Sy sn phm 60oC trong 4h.

Kt qu:

Hiu sut: 75% ( 0.41g)

Cm quan: tinh th vng

23

Tonc : 123,2-125,4oC.

b. Tng h p cht 3a

SNH

OO

BrS

NH

OO

O

CHO

ii

OH

CHO

+


Tc nhn v iu kin: ii) MeOH, Na2CO3, 80oC, 24h.

Tin hnh:

- Cn hn hp phn ng gm 240mg (2 mmol)p-hydroxyl

benzaldehyd cng 220mg K2CO3 vo trong bnh cu 50ml.

- Thm tip 10ml dung mi MeOH v gia nhit ln 80oC. Qu

trnh hot ha din ra trong vng 30-60 pht.

- Ha tan 1 mmol (0,28g) tinh th N-(3-bromopropyl)benzen

sulfonamide (2a) trong 10ml ung mi MeOH, ng pipet ht v a t t

vo dung dch c hot ha. Gi nhit 80oC, khy t, hi lu trong

khong 24h.

- Kim tra phn ng bng TLC vi pha ng DCM:MeOH=

40:1.

X l hn hp phn ng:

- Ct thu hi bt dung mi bng my ct quay nhit 40oC.

- Thm t t 20ml dung dch aci HCl 5 c lm lnh vo

hn hp phn ng, ng a thy tinh khuy u, xut hin ta mu trng

ng.

- Lc ta qua phu thy tinh, r a 3 ln vi 15ml nc ct nng

n khi dch lc trung tnh (th vi giy qu vn nng). Sy kh ta 60oC

trong khong 24h.

Kt qu:

24

Hiu sut: 60% (0.41mg).

Cm quan: tinh th trng ng.

Tonc: 188,0-190,9oC.

c.Tng h p cht 4a

SNH

OO

O

CHO

SNH

OO

O

S

NH

O

O

iiiS

NH

O

O

+


Tc nhn v iu kin: iii) EtOH, piperazin, 80oC, 24h.

Tin hnh:

- Cn 200mg cht 3a cng vi 120mg thiazolidin-2,4-dion vo

bnh cu 50ml.

- Thm tip 5ml EtOH khan v 0.12ml piperazin vo binh cu.

- Gia nhit 80oC, khuy t, lp sinh hn, hi lu trong 24h.

- Kim tra ph ng bng TLC vi pha ng DCM: MeOH:AcOH=

90:5:1.

X l hn hp phn ng:

- Ct thu hi bt dung mi bng my ct quay nhit 40oC.

- hn hp phn ng ra cc c m c sn 10ml HCl 5 c

lm lnh, to ta mu vng.

- Lc ta, r a ta bng nc lnh ti khi dch lc trung tnh.

- Sn phm c kt tinh li trong dung mi EtOH. Tinh th thu

c em sy kh 60oC trong 48 gi.

Kt qu:

Hiu sut: 91% (0.38g).

Cm quan: tinh th mu vng .

Tonc : 230,6-231,9oC

25

D liu ph c trnh by bng 3.3, 3.4, 3.5, 3.6.

3.1.1.3.Tng hp (Z)-N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)

phenoxy)propyl)-4-methylbenzenesulfonamid (4b)

a. Tng h p cht 2b

Quy trnh tin h nh tng t vi quy trnh tng hp cht 2a, i t 0.40g

(2mmol) cht 4-methylbenzen-1-sulfonyl chlorid (1b). Kt qu nh sau:

Hiu sut: 79% (0.46g).

Cm quan: tinh th mu trng nh vng

Tonc: 135,6-137,1oC.

b. Tng h p cht 3b

Cht N-(3-(4-formylphenoxy)propyl)-4-methylbenzensulfonamid (3b)

c tng hp t 0.30g (1mmol) N-(3-bromopropyl)-4-methylbenzen

sulfonamid (2b) vi p-hy roxybenzal ehy theo phng php tng t nh

tng hp cht 3a. Kt qu nh sau:

Hiu sut: 61% (0.20g).

Cm quan: tinh th mu trng .

Tonc: 199,1-201,6oC

c. Tng h p cht 4b

Cht N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)-2-methyl

phenoxy) propyl)-4-methylbenzensulfonamid (4b) c tng hp t 0.32g

(1mmol) cht N-(3-(4-formylphenoxy)propyl)-4-methylbenzensulfonamid

(3b). Qu trnh tng hp tng t nh tng hp cht 4a. Kt qu nh sau:

Hiu sut: 90% (0.38g).

Cm quan: tinh th mu vng.

Tonc : 250,6-251,3 oC.


3.1.1.4. Tng hp (Z)-N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)

26

phenoxy)propyl)-4-methoxylbenzensulfonamid (4c)

a. Tng h p cht 2c


(2mmol) cht 4-methoxybenzen-1-sulfonylchlorid (1c). Kt qu nh sau:

Hiu sut: 81% (0.49g).


Tonc : 140,1-142,7 oC.

b. Tng h p cht 3c

Cht N-(3-(3-formylphenoxy)propyl)-4-methoxybenzensulfonamid (3c)

c tng hp t 0.31g (1mmol) N-(3-bromopropyl)-4-methoxybenzen

sulfonamid (2b) v p-hy roxybenzal ehy . Phng php tng hp tng t

nh vi cht 3a. Kt qu nh sau:

Hiu sut: 62% (0.21g).

