Tổng Hợp Và Thử Hoạt Tính Kháng Tế Bào Ung Thư Của Một Số Dẫn Chất 2-Aryl-4-Quimazolinon

7/21/2019 Tng Hp V Th Hot Tnh Khng T Bo Ung Th Ca Mt S Dn Cht 2-Aryl-4-Quimazolinon

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B GIO DC V O TO B Y T

TRNG I HC DC H NI

NGUYNTHHUYN

TNG HP V TH HOT TNH KHNG TBO UNG TH CA MT S DN CHT

2- ARYL-4-QUINAZOLINON


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B GIO DC V O TO B Y T

TRNG I HC DC H NI

NGUYN TH HUYN

TNG HP V TH HOT TNH KHNG T

BO UNG TH CA MT S DN CHT

2- ARYL-4-QUINAZOLINON

LUN VN THC S DC HC

CHUYN NGNH: CNG NGH DC PHMV BO CH THUCM S: 60720402


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LI CM N

hon thnh kha lun ny, em xin tlng bit n su sc n: TS. Vn Th

MHuvTS. L Nguyn Thnhl nhng ngi c, ngi thy tn tnh hng

dn, to mi iu kin thun li v ng vin em trong sut qu trnh thc hin lun

vn ny.

Em cng xin cm n sgip nhit tnh ca: TS. Nguyn Minh Hng, TS.

Cao Bch Hu, ThS. o nh Cng, cnhn Trn Hu Gip, cnhn Nguyn Anh

Dng, cnhn H ThThoa, cnhn Nguyn ThT Oanh (Trung tm nghin cu v

pht trin thuc - Vin ha sinh bin - Vin Hn lm Khoa hc v Cng nghVit

Nam), cc thy c gio Bmn Ha hu c cngcc thy c gio trong cc Bmn,

phng ban, th vin - Trng i hc Dc H Ni.

Mc d c nhiu cgng nhng do hn chvthi gian, kin thc cng nh

ti liu tham kho nn lun vn ca em khng thtrnh khi nhng sai st trong ni

dung v hnh thc, em rt mong nhn c sgp ca cc thy c lun vn ca

em c hon thin hn.

Cui cng, con xin cm n bm, em cm n anh ch, bn b lun ng

vin, gip con/ em trong sut qu trnh hc tp v nghin cu va qua.

H Ni, ngy thng nm 2014

Hc vin


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MC LC

T VN 1

CHNG 1: TNG QUAN 2

1.1. 2-ARYL-4-QUINAZOLINON: DN CHT TNG NG SINHHC CA 3-ARYLISOQUINOLINON 2

1.1.1. 3-Arylisoquinolinon 2

1.1.2. Pht trin khung 3-arylisoquinolinon thnh 2-aryl-4-quinazolinon 5

1.1.3. Mt stc dng sinh hc ca dn cht 2-aryl-4-quinazolinon 6

1.1.3.1. Tc dng chng ung th 6

1.1.3.2. Mt stc dng khc 9

1.2. PHNG PHP TNG HP 10

1.2.1. Phn ng Niementowski V. v phn ng Niementowski V. mrng.

11

1.2.2. Phn ng ca Shishoo C. J. 12

1.2.3. Phn ng ngng tanthanilamid v benzoyl clorid 12

1.2.4. Phn ng ngng tanthranilamid v aldehyd 13

CHNG 2: NGUYN VT LIU, TRANG THIT BV PHNG PHPNGHIN CU 15

2.1. NGUYN VT LIU, HA CHT, DUNG MI 15

2.2. THIT BTH NGHIM 16

2.3. PHNG PHP NGHIN CU 16

2.3.1. Phng php tng hp 2- aryl-4-quinazolinon 16

2.3.2. Phng php tinh chv xc nh cu trc 16

2.3.3.

Phng php xc nh hot tnh khng tbo ung th 17

CHNG 3: KT QUNGHIN CU 19

3.1. TNG HP HA HC 19

3.1.1. Tng hp dn cht trung gian 2-amino benzamid 21


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4.1. VTNG HP HA HC 46

4.1.1.

Tng hp dn cht trung gian 2-amino benzamid v khng nh cutrc 46

4.1.2. Tng hp dn cht trung gian aldehyd thm v khng nh cu trc 48

4.1.3. Tng hp dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c) 48

4.2. VXC NH CU TRC 50

4.2.1. Phhng ngoi( IR) 50

4.2.2.

Phcng hng tht nhn proton (1H-NMR) 51

4.2.3. Phcng hng tht nhn 13C (13C-NMR) 53

4.2.4. Phkhi lng (MS) 55

4.3. VHOT TNH KHNG TBO UNG TH 57

KT LUN V KIN NGH 61

KT LUN 61

KIN NGH 61

TI LIU THAM KHO 64


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DANH MC CC K HIU, CH VIT TT

ATCC Tiu chun M(the American Type Culture Collection )13C-NMR Ph cng hng t ht nhn1H-NMR Ph cng hng t ht nhn proton

CTCT Cng thc cu to

CTPT Cng thc phn t

ppm dchchuyn ha hc (phn triu)DCM Dicloromethan

DMAC N,N-dimethylacetamid

DMEM Mi trng nui cy t bo (Dulbecco's Modified Eagle Medium)


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IR Ph hng ngoi (Infrared Spectrometry)

J Hng s tng tc (Hz)

KB Human epidemic carcinoma - t bo ung th da

LU Human lung carcinoma - t bo ung th phi

MCF-7 Human breast carcinoma - t bo ung th v

MIC Nng c ch ti thiu

MOM Methoxy methyl

MS Ph khi lng (Mass Spectrometry)

MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromid

PMB p-Methoxylbenzyl

SKLM Sc k lp mng

TLC Sc k bn mng (Thin Layer Chromatography)Tnc Nhit nng chy

DANH MC CC BNG, BIU

TT Tn bng Trang1 Bng 3.1 Kt qu tng hp cc dn cht 14a-kv 15a-c 35

2 Bng 3.2 Gi tr Rfv Tncca cc dn cht 14a-kv 15a-c 36

3 Bng 3.3 Kt qu phn tch ph khi lng (LC-MS) ca cc dn

cht 14a-kv 15a-c

38

4 Bng 3.4 S liu ph IR ca cc dn cht 14a-kv 15a-c 39

5 Bng 3.5 S liu ph H-NMR ca cc dn cht 14a-kv 15a-c 40

6 Bng 3.6 S liu ph C-NMR ca cc dn cht 14a-kv 15a-c 42

7 B 3 7 Kt th h t t h t b 14 k 15 45 57


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DANH MC CC HNH V, S

HNH V

TT Tn hnh Trang

1 Hnh 1.1 Cu trc hp cht 7,8-dimethoxy-2-methyl-3-(4,5-

methylendioxy-2-vinylphenyl) isoquinolin-1(2H)-on.