Cm quan: tinh th mu trng ng.

Tonc : 205,6-207,8oC

c. Tng h p cht 4c

Cht(Z)-N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)

propyl)-4-methoxybenzensulfonamid (4c) c tng hp t 0.34g (1mmol)

cht N-(3-(4-formylphenoxy)propyl)-4-methoxybenzensulfonamid (3c) v

thiazolidin-2,4-dion. Quy trnh tng hp tng t nh vi cht 4a. Kt qu

nh sau:

Hiu sut: 89% (0.39g).

Cm quan: tinh th mu vng nht.

Tonc: 260,6-261,7oC


3.1.1.5. Tng hp (Z)-N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)

phenoxy) propyl)-4-clorobenzensulfonamid (4d)

27

a. Tng h p cht 2d


(2mmol) cht 4-clorobenzen-1-sulfonylchlorid (1d). Kt qu nh sau:

Hiu sut: 70% (0.43g).


Tonc: 143,5-145,7oC.

b. Tng h p cht 3d

Qu trnh tng hp cht N-(3-(4-formylphenoxy)propyl)-4-cloro-

benzensulfonamid (3d) i t 0.31g (1mmol) cht N-(3-bromopropyl)-4-

chlorobenzensulfonamid (2d) cng vi 4-hydroxy benzaldehyd. Qu trnh

tng hp tng t nh vi cht 3a. Kt qu nh sau:

Hiu sut: 59% (0.2g).

Cm quan: tinh th mu vng nht.

Tonc: 202,5-203,9oC.

c. Tng h p cht 4d

Cht N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)propyl) -

4-cloro-benzensulfonamid (4d) c tng hp t 0.34g (1mmol) cht N-(3-

(4-formylphenoxy)propyl)-4-clorobenzensulfonamid (3d) v thiazolidin-2,4-

dion. Qu trnh tng hp din ra tng t nh tng hp cht 4a. Kt qu nh

sau:

Hiu sut: 88% (0.39g).

Cm quan: tinh th m u v ng m.

Tonc: 232,7-233,6oC.


Di y l bng tng hp cc ch s l ha v hiu sut tng hp ca

cc cht 4a-d:

28

Bng 3.1: Hiu sut v cc ch s ha l ca cc sn phm c tng h p

R

SNH

OO

O

S

NH

O

O

CHT R MU SC HIU SUT(%)

4a H Vng xn 91

4b 4-CH3 Vng nht 90

4c 4-OCH3 Vng nht 89

4d 4Cl V ng m 88

3.1.2. Ki tr tinh khit

tinh khit ca cc cht 4a-4b-4c-4d c kim tra bng sc k TLC

v o nhit nng chy (Tonc) ca chng.

Sc k lp mng (TLC): c tin hnh trn bn mng nhm trng silicagel

Merck 70-230 mesh, quan st vt sc i n t ngoi bc sng 254 nm.

Dung mi ha tan cc cht l aceton. Kt qu thu c trn sc u cho

thy mt vt gn, r hi soi i nh sng n t ngoi.

o n i nng chy: cc cht sau hi c tinh ch bng cch kt tinh

li u c dng tinh th rn c o im nng chy bng my o nhit

nng chy nhit in (Electrothermal digital). Nhit nng chy ca cc

cht dao dng trong khong 1-2oC.

Nh vy t kt qu chy sc k lp mng v o nhit nng chy ca 4

d n cht 4a-d, chng ti khng nh cc cht tng hp c l tinh khit v

c th s dng o ph IR, MS, 1H-NMR, 13C-NMR

29

Bng 3.2: Gi tr Rf v tonc ca cc sn phm cui 4a-4d

Cht R Ph ng Rf To

nc(oC)

4a H DCM:MeOH= 9:1 0.40 230,6-231,9

4b 4-CH3 DCM:MeOH= 9:1 0.40 250,6-251,3

4c 4-CH3O DCM:MeOH= 9:1 0.39 260,6-261,7

4d 4-Cl DCM:MeOH= 9:1 0.41 232,7-233,6

3.1.3. Xc nh cu trc

khng nh cu trc ca cc cht tng hp c chng ti tin hnh

ghi ph khi lng (MS) ca d n cht aldehyd trung gian v ghi ph hng

ngoi (IR), ph khi lng (MS), ph cng hng t proton (1H-NMR), ph

cng hng t carbon (13C-NMR) ca cc sn phm cui. Kt qu ph ca

cc cht c trnh by c th phn phn tch ph v ph lc.

Kt qu phn tch ph cc sn phm cui 4a-d:

a) Ph hng ngoi IR

Bng 3.3: Kt qu phn tch ph hng ngoi ca cc cht 4a-d

R

SNH

OO

O

S

NH

O

O

CHT R S sng (cm-1) ng vi cc o ng

C-O C=C(Ar) C=O C-H(Ar) CH(alken) NH

4a H 1264 1604

1569;1514

1742

1694 2937 3243 3519

4b 4-CH3 1266 1594

1568;1513

1735

1691 3121 3291 3445

4c 4-OCH3 1269 1569

1588;1566

1736

1690 3970 3121 3293

30

4d 4-Cl 1254 1596

1571;1510

1741

1695 3036 3274 3446

Ghi ch: l dao ng ha tr

Nhn xt: T d liu ph IR bng 3.4 v ph (ph lc 5-8) cho thy

cc cht u c s sng c trng vi cc ao ng ca cc nhm lin kt.

Trong c nh hp th c trng ca nhm C=O v nhm NH ca d vng

ami , nh hp th ca nhm ete C-O-C, nh hp th ca C-H benzen v

nh hp th ca C-H alken, cho thy sn phm c cu trc ph hp vi cng

thc cu to d kin.

b ) Ph MS

Bng 3.4: Kt qu phn tch ph khi lng ca cc cht sn phm cui

R

SNH

OO

O

S

NH

O

O

CHT R KLPT m/z

4a H 418 417,15[M-H]-

4b 4-CH3 432 430,5 [M-H]-

4c 4-OCH3 448 446,6 [M-H]-

4d 4-Cl 452 450,5 [M-H]-

Nhn xt: Qua kt qu phn tch ph bng 3.4 v ph ca 4 cht

4a-d (ph lc 1- 4), chng ti thy trn tt c cc ph u c pc phn t

c s khi ng bng s khi d kin ca cht tng ng vi cng mnh.

Ph t c pc phn mnh, cc pc phn mnh c cng nh. V vy c

th khng nh ph l ph hp vi cng thc ca 4 cht d kin 4a-d.

c) Ph cng hng t ht nhn 1H (

1H-NMR)

31

Bng 3.5: Kt qu phn tch ph 1H-NMR ca cc sn phm cui

R

SNH

OO

O

S

NH

O

O

6

23

45

1

1'

2'3'

4'

5'

6'

7'8'

9'

10'

STT CTCT S liu phn tch ph 1H-NMR

4a R= H

1H-NMR (500MHz, DMSO, ppm): 1,829 (2H, m, CH2);

2,92 (2H, t, J = 7.5Hz, CH2); 4,010 (2H, t, J = 6.0 Hz,

CH2) ; 7,01 (2H, d, J = 8.5Hz, H-2 ,6 ); 7,515 (2H, d, J =

9.0Hz, H-3 ,5 ); 7,572 (2H, t, J = 7.5Hz, H-3,5); 7,632

(1H, t, J = 1.0Hz, H-4) ; 7,696 (1H, s, H-7 ); 7,730 (1H, s,

NH); 7,797 (2H, t, J = 7.5Hz, H-2,6); 12,500 (1H, s, NH)

4b R= CH3

1H-NMR (500MHz, DMSO, ppm): 1,827 (2H, m,

CH2) ; 2,341 (3H, s, CH3); 2,900 (2H, t, J = 6.5 Hz , CH2)

; 3,988 (2H, t, J = 6.0Hz, CH2); 6,995 (2H, t, J = 9Hz, H-

2 ,6 ); 7,3 6 (2H, d, J = 8Hz, H-3 ,5 ); 7,513 (2H, d, J =

9Hz, H-3,5); 7,610 (1H, s, H-7 ); 7,666 (2H, d, J = 8Hz,

H-2,6); 7,729 (1H, s, NH).

4c R=OCH3

1H-NMR (500MHz, DMSO, ppm): 1,822(2H, m, CH2);

2,886 (2H, t, J = 6.5Hz, CH2); 3,799 (3H, s, CH3); 4,016

(2H, t, J = 6Hz, CH2); 6,997 (2H, d, J = 4Hz, H-2 ,6 );

7,059-7,077 (2H, m, H-3,5); 7,523 (2H, d, J = 5.5Hz, H-

3 ,5 ); 7,5 3 (1H, s, H-7 ) ; 7,705 (1H, s, NH); 7,726 (2H,

d, J = 3Hz, H-2,6).

32

STT CTCT S liu phn tch ph 1H-NMR

4d R= Cl

1H-NMR (500MHz, DMSO, ppm): 1,829 (2H, m, CH2);

2,94 (2H, t, J = 6Hz, CH2); 3,991 (2H, t, J = 6Hz, CH2);

6,994 (2H, d, J = 8.5Hz, H-2 ,6 ); 7,512 (2H, d, J = 8.5Hz,

H-3 ,5 ); 7,616 (2H, d, J = 8Hz, H-3,5); 7,723 (1H, s, H-

7 ); 7,786 (2H, d, J = 8.5 Hz, H-2,6); 7,819 (1H, s, H-NH).

Ghi ch: : chuyn dch ha hc (ppm); s: singlet; d: doublet; t: triplet;

m: multiplet a vch.

Nhn t: T ph 1H-NMR ca cc cht tng hp c c th thy s

lng proton, dch chuyn, bi tn hiu l ph hp vi cng thc cu

to d kin ca c 4 cht 4a-d. Cc ph u c tn hiu proton ca nhm NH,

proton ca 2 vng benzen nm trong vng dch chuyn t 7,0-8,0 ppm v 4

proton ca cu ni nm trong vng dch chuyn t 1,0-4,0 ppm. Tn hiu ca

proton nhm NH trong vng thiazolidin xut hin dng vch n trn ph

ca cht 4a, nhng ph ca cht 4b-d khng c tn hiu ny. C th do

proton ca nhm NH linh ng d b trao i nn cho tn hiu rt yu hoc

khng cho tn hiu trn ph . Cc d n cht c nhm th methyl v methoxy

u xut hin tn hiu proton c trng.

d) Ph cng hng t ht nhn 13

C (13

C-NMR)