2

2 Hnh 1.2 Cu trc dy hp cht 3-arylisoquinolinon trong nghin

cu ca Cho v cng s

3

3 Hnh 1.3 Cu trc cc hp cht 3-arylisoquinazolinon trong nghin

cu ca Cho v cng s

3

4 Hnh 1.4 Cu trc mt s dn cht 3-arylisoquinolinon c hot 4


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9 Hnh 1.9 Cu trc hp cht 2- aryl-6-substituted quinazolinon 8

10 Hnh 1.10 Cu trc ca dn cht Ratitrexed 9

11 Hnh 1.11 Cu trc ca hpcht Methaqualon 9

12 Hnh 4.1 Ph hng ngoi ca cht 15c 51

13 Hnh 4.2 a)Ph 1H-NMR; b) Ph 1H-NMR gin rng ca cht 15c 52, 53

14 Hnh 4.3 a)Ph 13C-NMR; b) Ph 13C-NMR gin rng ca cht

15c

54, 55

15 Hnh 4.4 Ph khi lng (MS) ca cht 15c 56

S

TT Tn s Trang1 S 1.1 Thit k cc dn cht 2-aryl-4-quinazolinon da trn

phng php nhm th ng cu sinh hc

6

2 S 1.2 Phn ng tng hp Niementowski V. 11

3 S 1.3 Phn ng tng hp Niementowski Vci tin 11

4 S 1.4 Phn ng tng hp ca Patel V.S v Patel S.R 11

5 S 1.5 Phn ng tng hp ca Shishoo C.J v cng s 12

6 S 1.6 Phn ng tng hp ca Hour M. J. v cng s 12

7 S 1 7 Phn ng ngng t anthranilamid v benzoyl clorid ci 13


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12 S 3.3 Tng hp cc dn cht 2-aryl-4-quinazolinon 20,25

13 S 3.4 Tng hp 2-amino-5-methyl benzamid 21

14 S 3.5 Tng hp 2-amino-4-methyl benzamid 22

15 S 3.6 Tng hp 2-amino-5-(dimethylamino) benzamid 23

16 S 3.7 Tng hp 2-(dimethylamino)benzaldehyd 24

17 S 4.1 C ch tng hp cc cht 2-aryl-4-quinazolinon 49


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T VN Hin nay tlmc cc bnh ung th c xu hng gia tng hu ht cc quc

gia trn thgii, ng thhai sau bnh tim mch cc nc pht trin [4].Theo t

chc Y tThgii c tnh trn ton cu c khong 20 triu ngi ang mc ung th,

trong c khong 6 triu ngi cht hng nm. T l cht do ung th chim 12%

trong cc nguyn nhn gy tvong ngi. Cng xu hng trn thgii th ti Vit

Nam theo c tnh c n 150.000 ca mi mc v khong 75.000 ngi cht v ung

th hng nm[3].

Trong qu trnh tm kim cc thuc chng ung thmi, nhiu nghin cu hin

nay tp trung vo vic tm kim cc cht c hot tnh khng tbo ung th[24].Mt

trong nhng dy hp cht c hot tnh gy c tbo c ch hin nay l dy hp

cht 3-arylisoquinolinon c pht hin vo nhng nm cui thk19 [9]. Da trn

pht hin ny nhiu nghin cu pht trin cu trc ca 3-arylisoquinolinon nhm tm

kim cc hp cht mi c tc dng khng tbo ung th c nhiu nh khoa hc

quan tm v nghin cu [6-10]. Mt trong nhng hng pht trin cu trc l thay i

cc nhm chc, nhm th tng ng sinh hc ca 3-arylisoquinolinon to nn

dy hp cht 2-aryl-4-quinazolinon. Kt quca mt snghin cu cho thy cc dn

cht ny thhin hot tnh khng tbo ung th tt [6-11;15-19].

Hi nhp vi xu hng nghin cu ca th gii trong vic tm kim cc dncht 2-aryl-4-quinazolinon c hot tnh khng tbo ung th tt, lun vn: Tng hp

v th hot tnh khng t bo ung th ca mt s dn cht 2-aryl-4-

quinazolinon c tin hnh vi hai mc tiu :


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CHNG 1: TNG QUAN

1.1.

2-ARYL-4-QUINAZOLINON: DN CHT TNG NG SINH HCCA 3-ARYLISOQUINOLINON

1.1.1.

3-Arylisoquinolinon

Dy hp cht 3-arylisoquinolinon c gio s Cho v cng spht trin trong

qu trnh nghin cu tng hp cc hp cht tnhin benzo[c]phenanthridin fagaronin

vo nm 1998.Dy hp cht ny c tc dng khng tbo ung th tt da trn sc

chenzym topoisomerase I trong qu trnh sao chp ADN. Mt trong nhng hp cht

c tc dng khng tbo ung th rt tt nng nanomol l 7,8-dimethoxy-2-

methyl-3-(4,5-methylendioxy-2-vinylphenyl)-isoquinolin-1(2H)-on (Hnh 1.1) [10].

N

O

H3CO

OCH3

O

O

(IC50= 0,2 nM, SKMEL-2)

Hnh 1.1: Cu trc hp cht 7,8-dimethoxy-2-methyl-3-(4,5-methylendioxy-2-

vinylphenyl)isoquinolin-1(2H)-on.

Trong qu trnh tm kim cht chng ung th mi, Cho v cng s sdng

hp cht 7,8-dimethoxy-2-methyl-3-(4,5-methylendioxy-2-vinylphenyl)-isoquinolin-

1(2H)-on lm cht dn ng tng hp cc dn cht 3-arylisoquinolinon. Trong

nghin cu ny, Cho v cng s tng hp c 12 dn cht 3-arylisoquinolinon,


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NH

O

R1

R2

R1= H; 6-CH3; 5-N(CH3)2R2= H; 3,4-OCH2O; 4-CF3; 4-CH3;

2-CH3; 4-Cl; 4-Br; 4-OCH3

Hnh 1.2: Cu trc dy hp cht 3-arylisoquinolinon trong nghin cu ca

Cho v cng s

Cng cng xu hng nghin cu trn nm 2009, Cho v cng stip tc tng

hp c 9 dn cht 3-arylisoquinolinon (Hnh 1.3) v thnghim hot tnh sinh hc

trn 3 dng tbo ung thgm: ung th phi, ung th i trng, v ung th bung

trng. Trong , hp cht c nhm thR1 = CH3; R2 = R3= R4 = H; R5= PMB (p-

methylbenzyl); v hp cht c nhm thR2 = CH3; R1 = R3= R4 = H; R5= PMB l 2hp cht c hot tnh khng tbo ung th caotrn c3 dng tbo ung thvi IC50

t2,37g/ml n 13,27g/ml [8].