Bng 3.6: Kt qu phn tch ph 13C-NMR ca cc sn phm cui

R

SNH

OO

O

S

NH

O

O

6

23

45

1

1'

2'3'

4'

5'

6'

7'8'

9'

10'

STT Cng thc

cu to

S liu phn tch ph 13

C-NMR

33

4a R= H

13C-NMR (125MHz, DMSO, ppm): 167,903 (C-

10 ); 167,377 (C-9 ); 160,150 (C-8 ); 1 0,37 (C-

1 ); 132,326 (C-1) ; 132,000 (C-2, C-6); 131,812

(C-4); 129,182 (C-3, C-5); 126,405 (C-3 , C-5 );

125,461 (C-4 ); 120,266 (C-7

); 115,291 (C-2 , C-

6 ); 6 ,945 (CH2); 39,499 (CH2); 28,700 (CH2).

4b R= CH3


10 ); 167, 53 (C-9 ); 160,149 (C-8 ); 1 2,551 (C-

1 ); 137,512 (C-1);131,990 (C-2, C-6); 131,779

(C-4); 129.585 (C-3, C-5); 126.476 (C-3 , C-5 );

125,456 (C- ); 120,302 (C-7 ); 115,277 (C-2 , C-

6 ); 6 ,920 (CH2); 39,333 (CH2); 28,653 (CH2),

20,918 (CH3).

4c R= OCH3


10 ); 167, 22 (C-9 ); 162,052 (C-8 ); 160,155 (C-

1 ); 131,986 (C-2, C-6); 131,782 (C-1); 128,595

(C-3, C-5); 125,447 (C-4); 120,268 (C-4 ); 115,265

(C-3 , C-5

); 114,831 (C-7

); 114,274 (C-2

, C-6

);

64,941 (CH2); 55,544 (CH2); 39,500 (CH2);

28,623 (CH3).

4d R= Cl


10 ); 167,561 (C-9 ); 160,07 (C-8 ); 139,261 (C-

1 ); 137,220 (C-1) ; 131,971 (C-2, C-6); 131,691

(C-4); 129,295 (C-3, C-5) ; 128,365 (C-3 , C-5

);

125,499 (C-4 ); 120,410 (C-7

); 115,234 (C-2

, C-

6 ); 64,793 (CH2); 39,497 (CH2); 28,621 (CH2).

Ghi ch: : chuyn dch ha hc (ppm).

34

Nhn xt: Qua kt qu phn tch ph bng 3.6 v ph cc cht

phn ph lc (ph lc 21-32) chng ti nhn thy :

S lng carbon, dch chuyn ha hc ca cc pic l ph hp vi

cng thc cu to d kin. Tt c cc cht u c 2 pic ca nhm C=O, 6 pic

ca vng benzen v 3 pic ca nhm CH2. D n cht methyl v methoxy u

xut hin pic ring bit ca nhm th.

Nh vy kt hp vi ph IR, MS, 1H-NMR c th khng nh cc cht

chng ti tng hp c cng thc cu to ng nh kin. Trn c s cc

cht ny tip tc c em i th hot tnh sinh hc.

3.2. TH HOT TNH SINH HC

Cc cht 4a-4d c tin h nh th tc ng in vitro trn ng t b o

ung th i tr ng (S 620) ti hoa Dc, Trng i hc uc gia

Chungbuk Cheongju, H n uc theo phng php MTT v gi tr IC50 c

t nh trn phn mm GraphPa Prism. Kt qu c trnh b y bng 3.7.

Bng 3.7: Tc ng hng t b o ung th i tr ng (SW620)

R

SNH

OO

O

S

NH

O

O

CHT R c tnh t bo IC50(g/ml) 4a H >30

4b 4-CH3 >30

4c 4-OCH3 >30

4d 4-Cl 10,89 hi ch : IC50: nn (g/m in a o n

Nhn xt: Ch c cht 4d c tc dng c ch pht trin t b o ung th,

gi tr IC50 =10,89 g/mL. Cc cht cn li khng c tc dng c ch pht

trin t b o ung th.

3.3. BN LUN

35

3.3.1. Tng hp ha hc

* Vi phn ng tng hp thiazolidin-2,4-dion:

- Phn ng xy ra d dng v hiu sut cao.

* Vi phn ng tng hp cc cht 2a-d:

- Phn ng gia d n xut benzensulfoclorid v amin bc 1 xy ra theo

c ch SN2 :

Hnh 3.1: phn ng tng h p cc cht 2a-d

- Xc tc phn ng n y thng l cc amin bc 3 nh triethylamin

(TEA), pyridin, quinolin, 4-dimethylaminopyridin. Qua qu trnh thc

nghim, TE c la chn lm xc tc. TEA c tc dng hp th HCl

sinh ra trong qu trnh (trnh cho phn ng chy theo chiu ngc li). Lng

TEA tha c loi i bng dung dch HCl long. Cn ch l phn ng din

ra nhit thng, khi nh TEA phi nh t t v va (0,6ml) vo hn

hp ngm trong nc , phn ng khng sinh nhit v mi trng phn

ng khng qu base, khng to ra cc sn phm khng mong mun trong qu

trnh phn ng.

- Tc nhn acyl ha dng trong phn ng ny l cc sulfonyl clorid, cht

ny d b phn hy bi nc nn phn ng phi c tin hnh trong mi

trng han nc (s dng dung mi DMF khan, cc dng c v ha cht

u phi c sy h trc khi tin hnh phn ng).