NH

OR1= H; CH3R2= H; CH3R3= H; OCH3R4= H; OCH3R5= PMB; MOM

R1

R2

R3

R4

OR5

Hnh 1.3: Cu trc cc hp cht 3-arylisoquinolinon trong nghin cu caCho v cng s

Trn th gii cng c rt nhiu nghin cu tng hp v th hot tnh khng t


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c tnh [17,18]. Bn cnh dn cht cha vng thm vtr s3 ca vng quinazolinon

cc d vng khc c c tnh thm nh: thiophen, pyridin, furan cng c hot tnhkhng tbo ung th[18].(Hnh 1.4)

NH

O

Y1

Y2

R5

R4

R3

R2

R1NH

O

R1

R2

R3

R4

NH

Ar

O

Y1

Y2

Y1,2= H, N(CH3)2R 1-5= H, OCH3, Cl, Br, OC2H5, ...

Ar: Thiophenyl;pyridinyl; f uranyl

Hnh 1.4: Cu trc mt sdn cht 3-arylisoquinolinon c hot tnh chng ung

th caoc bit tc giKazuo Hatturi v cng scng ty dc phm Chugai, Nht

Bn cng tng hp v ng k bn quyn vdy hp cht 3-arylisoquinolinon vi

hot tnh chng ung th. Nhm hp cht tng hp c thtc dng sinh hc trn t

bo ung th trc trng v thhin tc dng rt cao nng IC50khong 1 nanomol

(Hnh 1.5) [15,16].

NH

O

(H3C)2N NH

O

(H3

C)2

N

NH

O

(H3C)2NN(CH

3)

2

HCT 116

IC50= 1,1 nM

H3

CO

OCH3OCF3

HCT 116

IC50= 8,9 nM

HCT 116

IC50= 3,5 nM

Hnh 1.5: Cu trc nhm hp cht 3-arylisoquinolinon c tc dng trn


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1.1.2.

Pht tr in khung 3-aryli soquinoli non thnh 2-aryl-4-quinazolinon

Vi mc tiu tm kim cc cht c hot tnh chng ung th, lun vnsdng

phng php nhm thng cu sinh hc trong thit k thuc pht trin cu trc

ha hc ca dn cht 3-arylisoquinolinon. Phng php nhm thng cu sinh hc l

mt phng php tip cn thay i cht dn ng, hoc thay i trong qu trnh

chuyn ha thuc m khng lm thay i nhiu vmt cu trc ha hc [2,20]. Trong

lnh vc nghin cu v pht trin thuc, nhm thng cu sinh hc trthnh mt

trong cc cng cc ng dng rt c hiu quthit kcu trc. Sd nh vy l

v sthay thbng cc nhm ng cu sinh hc thng em li cc cht c hot tnh

sinh hc kh tng tnhau nhng li c skhc nhau r rt vcc tnh cht l ha hc

khc nh phn cc, bn ha hc, v.v Cho n nay nhm ng cu sinh hc

thng c coi l nhng nhm hoc cht c tnh cht l ha hc tng tnhau v c

mt loi hot tnh sinh hc tng tnhau [2].

Hin nay c 6 kiu thay th hay c p dng trong phng php s dng

nhm ng cu sinh hc cho thit kcu trc, bao gm: thay thnguyn thoc nhm

c ha tr1, thay thnguyn thoc nhm c ha tr2, thay thnguyn thoc nhmc ha tr3, thay thbng cc vng tng ng, thay thbng cc nhm c phn

cc tng tnhau, v thay thbng cc nhm chc c cu trc o ngc [2].

Phng php thay thbng vng tng ng c coi l cc nhm ng cu

sinh hc ca nhau (cc vng ng cu sinh hc), l mt trong cc kthut thit kcu

trc c sdng phbin nht c bit hiu qu. C th tm thy rt nhiu nghin

cu khoa hc sdng kthut thay thbng cc vng ng cu sinh hc c cng

b. c bit, sthay th-CH= bngN= trong cc vng thm l trng hp hay gp

v hiu qu nht trong s cc nhm ng cu sinh hc kinh in [2]


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NH

O

3-arylisoquinolinon

R2

R1R

3

NH

N

O

R2

R1R3

2-aryl-4-quinazolinon

S 1.1: Thit kcc dn cht 2-aryl-4-quinazolinon da trn phng php

nhm thng cu sinh hc

1.1.3.

Mt stc dng sinh hc ca dn cht 2-aryl-4-quinazolinon

Trn thgii c nhiu cng trnh nghin cu tng hp v thhot tnh sinh

hc cho thy cc dn cht c tng hp tquinazolinon c nhm thvtr s2 c

tc dng sinh hc phong ph nh: chng ung th, an thn, khng khun, khng nm,

v.v c bit, cc dn cht c nhm th v tr s 6 hay v tr s 7 vng

quinazolinon v cc nhm th(CH3, OCH3, OCF3, ) vtri 2,3, ca vng thm

vtr s2 ca vng quianzolinon cho thy hot tnh sinh hc ca cc dn cht tng ln

ng k.

1.1.3.1. Tc dng chng ung th

V tc dng chng ung th, trn thgii cmt scng trnh nghin cu

khoa hc ca cc dn cht 2- aryl - 4- quinazolinon.

Tc giMann-Jen Hour v cc cng s cng bkt quvtng hp v th

tc dng gy c t bo ca 6-alkylamino- v 2,3-dihydro-3-methoxy-2-phenyl-4-

quinazolinon v cc hp cht lin quan. Da trn cu trc khung cc tc gi tng

hp c 18 dn cht. Trong cc hp cht c R6 l cc nhm thdvng cha N;


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NH

N

O

R5'

R6

R7

R4'

R3

'

R2'

R6 = H; OCH3; OCH2O; N(CH3)2;

R7 = R2' = R4' = R5' = H; OCH3

R3' = OCH3

N N N CH3 ON; ; ;

Hnh 1.6: Cu trc nhm hp cht 6-alkylamino- v 2,3-dihydro-3-

methoxy-2-phenyl-4-quinazolinon

Nm 2007, tc giMann-Jen Hour v cc cng stip tc nghin cu vdn

cht 6-pyrrolidinyl-2-(2-subtituted phenyl)-4-quinazolinon. Nhm hp cht tng hp

c cho tc dng tt i vi vic c chspht trin ca tbo ung th mu ngi

v chut thnghim vi gi trEC50t0,30 10,10M.Trong , nhm thR l -

F, -Cl v -N(CH3)2cho hot tnh khng tbo ung th cao nht [22].

NH

N

O

N

R = F,Cl, OCF3, OH, OCH3, OC2H5, N(CH3)2

R

Hnh 1.7: Cu trc nhm hp cht 6-pyrrolidinyl-2-(2-subtituted phenyl)-

4-quinazolinon

Nm 2011, tc giYang C. Wu v cng stin hnh thhot tnh chng khi u

2 ( h l 1 l) 6 lidi l 4 i li d b h


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NH

N

O

N

Hnh 1.8: Cu trc hp cht 2- (naphtalen-1-yl)-6-pyrolidinyl-4-quinazolinon

Gn y nht nm 2013, tc giMann-Jen Hour v cc cng stip tc cng b

kt quthtc dng sinh hc trn 5 dng tbo ung thngi: khi u c tnh, ung th

phi, ung th biu m khng nhphi, ung th gan v ung th vm hng ca 15 dn

cht 2- aryl-6-substituted quinazolinon tng hp c. Kt qucho thy c 6 dn cht

c tc dng gy c tbo mnh nng IC50 t0,07 M n 8,89 M trn c5

dng tbo ung th.Trong hp cht c nhm thR6l pyrrolidinyl v R2l vng

napthalenyl cho tc dng gy c tbo mnh nht nng IC50 t0,03-1,35

M

trn 5 dng tbo ung th thnghim [21].

N

N

ON

R6 =

R6 =

R6 =

R6 =

R6 = OCH3

R6 = N(CH3)2

NR2 =

R2 =

R2 =

N

S

NH

N

R6

R2

O

Hnh 1.9: Cu trc nhm hp cht 2- aryl-6-substituted quinazolinon

Trong nhng nm gn y mt sdn cht 4(3H)-quinazolinon c nhm th

v tr s 2 c s dng lm tc nhn chng ung th Ratitrexed (ZD 1694) c


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NH

N

O

CH3

NS

NH

CH3O

HOOC(H2C)2

HOOC

Hnh 1.10: Cu trc ca hp cht Ratitrexed

Nh vy, tc dng chng ung th hay hot tnh c tbo trn tbo ung th

ca cc dn cht quinazolinon l tc dng sinh hc c cc nh khoa hc quan tm

nht. V vy, trong nghin cu ny chng ti tp trung nghin cu hot tnh khng cc

tbo ung th.Ngoi ra, dn cht 2-aryl-4-quinazolinon cn nhiu tc dng sinh hc

phong ph khc nh: an thn, gy ng, khng khun, khng nm

1.1.3.2.

Mt stc dng khc

Tc dng an thn, gy ng

Methaqualon l thuc an thn c nh khoa hc ngi n Gujiral M.L.

pht minh vo nm 1955 trong chng trnh nghin cu thuc phng chng st rt v

c a ra thtrng nh l mt thuc an thn khng gy nghin vo nm 1966 di

tn bit dc: Renonal, Melsed, hay Mandrax [30].

Mc d, Methaqualon c nhiu tc dng ph, nhng vn c nhiu nghin cu

tip theo tm kim thuc c tc dng an thn, gy ngtng tnh Methaqualon

nhng c tnh thp hn, chyu l cc nghin cu tng hp v thsng lc tc dng

an thn, gy ngca cc hp cht 2-alkyl-3-aryl-4-quinazolinon [12].

N


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Tc dng khng khun, khng nm

Vtc dng khng khun, khng nm ca cc dn cht 2-aryl-4-quinazolinon,

trn thgii c nhiu cng trnh khoa hc nghin cu vtc dng ny.

Nm 2007, hai nh khoa hc ngi Ai Cp l Awwad A. Radwan v Salah G.

Ali tin hnh nghin cu ti tng hp cc dn cht 4(3H)- quinazolinon mi c

hot lc khng khun, khng nm. Trong nghin cu ny mt lot cc dn cht 4(3H)-

quinazolinon c tng hp c hot tnh khng khun tt [5].Gn y nht nm 2012, G.Khodarahmi vHassanzadeh cng cc cng s tip

tc nghin cu hot tnh khng khun, khng nm v hot tnh gy c tbo ca mt

sdn cht Quinazolinon mi tng hp. Kt qu th nghim cho thy cc dn xut

tng hp c hiu lc vi cvi khun Gram dng v Gram m c bit trn hai chng

Staphylococcus aureusvPseudomonas aeruginosa c hiu lc cao nng mg/ml

[13].

Ngoi ra, dn cht 2-aryl-4-quinazolinon cn nhiu tc dng sinh hc phong

ph khc nh: tc dng chng ng kinh, tc dng lm mm c, tc dng li tiu,

v.v

Ti Vit Nam, hin nay cha c nghin cu no v dn cht 2-aryl-4-

quinazolinon.Nh vy, trong lun vn ny sdngphng php thay thvng ng

cu sinh hc trong thit kcu trc cc dn cht 2-aryl-4-quinazolinon tdn cht 3-

arylisoquinolinon, vn c bit n l dn cht c tc dng khng tbo ung th tt,

vi mong mun tm kim sng lc nhng hp cht c hot tnh khng ung th c trin

vng.
http://www.ncbi.nlm.nih.gov/pubmed/?term=Hassanzadeh%20F%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Hassanzadeh%20F%5Bauth%5D


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1.2.1.

Phn ng Niementowski V. vphn ng Niementowski V. mrng.

Phng php tng hp dn cht quinazolin-4-on phbin nht l phn ng ln

u tin c Niementowski V. m tnm 1885 v ngy nay phn ng mang tn ng

[28]. Khi un nng acid anthranilic vi mt lng d formamid 120oC, nc c

gii phng v hu nh acid anthranilic c chuyn hon ton thnh quinazolin-4-on.

C nhiu ci tin i vi phn ng Niementowski V., phn ng c th tin hnh vi

cc dn cht ca acid anthranilic th cho cc dn cht 2-aryl-4-quinazolinon. Tuynhin, theo quy lut cn tin hnh phn ng nhit cao hn v thi gian phn ng

ko di hn.

HN

COOH

R1 HCONH2

R

O

N

R1NH

O

R

S 1.2: Phn ng tng hp ca Niementowski V.

Phn ng cng c th thc hin c vi cc amid mch thng to thnh cc

dn cht thalkyl vtr s2 [7]. Ni chung phi tin hnh phn ng nhit cao

hn v hiu sut gim i khi khi lng phn tamid tng ln.Phn ng Niementowski V. cng c th tin hnh bng cch ngng t gia

amid ca acid anthranilic vi ethyl orthoformat [25] .

NH2

CONH2

Cl

NH

N

O

ClCH2(OC2H5)2

O(CH2CH2OH)2

S 1.3: Phn ng tng hp Niementowski V ci tin.