- Trong 2 thnh phn chnh tham gia phn ng, thc t thng ng

2-bromoethanamin do tc nhn ny d loi b bng dung dch HCl.

* Vi phn ng tng hp cc cht 3a-d:

36

- Phn ng th gia d n xut halogen v mt tc nhn base c cp in

t t o hay gi u electron nh cc alcol, phenol hay ester cng theo c ch

SN2 .

Hnh 3.2: phn ng tng h p cc cht 3a-d

- S ng K2CO3 chuyn nhm phenol th nh phenolat, nhm tng h

nng phn ng vi cc d n xut brom trong dy. p-hydroxybenzaldehyd c

ha tan trong ung mi l methanol sau thm K2CO3 ng bt, gia nhit

v huy trn trong 30-60 pht nhm hot ha al ehy . Giai on ny rt

quan trng v nu hot ha khng tt adehyd s khng phn ng sinh ra

sn phm.

- Bn cnh , trong qu trnh thc hin cc phn ng to dy cht 3a-d,

i hi cn -hydroxybenzaldehyd v cn phi loi b cht ny trong qu

trnh tinh ch (ha tan ta vi dung mi DCM, lc vi nc NaHCO3 bo ha

ha tan benzal ehy , sau chit ly phn dung mi v tin hnh ging

phn x l). Do trong cng thc ca 4-hydroxybenzaldehyd cn cha nhm

cbonyl nn nu cn cht ny, s c th xy ra phn ng ngng t aldol

vi thiazolidin-2,4-dion trong phn ng tip theo to dy cht 4a-d, nn nh

hng n s tinh khit ca cc sn phm cui. V vy cn cho 4-hydroxy

benzaldehyd vi lng va trnh phn ng ph giai on tip theo.

* Vi cc phn ng tng hp cc cht 4a-d:

- y l phn ng ngng t aldol gia cc aldehyd vi nhm methylen

ca vng thiazoldidin-2,4- ion, c tin h nh trong mi trng ethanol vi

37

xc tc l piperazin. Vng thiazolidin-2,4- ion c hai nhm carbonyl ht in

mnh cng thm xc tc piperazin c t nh base o l m tng h nng phn

ng ca nhm methylen v tr s 5. Phn ng ngng t cho hiu sut cao

(trung bnh xp x 90%).

- C ch phn ng xy ra theo hai giai on:

+ Giai on cng hp: (xem hnh 3.3) nhm methylen v tr s 5 c

cc hy ro linh ng c th ng tch hi nguyn t cacbon hi c mt

xc tc base, y s dng xc tc l piperazin hnh th nh tc nhn i nhn

mnh. Anion va hnh th nh tn cng v o cacbon mang in t ch ng ca

nhm cacbonyl trong al ehy to th nh sn phm cng hp. Giai on din ra

theo s :

Hnh 3.3: Giai on cng h p

+ Giai on ngng t: (xem hnh 3. ) i tc ng ca proton, mt

phn t nc c loi ra to th nh lin t i, qu trnh xy ra ng o

sn phm to th nh c mc nng lng thp nh h ni i lin hp. Giai

on din ra theo s sau:

38

Hnh 3.4: Giai on n n

3.3.2. Tc dng sinh hc

nh gi mc ging thuc theo 5 quy tc Lipinsky c trnh by

trong bng 3.8.

Bng 3.8: nh gi mc ging thuc theo quy tc Lipinsky

R

SNH

OO

O

S

NH

O

O

CHT R logP MW S NH, OH S N,O

4a H 2,81 418 2 7

4b 4-CH3 3,36 432 2 7

4c 4-OCH3 2,89 448 2 7

4d 4-Cl 3,46 452 2 7

Nhn xt: Tt c cc cht u tha mn c 5 yu cu ca quy tc

Lipinsky v ging thuc.

Gi tr IC50 cao i vi ba cht 4a, 4b v 4c (IC50>30 g/mL) nn 3 cht

ny khng c hot tnh, cht 4d cho gi tr IC50 =10,89 g/ mL, gi tr ny

mc trung bnh. So snh vi cht c nhm th 4-Cl cng b trc y

39

trong lun vn thc s c hc ca Lm Th Ha th 4d cng c c tnh trn

dng t b o S 620 cao hn (IC50 = 10,89 g/mL vi 12,3 g/mL). Tuy

nhin, khi so snh vi cht c nhm th 2-Cl v 3-Cl, th c tnh li thp

hn. C th nhn thy n xut ca nhm th clo cho hot t nh tt hn cc

n cht hng c nhm th.

40

KT LUN V KIN NGH

1. KT LUN

T cc kt qu nghin cu trnh b y c th rt ra 1 s kt lun sau

1.1. V tng hp v khng nh cu trc

tng hp c cc cht nh in, cc cht u cha c cng

b trong bt t i liu n o, bao gm:

- N-(3-(4-((2,4-dioxothiazolidin-5-yliden)methyl)phenoxy)propyl)

benzensulfonamid


methyl benzensulfonamid.


methoxy benzensulfonamid.


clorobenzensulfonamid.

* Cu trc ca cc sn phm c xc nh bng cch phn tch cc

ph MS, IR, 1H-NMR,

13C-NMR.

1.2. V hot tnh sinh hc

Bc u th c hot t nh c ch t b o ung th i tr ng ca cc

cht tng hp c. Kt qu cho thy:

- Tc ng c ch t b o ung th: ch c cht 4d th hin tc ng c

ch ng t b o ung th S 620, 3 cht cn li khng c hot tnh.

2. KIN NGH

- Tin hnh th hot tnh khng t b o ung th in vitro ca cc cht

tng hp c trn cc dng t b o ung th hc nh: MCF-7: ung th v,

PC3: ung th tuyn tin lit, sPC: ung th tuyn ty, tm ra cht c tc dng

mnh l m c s cho vic th tc dng in vivo.

- Tin h nh th hot t nh ca cc cht tng hp c trn mt s ch

41

tc ng hc c p ng vi nhm thiazoli in-2, - ion c a ra trong

cc nghin cu: HDAC, PPAR-, PTP1B.

- Tin h nh tng hp cc n cht thiazoli in-2,4-dion vi cc nhm th

hc nhau, c th thay Cl bng Br, I, F hoc thay i v tr ca nhm th Cl.

TI LIU THAM KHO

Ting Vit

1. Trn Mnh Bnh, uang t (2007), Ha h p I, NXB Y hc.

2. Nguyn Hi Nam (2011), Lin quan cu trc v tc dng sinh hc, Ti liu

a i hc, i hc Dc H Ni.

3. V Th Thanh Tm (2013), Tng hp mt s aci hy roxamic hng c

ch histondeacetylase, Kha lun tt nghi c s, Th vin i hc Dc

H Ni, H Ni.

4. Lm Th Ha (2013), Nghin cu tng hp v th tc dng sinh hc ca 1

s d n cht thiazolidindion, Lun vn d c hc, Th vin i hc

Dc H Ni,H Ni.

5. Phm Khnh Phong Lan (2007), n q an x nh

cu trc h p cht h , Quyn 1, Ti liu sau i hc, i hc y c

thnh ph H Ch Minh.

6. Phm Khnh Phong Lan(2007), n q an x nh

cu trc h p cht h , Quyn 2, Ti liu sau i hc, i hc y c

thnh ph H Ch Minh.

7. PGS.TS Trn T An (2007), Ha phn tch tp 1, NXB Y hc.

Ting Anh

8. Chan ra V., (2008), Structure of the intact PP R-gamma-RXR-nuclear

receptor complex on ND, National Institutes of Health, 456(7220), 350-

356.

9. Blanquicett C., Roman J., Hart C.M. (2008), "Thiazolidinediones as anti-

cancer agents", Cancer therapy, 6(A), 25.

10. Cress W.D., Seto E. (2000), "Histone deacetylases, transcriptional control,

and cancer", Journal of cellular physiology, 184(1), 1-16.

11. Faine A.L. et al, (2011), "Anti-inflammatory and antioxidant properties of

a new aryliden-thiazolidinedione in macrophages", Current medicinal

chemistry, 18(22), 3351-3360.

12. Alegaon S.G., Alagawadi K.R. (2013), " Synthesis, characterization, and

biological evaluation of thiazolidine-2,4-dione derivatives ", Medicinal

Chemistry Research, 987-994.

13. Lee H., et al., (2005), Epitope analysis of PP R gamma monoclonal

antibo y Pg 8.3 an its application for screening PP R gamma ligan s,

Journal of Immunological Methods, 296, 125-134

14. Bhattarai B.R et al, (2009), "Thiazolidinedione derivatives as PTP1B

inhibitors with antihyperglycemic and antiobesity effects", Bioorganic &

medicinal chemistry letters, 19(21), 6161-6165.

15. Bieliauskas A.V, Weerasinghe Sujith VW, Pflum Mary Kay H (2007),

"Structural requirements of HDAC inhibitors: SAHA analogs functionalized

adjacent to the hydroxamic acid", Bioorganic & medicinal chemistry letters,

17(8), 2216-2219.

16. Patil V. et al, (2010), "Synthesis and primary cytotoxicity evaluation of

new 5-benzyliden-2, 4-thiazolidinedione derivatives", European journal of

medicinal chemistry, 45(10), 4539-4544.

17. Seely B.L. et al, (1996), "Protein tyrosine phosphatase 1B interacts with

the activated insulin receptor", Diabetes, 45(10), 1379-1385.

18. Shul'gina MV. et al, (1996), "Mechanisms of the antibacterial activity of

some thiazolidinedione derivatives", Pharmaceutical Chemistry Journal,

30(6), 355-358.

19. Johnstone R.W. (2002), "Histone-deacetylase inhibitors: novel drugs for

the treatment of cancer", Nature Reviews Drug Discovery, 1(4), 287-299.

20. Jung M. (2001), "Inhibitors of histone deacetylase as new anticancer

agents", Current medicinal chemistry, 8(12), pp, 1505-1511.

21. McIntyre R.S. et al., (2007), "Thiazolidinediones: From antioxidant to

neurotherapeutic?", Medical hypotheses, 69(4), 773-777.

22. Mohan R. et al., (2012), "Design, synthesis, and biological evaluation of

novel 2, 4-thiazolidinedione derivatives as histone deacetylase inhibitors

targeting liver cancer ell line", Medicinal Chemistry Research, 21(7), 1156-

1165

23. Shital L. Nawale and Avinash S. Dhake (2012)," Synthesis and

evaluation of novel thiazolidinedione derivatives for antibacterial activity",

Der Pharma Chemica, 4(6),2270-2277.