Patel V.S v Patel S.R. ci tin phn ng Niementowski V. bng phn ng

ng ng gia cc acid N ac lantharanilic th i formamid nhit t 100oC n


22/134

1.2.2.

Phn ng ca Shishoo C. J.

Theo Shishoo C.J.v cng s, cc dn cht quinazolin-4-on thvtr s2 c

thtng hp ddng bng phn ng gia ester methyl anthranilat vi cc nitril vi s

c mt ca kh hydroclorid khan trong dioxan [32]. (S 1.5)

NH2

OR'

O

NH

N

O

RC NHR X

S 1.5: Phn ng tng hpca Shishoo C.J. v cng s.

Phn ng ny c nhc im l kh hydroclorid bay hi trong qu trnh phn

ng dn mn dng cv thit bth nghim nn t c sdng.

1.2.3.

Phn ng ngng tanthani lamid vbenzoylclorid

Phn ng ngng tanthranilamid v benzoylclorid l phn ng hay c s

dng trong tng hp cc dn cht 2-aryl-4-quinazolinon.

Hour M. J. v cng s c rt nhiu nghin cu v hp cht 2-aryl-4-

quinazolinon. Trong nghin cu tng hp v thhot tnh sinh hc ca nhm dn cht

6-pyrrolidinyl-2-(2-substited phenyl)-4-quinazolinon, ng v cng s tng hpc hp cht 2-(2-dimethylaminophenyl)-6-pyrrolidinyl-4-quinazolinon bng cch s

dng NaHSO3 lm xc tc trong mi trng N,N-dimethylacetamid (DMAC). Phn

ng c unhi lu150oC trong khong 2 gi, sau hn hp phn ng vo

nc (S 1.6). Hiu sut phn ng l 25,0% [23].

NH2

NH2

N

NH

NaHSO3, DMAC

150oC(H C) N

Cl

O

N(CH3)2


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Nm 2013, hai nh khoa hc Monireh Shakiba Nahad v Ghodsi Mohammadi

Ziarani nng cao hiu sut phn ng ngng tanthranilamid v benzoylclorid bng

cch sdng cht xc tc SBA-Pr-SO3H, mt acid c cu trc nano, trong dung mi

ethanol hoc dimethylformamid (DMF), hn hp phn ng c un nng 130oC.

Hiu sut phn ng l 52 - 91% [26]. (S 1.7)

NH2

NH2

O

N

NH

O

SBA-Pr-SO3H

C2H5OH/DMF, 130oC

Cl

O

R

R

R = 3-Cl; 4-Cl; 2,4-(Cl)2; 2-CH3

S 1.7:Phn ng ngng tanthranilamid v benzoyl clorid ci tin

1.2.4. Phn ng ngng tanthrani lamid valdehyd

Cng theo Hour M. J. v cng s th cc dn cht 2-aryl-4(3H)-quinazolinon

c tng hp bng cch ngng tdn cht ca anthranilamid v benzaldehyd. Tng

tphn ng ngng tanthranilamid v benzoyl clorid, phn ng ny sdng NaHSO3

lm cht xc tc phn ng ngng t v DMAC lm dung mi phn ng. Phn ng

c un hi lu trong 2 ginhit 150oC. Hiu sut phn ng l 75 - 95%.

NH2

R

NH2

O

H R'

O N

R

NH

O

R'NaHSO3, DMAC

150oC

S 1.8: Phn ng tng hpca Hour M. J. v cng s

Phng php ca Hour M J c s dng tng hp nhiu dn cht th C2


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dimethyl sulfoxid (DMSO), phn ng c un nhit 100oC trong 12-36 gi, v

cho hiu sut phn ng 38 - 98% [27].

NH2

NH2

O

H

O

R NH

N

O

RDMSO, 100oC

12-36h

S 1.9: Phn ng tng hp ca Na Yeun Kim v Cheol-Hong Cheon


25/134

CHNG 2: NGUYN VT LIU, TRANG THIT BV PHNG

PHP NGHIN CU2.1. NGUYN VT LIU, HA CHT, DUNG MI

Cc ha cht, dung mi dng trong qu trnh tng hp c xut xtcc cng ty

nh: Merk, Sigma-Aldrich, Trung Quc,v.v Cc ha cht ny c s dng trc

tip khng qua tinh chthm. Cc ha cht c trnh by bng di y:

TT Nguyn liu Xut x TT Nguyn liu Xut x

1 2- Methylbenzaldehyd Merk 16 Ethylacetat Trung

Quc

2 3- Methylbenzaldehyd Merk 17 Nc ct VN

3 2-Trifloromethylbenzaldehyd Merk 18 CDCl3 Merk

4 3-Trifloromethylbenzaldehyd Arcros 19 DMSO-d6 Merk

5 2-

Trifloromethoxybenzaldehyd

Arcros 20 Dimethylformamid Merck

6 3-

Trifloromethoxybenzaldehyd

Arcros 21 Kh H2 Vit

Nam

7 2- Florobenzaldehyd Merk 22 Acid 5-cloro-2-nitrobenzoic Merk

8 3- Florobenzaldehyd Merk 23 2-amino-4-methylbenzonitril Merk

9 Naphthalen-1-carbaldehyd Merk 24 Acid5-methyl-2-nitrobenzoic Merk

10 Methanol Merk 25 Ammonia Water Trung

Quc

11 Ethanol Trung

Quc

26 NaHSO3 Trung

Quc

12 Diclomethan Merck 27 N,N-dimethylacetamid Merk


26/134

2.2.

THIT BTH NGHIM

Dng cthy tinh: bnh cu 2 cdung tch 100ml, bnh cu 100ml, 50ml, sinh hn,

phu, cc thy tinh cc loi, bnh lc ht, phu Buchner, bnh nn, bnh chit

Cn kthut in tShimadzu (Nht Bn).

Bm ht chn khng DIVAC.1.21 (M).

My ct quay Buchi R210 (Thy S).

Tsy Memmert (c).

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

AVANCE Spectrometer AV500 (BRUKER, c), Vin ha hc - Vin Hn lm

Khoa hc v Cng nghVit Nam.

My o phkhi khi lng LC-MSD-Trap-SL - Vin Ha hc cc hp cht thin

nhinVin Hn lm Khoa hc v Cng nghVit Nam

My o phhng ngoi c ghi trn my Perkin Elmer ti Vin Ha hc - Vin

Hn lm Khoa hc v Cng nghVit Nam

My o nhit nng chy nhit in Electrothermal digital.

My khuy tgia nhit IKA-RTC (c).

2.3. PHNG PHP NGHIN CU

2.3.1.Phng php tng hp 2- aryl-4-quinazolinon

Sdng cc phng php tng hp hu c kinh in v hin i tng hp cc

dn cht dkin.