24. Schoonjans Kristina, Staels Bart, Auwerx Johan (1996), "Role of the

peroxisome proliferator-activated receptor (PPAR) in mediating the effects of

fibrates and fatty acids on gene expression", Journal of lipid research, 37(5),

pp. 907-925.

25. Pattan Shashikant R, Kekare Prajact, NS Dighe, SB Bhawar, Nikalje Ana,

Pati Ashwini and MB Hole (2009)," Synthesis and Evaluation of Some New

Thiazolidinedione Derivatives for Their Antidiabetic Activities ",Asian J.

Research Chem,123-126.

26. Pattana Shashikant R, Kekareb Prajact, Ashwini Patilc, Ana Nikaljec, BS

Kitturd (2009)," Studies on the Synthesis of Novel 2,4-Thiazolidinedione

Derivatives with Antidiabetic Activity" Iranian Journal of Pharmaceutical

Sciences, 5(4): 225-230

27. Bashir A. Bhat,Shashikanth Ponnala, Devi Prasad Sahu, Priti Tiwari,

Brajendra K.Tripathi and Arvind K.Srivastava (2004),"Synthesis and

antihyperglycemic activity profiles of novel thiazolidinedione derivatives",

Bioorganic & Medicinal Chemistry, 58575864.

28. A. Consoli & G. Formoso (2013), "Do thiazolidinediones still have a role

in treatment of type 2 diabetes mellitus?" Diabetes, Obesity and Metabolism,

967977.

29. Bharat Raj Bhattarai, Bhooshan Kafle, Ji-Sun Hwang, Seung Wook Ham,

Keun-Hyeung Lee, Hwangseo Park, Inn-Oc Han, Hyeongjin Cho (2010),

"Novel thiazolidinedione derivatives with anti-obesity effects: Dual action as

PTP1B inhibitors and PPAR-c activators", Bioorganic & Medicinal

Chemistry Letters, 67586763

30. M.C.nsoy, O.B, Dndar, N.Atlantar, R.Ertan(2006), "Synthesis and

Antimicrobial Activity of some new 3-substituted benzyl-5-(4-cloro-2-

piperidin-1-yl-thiazole-5-yl-methylene)thiazolidin-2,4-dion Derivaties ",

Turk, J.Chem, (30), 355-360.

31. Nam N.H. et al. (2011), "Benzothiazole -containing hydroxamic acids as

histone deacetylase inhibitors and antitumor agents", Bioorganic & Medicinal

Chemistry Letters, 21(24), pp. 75097512.

32. Nam N.H., et al., (2011), Novel Hy roxamic aci s having histone

deacetylase inhibiting activity and pharmaceutical composition for

treating cancer comprising the same as active ingre ient, Korean patent No

10-2011-0050864.

33. Kim D., et al., (2003), Synthesis an biological evaluation of 3-(4-

substitutedphenyl)-N-hydroxy-2-propenamides, a new chass of histone

deacetylse inhibitors, J.Med.Chem., 46, p. 4745-5751.

34. n rianov V., et al., (2009), Novel ami e erivatives as inhibitors

of histone deacetylase: Design, synthesis and S R, European Journal

of Medicinal Chemistry, 44(3), p. 1067-1085.

35. Dow G.S., et al., (2008), ntimalarial activity of phenylthiazol-

bearing hydroxamate-base histone eacetylase inhibitors, Antimicrobial

agents and chemotherapy, 52, p. 3467-3477.

36. Mehen ale M., et al., (2012), Synthesis an evaluation of the

hypoglycemic and hypolipidemic activity of 5-benzylidene-2,4-

thiazolidinedione analogs in a type 2 iabetes mo el, Med Chem Res,20,

642-647.

37. Avupati V.R et al,(2012), Sythesis, characterization an biological

evaluation of some novel 2,4-thiazolidindions as potential cyttoxic,

antimicrobial ans antihyperglycemic agents, Bioorganic and Medicinal

Chemistry Letters, 22, 6442-450.

38. Deepak K Aneja et al, (2011), Synthesis of new pyrazolyl-2,4-thiazolidin

iones as antibacterial an antifungal agent, Organic and Medicinal

Chemistry Letters, 1-15

PH LC

Ph lc 1: Ph khi lng ca cht 4a

Ph lc 2: Ph khi lng ca cht 4b

Ph lc 3: Ph khi lng ca cht 4c

Ph lc 4: Ph khi lng ca cht 4d

Ph lc 5: Ph hng ngoi ca cht 4a

Ph lc 6: Ph hng ngoi ca cht 4b

Ph lc 7: Ph hng ngoi ca cht 4c

Ph lc 8: Ph hng ngoi ca cht 4d

Ph lc 9: Ph H1-NMR ca cht 4a

Ph lc 10: Ph H1-NMR m rng ca cht 4a


Ph lc 12: Ph H1-NMR ca cht 4b

Ph lc 13: Ph H1-NMR m rng ca cht 4b


Ph lc 15: Ph H1-NMR ca cht 4c

Ph lc 16: Ph H1-NMR m rng ca cht 4c


Ph lc 18: Ph H1-NMR ca cht 4d

Ph lc 19: Ph H1-NMR m rng ca cht 4d


Ph lc 21: Ph C13-NMR ca cht 4a

Ph lc 22: Ph C13-NMR m rng ca cht 4a


Ph lc 24: Ph C13

-NMR ca cht 4b

Ph lc 25: Ph C13

-NMR m rng ca cht 4b

Ph lc 26: Ph C13


Ph lc 27: Ph C13

-NMR ca cht 4c

Ph lc 28: Ph C13

-NMR m rng ca cht 4c

Ph lc 29: Ph C13-NMR m rng ca cht 4c

Ph lc 30: Ph C13-NMR ca cht 4d

Ph lc 31: Ph C13-NMR m rng ca cht 4d


Ph lc 1: Ph khi lng ca cht 4a

C:\LTQ Orbitrap\...\Dung_2_120824160948 8/31/2012 3:00:11 PM Dung_2.4a

Dung_2_120824160948 #1511 RT: 9.34 AV: 1 NL: 3.42E4

T: ITMS - c ESI Full ms [50.00-800.00]

50 100 150 200 250 300 350 400 450

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Rela

tive A

bundance

417.1546

149.1159 346.2292

325.3794

167.1257 311.3499285.1730183.1214

358.269991.0456 257.1882108.1116 447.2584229.200764.9858 205.3339

SNH

OO

O

S

NH

O

O

Ph lc 2: Ph khi lng ca cht 4b

SNH

OO

O

S

NH

O

O

CH3

Ph lc 3: Ph khi lng ca cht 4c

SNH

OO

O

S

NH

O

O

OCH3

Ph lc 4: Ph khi lng ca cht 4d

SNH

OO

O

S

NH

O

O

Cl

Ph lc 5: Ph hng ngoi ca cht 4a

Ten may: GX-PerkinElmer-USA Resolution: 4cm-1

BO MON HOA VAT LIEU-KHOA HOA-TRUONG DHKHTN

Nguoi do: Phan Thi Tuyet MaiTen mau:12aDate: 10/15/2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

0.0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100.0

cm-1

%T

3519

3243

2937

1742

1694

1604

1569

1514

1479

1447

1424

1399

1321

1308

1264

1181

1157

1092

1071

1050

1014

944

901

824

744

724

689

644

607

589

563

533

405

SNH

OO

O

S

NH

O

O

Ph lc 6: Ph hng ngoi ca cht 4b



Nguoi do: Phan Thi Tuyet MaiTen mau: 12dDate: 10/15/2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

0.0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

97.7

cm-1

%T

3445

3291

3121

2970

2875

2788

1735

1691

1594

1568

1513

1464

1425

1332

1266

1225

1182

1156

1124

1092

1078

1024

972

910

836

824

814

691

662

642

608

576

541

490

SNH

OO

O

S

NH

O

O

CH3

Ph lc 7: Ph hng ngoi ca cht 4c



Nguoi do: Phan Thi Tuyet MaiTen mau: 12eDate: 10/15/2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

0.0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

97.3

cm-1

%T

3293

3121

2970

2941

2839

2794

1763

1736

1690

1596

1588

1566

1514

1496

1460

1426

1334

1314

1300

1269

1261

1230

1183

1154

1109

1098

1079

1020

972

908

856

837

817

718

691

666

641

608

580

556

540532

491

SNH

OO

O

S

NH

O

O

OCH3

Ph lc 8: Ph hng ngoi ca cht 4d



Nguoi do: Phan Thi Tuyet MaiTen mau:12bDate: 10/15/2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

0.0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

97.0

cm-1

%T

3446

3274

3141

3036

2929

2768

1741

1695

1596

1571

1510

1474

1421

1394

1328

1254

1227

1180

1156

1091

1068

1013

968

904

826

755

705

688

640

618

608

568

541

532

483

SNH

OO

O

S

NH

O

O

Cl

Ph lc 9: Ph H1-NMR ca cht 4a

SNH

OO

O

S

NH

O

O


SNH

OO

O

S

NH

O

O

Ph lc 12: Ph H1-NMR ca cht 4b

SNH

OO

O

S

NH

O

O

CH3


SNH

OO

O

S

NH

O

O

CH3

Ph lc 15: Ph H1-NMR ca cht 4c

SNH

OO

O

S

NH

O

O

OCH3


SNH

OO

O

S

NH

O

O

OCH3

Ph lc 18: Ph H1-NMR ca cht 4d

SNH

OO

O

S

NH

O

O

Cl


SNH

OO

O

S

NH

O

O

Cl

Ph lc 21: Ph C13

-NMR ca cht 4a

SNH

OO

O

S

NH

O

O


SNH

OO

O

S

NH

O

O

Ph lc 24: Ph C13-NMR ca cht 4b

SNH

OO

O

S

NH

O

O

CH3

Ph lc 25: Ph C13-NMR m rng ca cht 4b

SNH

OO

O

S

NH

O

O

CH3

Ph lc 26: Ph C13


SNH

OO

O

S

NH

O

O

CH3

Ph lc 27: Ph C13-NMR ca cht 4c

SNH

OO

O

S

NH

O

O

OCH3


SNH

OO

O

S

NH

O

O

OCH3

Ph lc 30: Ph C13-NMR ca cht 4d

SNH

OO

O

S

NH

O

O

Cl


SNH

OO

O

S

NH

O

O

Cl

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Transcript of Tổng hợp và thử tác dụng sinh học một số dẫn chất Benzensulflonamid mang khung...