Theo di tin trnh phn ng v s bnh gi tinh khit cc cht bng sc k

lp mng (SKLM).


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2.3.3.

Phng php xc nh hot tnh khng tbo ung th

Th hot tnh khng tbo ung th ca cc dn cht tng hp c theo

phng php MTTl php thc tbo chun nhm sng lc, pht hin cc cht

c khnng km hm spht trin hoc dit tbo ung th iu kin in vitro [14,

31].

2.3.3.1.

Nguyn tc:y l phng php thnghim in vitroo stng sinh v sng st ca t

bo ung th c nui cy trong a 96 ging.

Hp cht MTT c tn khoa hc l 3-(4,5-dimethyl-2-thiazolyl)-2,5-

diphenyltetrazolium bormid, c mu vng c thm vo mi ging v tbo c

37oC, 5% CO2. Mu vng bin i thnh formazan tm trong ty thca tbo sng.

Khnng hp thca dung dch c mu ny c thc nh lng bng my quang

phkbc sng 540 600nm. Sbin i mu chxy ra khi enzym reductase

trong ty thhot ng, v nh vy schuyn i lin quan trc tip n slng t

bo sng st. Nhm nghin cu sdng phng php ny nghin cu c tnh ca

cc dn cht tng hp c trn bn dng tbo ung th ngi: tbo ung th biu

m - KB, tbo ung th gan - HepG2, tbo ung th phi - LU, tbo ung th v -

MCE7. Phng php ny hin ang c p dng ti Vin nghin cu ung th quc

gia M(NCI).

2.3.3.2. Dng tbo thnghim:

Cc dng tbo ung th ngi c cung cp bi ATCC gm:

- KB (Human epidemic carcinoma) t bo ung th biu m


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2.3.3.4. Tin hnh:

a. Chun btbo.

Cc dng tbo ung th nghin cu c nui cy trong cc mi trng nui cy

ph hp c bsung thm 10% huyt thanh bo thai b (FBS) v cc thnh phn cn

thit khc iu kin tiu chun (5% CO2; 37oC; m 98%; v trng tuyt i).

Ty thuc vo cc c tnh ca tng dng tbo khc nhau, thi gian cy chuyn

cng khc nhau.Tbo pht trin pha log sc sdng thc tnh.

b. Quy trnh xc nh hot tnh khng tbo ung th.

- Pha 200 l dung dch tbo pha log nng 3 x 104tbo/ml vo mi ging (a

96 ging) trong mi trng DMEM cho cc dng tbo HepG2, MCF7, KB, LU.

-

Mu thc pha long sao cho t n nng cui cng l 128 g/ml; 32 g/ml;

8 g/ml; 2 g/ml; 0,5 g/ml. 37oC, 5% trong 3 ngy.

- Ging iu khin (i chng dng) chgm 200 l dung dch tbo 3 x 104 t

bo/ml.

-

Sau 3 ngy nui cy; tip vi MTT 0,2mg/ml 37o

C trong 4 gi.- Loi bmi trng, thm 100 l DMSO lc u formazan c thha tan hon

ton.

- c mt quang bc sng 540 nm trn my Spectrophotometter Genios

TECAN. Mt quang phn nh slng tbo cn sng st.

c.

Tnh kt qu:

Phn trm km hm spht trin ca tbo (Growth inhibition) c tnh ton

da trn sliu o mt quang hc OD trn my quang phTECAN theo cng thc


29/134

CHNG 3: KT QUNGHIN CU

3.1. TNG HP HA HC

Dn cht 2-aryl-4-quinazolinon c tng hp theo cc bc sau:

Tng hp cc dn cht trung gian 2-aminobenzamid.

NO2

COOH

NO2

COCl

NH4

OH

Dicloromethan CONH2

KOH

C2

H5

OH

CH3

NH2

CONH2

H3C NH2

CN

H3C NH 2

CONH2

H3C H3C H3C

NO2

SOCl2

H2, 10% Pd/C

CH3OH

NO2

COCl

NH 4OH

Dicloromethan

NO2

CONH2

(H3C)2N

NH2

CONH2

Cl

NO2

Cl ClCOOH

SOCl2

(H3C)2N

NO2

CONH2

H2, 10% Pd/C

CH3OHDMF, 110oC

NH(CH3)2

1 2 3

4

5 6

7 8 9

10 11

S 3.1: Tng hp cc dn cht trung gian 2-aminobenzamid

Tng hp dn cht trung gian 2-(dimethylamino)benzaldehyd.


30/134

Tng hp cc dn cht 2-aryl-4-quinazolinon bng phn ng ngng tcc dn cht

2-aminobenzamid vi cc aldehyd thm theo s phn ng sau: (S 3.3)

R1

NH2

CONH2

OHC

R2

NaHSO3

N,N-dimethylacetamid

150oC

NH

N

O

R1

R21

234

56

7

8 1'

2'3'

4'

5'

6'

R1

NH2

CONH2

CHO

NaHSO3


150oC

NH

N

O

R1

1 234

56

7

8

14a-k

15a-c

14a: R1 = 6-CH3; R2 = 2-CH3 15a:R1 = 6-CH3

14b: R1 = 6-CH3; R2 = 3-CH3 15b:R1 = 7-CH3

14c: R1 = 6-CH3; R2 = 2-CF3 15c:R1 = 6-N(CH3)2

14d: R1 = 6-CH3; R2 = 3-CF3

14e: R1 = 6-CH3; R2 = 2-OCF3

14f: R1 = 6-CH3; R2 = 3-OCF3

14g: R1 = 6-CH3; R2 = 2-F

14h: R1 = 6-CH3; R2 = 3F

14i: R1 = 6-CH3; R2 = 2-N(CH3)214j: R1 = 7-CH3; R2 = 2-N(CH3)2

14k: R1 = 7-CH3; R2 = 2-OCF3

S 3 3: Tng hp cc dn cht 2-aryl-4-quinazolinon


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3.1.1.

Tng hp dn cht trung gian 2-aminobenzamid

3.1.1.1.

Tng hp 2-amino-5-methylbenzamid

Cng thc:

H3C

NH2

CONH2

1

23

4

5

CTPT: C8H10N2O; KLPT: 150,18

S :

NO2

COOH

NO2

COCl

NH4

OH

Dicloromethan CONH2

CH3

NH2

CONH2

H3C H3C H3C

NO2

SOCl2

H2, 10% Pd/C

CH3OH

1 2 3

4

S 3.4: Tng hp 2-amino-5-methylbenzamid.

Gm 2 giai on:- Tng hp 5-methyl-2-nitrobenzamid (3).

- Tng hp 2-amino-5-methylbenzamid (4).

Tin hnh:

Tng hp 5-methyl-2-nitrobenzamid (3).

Nhttthionyl clorid (7ml; 90mmol) vo bnh cu cha 5,43g (30mmol) acid

5-methyl-2-nitrobenzoic 1. Hn hp ny c un hi lu50oC trong 4 gi, sau

loi thionyl clorid bng ht chn khng. Sn phm 2 c ha tan trong 30ml DCM,


32/134

Tng hp 2-amino-5-methylbenzamid (4).

Thm 200ml dung dch methanol vo bnh cu cha 4,418g (24,5mmol) 5-

methyl-2-nitrobenzamid 3 trn. Sau thm t t250mg 10%Pd/C vo bnh phn

ng. Hn hp phn ng c hydro ha nhit phng. Sau 8h kt thc phn ng

lm lnh, lc loi bxc tc, ct loi dung mi thu c 2-amino-5-methylbenzamid 4

(3,458g cht bt mu trng). Hiu sut 94%.

3.1.1.2.

Tng hp 2-amino-4-methylbenzamid (6)Cng thc:

H3C NH2

CONH2

1

23

4

5

6

CTPT: C8H10N2O; KLPT: 150,18S :

KOH

C2H5OH

H3C NH 2

CN

H3C NH 2

CONH2

5 6

S 3.5: Tng hp 2-amino-4-methylbenzamid.

Tin hnh:

Ly 1,32g(10mmol) 2-amino-4-methylbenzonitril 5 cho vo bnh cu 100ml.

Thm tt24ml EtOH vo khuy n khi tan hon ton, sau thm 2,8g (50mmol)

KOH vo hn hp trn. Hn hp c un hi lu90oC trong mi trng kh N2v

theo di phn ng bng SKLM vi hdung mi trin khai n-hexan-ethylacetat (1:1).

Sau 24h kt thc phn ng, thm nc vo v chit hn hp phn ng bng

ethylacetat. Dch ethylacetat c lm kh qua natri sulfat, cui cng c ct loi dung


33/134

3.1.1.3.

Tng hp 2-amino-5-(dimethylamino)benzamid

Cng thc:

(H3

C)2N

NH2

CONH2


S :

NO 2

COCl

NH4OH

Dicloromethan

NO 2

CONH2

(H3C)2N

NH 2

CONH2

Cl

NO 2

Cl ClCOOH

SOCl2

(H3C)2N

NO2

CONH2

H2, 10% Pd/C

CH3OHDMF, 1100C

NH(CH3)2

7 8 9

10 11

S 3.6: Tng hp 2-amino-5-(dimethylamino)benzamid.

Gm 3 giai on:

- Tng hp 5-cloro-2-nitrobenzamid(9).

-

Tng hp 5-(dimethylamin)- 2-nitrobenzamid(10).- Tng hp 2-amino-5-(dimethylamin)benzamid(11).

Tin hnh:

Tng hp 5-cloro-2-nitrobenzamid(9).

Cc bc tin hnh tng hp cht 9 tng tcht 3. Cht trung gian 5-cloro-2-

nitrobenzamid 9c tng hp t(0,6ml; 10mmol) thionylclorid v 500mg (2,5mmol)

acid 5-cloro-2-nitrobenzoic 7.

Khi lng sn phm: 480mg cht bt mu trng. Hiu sut 96%.


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Tng hp 2-amino-5-(dimethylamin)benzamid(11).

Cc bc tin hnh tng hp cht 11 tng tcht 4. Cht trung gian 2-amino-

5-(dimethylamin)benzamid 11 c tng hp t480mg (2,3mmol) 5-(dimethylamin)-

2-nitrobenzamid 10 trn v 30mg 10%Pd/C trong 20ml dung dch methanol. Sn

phm thu c 2-amino-5-(dimethylamin)benzamid 11 (300mg cht bt mu trng).

Hiu sut 72%.

3.1.2.

Tng hp dn cht trung gian aldehyd thm

a scc hp cht trung gian aldehyd thm c sdng l cc hp cht c

sn s dng trc tip. Ngoi ra, c mt dn cht trung gian l 2-

(dimethylamino)benzaldehyd 13 c tng hp thm.

Cng thc:

NCH3H3C

OHC

CTPT: C9H11NO; KLPT: 149,19

S :

NCH3H3C

OHCOHC

F

NH(CH3)2

K2

CO3

, DMF, 1100C

12 13

S3.7: Tng hp 2-(dimethylamino)benzaldehyd.

Tin hnh:

Ly 1ml (1 178g 9 5mmol) 2-fluorobenzaldehyd 12 vo bnh cu 50ml Thm


35/134

cui cng c ct loi dung mi. Cn c tinh ch bng sc k ct thu c 2-

(dimethylamino)benzaldehyd 13 l cht du mu trng ng.

Khi lng sn phm: 1,3g. Hiu sut phn ng : 92%.

3.1.3.

Tng hp dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c)

R1

NH2

CONH2

OHC

R2

NaHSO3


150oC

NH

N

O

R1

R21

234

56

7

8 1'

2'

3'

4'

5'

6'

R1

NH2

CONH2

CHO

NaHSO3


150oC

NH

N

O

R1

1 234

56

7

8

14a-k

15a-c

S 3.3: Tng hp cc dn cht 2-aryl-4-quinazolinon.

Quy trnh tng hp chung:

Cho vo bnh cu 2mmol (4hoc 6hoc 11), tng ng 2 mmol aldehyd thm,

208mg NaHSO3v 2ml DMAC. Khuy u cho hn hp tan hon ton v un hi lu

nhit 150oC trong 2 gi. Theo di phn ng bng SKLM vi hdung mi trin

khai n-hexan/ ethylacetat. Sau khi kt thc phn ng ngui bnh phn ng, hn

hp phn ng vo nc , thy c kt ta to thnh th tin hnh lc ht kit, ra tanhiu ln bng nc ct. Ra tip vi ln bng dung mi thch hp (EtOH lnh,

methanol, etylacetat). Sy kh ta thu c trong chn khng. Sau y l kt quc

th:


36/134

Tin hnh:

Hp cht 14a c tng hp t (2mmol) cht 4; 0,23ml(2mmol) 2-

methylbenzaldehyd; 208mg (2mmol) NaHSO3; trong 2ml DMAC.

Sn phm thu c l 386mg cht bt mu trng ng. Hiu sut 77%.(bng 3.1)

Nhit nng chy: 215-216oC. (bng 3.2)

Rf= 0,75 (TLC, Silicagel 60 F254, hdung mi n-hexan: EtOAc (2:1))(bng 3.2)

ESI_MS: xem phlc 2.1, bng 3.3.IR(KBr, max(cm

-1)):xem phlc 2.2, bng 3.4.1H-NMR (500MHz, DMSO-d6), (ppm): xem phlc 2.3, bng 3.5.13C-NMR (125MHz, DMSO-d6), (ppm): xem phlc 2.4, bng 3.6.

6-Methyl-2-m-tolyl quinazolin-4(3H)-(14b)

Cng thc:

NH

N

H3

C

O

CH3


Tin hnh:

Cc bc tin hnh tng hp cht 14b tng tcht 14a, t300mg (2mmol)

cht 4; 0,24ml(2mmol) 3-methylbenzaldehyd; 208mg (2mmol) NaHSO3; trong 2ml

DMAC.

Sn phm thu c l 450mg cht bt mu trng ng. Hiu sut 90%.(bng 3.1)



37/134

6-Methyl-2-(2-(trif luoromethyl)phenyl)quinazolin-4(3H)-on (14c)

Cng thc:

NH

N

CF3H3C

O

CTPT: C16H11F3N2O; KLPT: 304,27

Tin hnh:

Cc bc tin hnh tng hp cht 14c tng tcht 14a, t 300mg (2mmol)

cht 4; 0,26ml(2mmol) 2-trifluoromethylbenzaldehyd; 208mg (2mmol) NaHSO3trong

2ml DMAC.

Sn phm thu c l 290mg cht bt mu vng nht. Hiu sut 48%.(bng 3.1)Nhit nng chy: 195-196oC. (bng 3.2)


ESI_MS: xem phlc 4.1, bng 3.3.

IR(KBr, max(cm-1)):xem phlc 4.2, bng 3.4.

1H-NMR (500MHz, DMSO-d6), (ppm): xem phlc 4.3, bng 3.5.13C-NMR (125MHz, DMSO-d6), (ppm): xem phlc 4.4, bng 3.6.

6-Methyl-2-(3-(trif luoromethyl)phenyl)quinazolin-4(3H)-on (14d)

Cng thc:

NH

N

H3C

CF3


38/134

Sn phm thu c l 500mg cht bt mu vng nht. Hiu sut 82%. (bng

3.1)





1

H-NMR (500MHz, DMSO-d6), (ppm): xem phlc 5.3, bng 3.5.13C-NMR (125MHz, DMSO-d6), (ppm): xem phlc 5.4, bng 3.6.

6-Methyl-2-(2-(trif luoromethoxy)phenyl)quinazolin-4(3H)-on (14e)

Cng thc:

NH

N

H3C

O

OCF3

CTPT: C16H11F3N2O2; KLPT: 320,27

Tin hnh:

Cc bc tin hnh tng hp cht 14e tng t cht 14a, t300mg (2mmol)

cht 4; 0,29ml(2mmol) 2-(trifluoromethoxy)benzaldehyd; 208mg (2mmol) NaHSO3

trong 2ml DMAC.


3.1)




39/134

6-Methyl-2-(3-(trif luoromethoxy)phenyl)quinazolin-4(3H)-on (14f)

Cng thc:

NH

N

H3C

O

OCF3


Tin hnh:

Cc bc tin hnh tng hp cht 14f tng t cht 14a, t300mg (2mmol)


trong 2ml DMAC.

Sn phm thu c l 520mg cht bt mu vng nht. Hiu sut 96%. (bng3.1)




IR(KBr, max(cm-1)):xem phlc 7.2, bng 3.4.1H-NMR (500MHz, DMSO-d6), (ppm): xem phlc 7.3, bng 3.5.13C-NMR (125MHz, DMSO-d6), (ppm): xem phlc 7.4, bng 3.6.

2-(2-F luorophenyl)-6-methyl quinazolin-4(3H)-on (14g)

Cng thc:

N


40/134

Sn phm thu c l 353mg cht bt mu vng. Hiu sut 70%. (bng 3.1)





1H-NMR (500MHz, DMSO-d6), (ppm): xem phlc 8.3, bng 3.5.13

C-NMR (125MHz, DMSO-d6), (ppm): xem phlc 8.4, bng 3.6.

2-(3-F luorophenyl)-6-methyl quinazolin-4(3H)-on (14h)

Cng thc:

NH

N

H3C

O

F

CTPT: C15H11FN2O; KLPT: 254,26

Tin hnh:

Cc bc tin hnh tng hp cht 14h tng tcht 14a, t300mg (2mmol)

cht 4; 0,21ml(2mmol) 3-fluorobenzaldehyd; 208mg (2mmol) NaHSO3 trong 2ml

DMAC.

Sn phm thu c l 455mg cht bt mu vng. Hiu sut 90%. (bng 3.1)




IR(KBr, max (cm-1)): xem ph lc 9.2, bng 3.4.


41/134

2-(2-(Dimethylamino)phenyl)-6-methyl quinazolin-4(3H)-on (14i)

Cng thc:

NH

N

H3C

O

N(CH3)2


Tin hnh:

Cc bc tin hnh tng hp cht 14i tng t cht 14a, t 300mg (2mmol)

cht 4; 300mg (2mmol) cht 13; 208mg (2mmol) NaHSO3trong 2ml DMAC.

Sn phm thu c l 432mg cht bt mu trng ng. Hiu sut 77%. (bng

3.1)



ESI_MS:xem phlc 10.1, bng 3.3.


2-(2-(Dimethylamino)phenyl)-7-methyl quinazolin-4(3H)-on (14j)

Cng thc:

NH3C


42/134

Sn phm thu c l 340mg cht bt mu trng ng. Hiu sut 61%. (bng

3.1)



ESI_MS:xem phlc 11.1, bng 3.3


1


7-Methyl-2-(2-(trif luoromethoxy)phenyl)quinazolin-4(3H)-on (14k)

Cng thc:

NH

N

O

H3C

OCF3


Tin hnh:

Cc bc tin hnh tng hp cht 14k tng tcht 14a, t300mg (2mmol)


trong 2ml DMAC.


3.1)




43/134

6-Methyl-2-(naphthalen-1-yl)qui nazolin-4(3H)-on (15a)

Cng thc:

NH

N

H3C

O


Tin hnh:

Cc bc tin hnh tng hp cht 15a tng tcht 14a, t300mg (2mmol)

cht 4; 0,27ml (2mmol) 1-naphthaldehyd; 208mg (2mmol) NaHSO3 trong 5ml

DMAC. Lc ra ta vi ethanol lnh.

Sn phm thu c l 438mg cht bt mu vng m. Hiu sut 76%. (bng

3.1)





7-Methyl-2-(naphthalen-1-yl)qui nazolin-4(3H)-on (15b)

Cng thc:

NH3C


44/134

Sn phm thu c l 266mg cht bt mu vng m. Hiu sut 70%. (bng

3.1)





1


6-(Dimethylamino)-2-(naphthalen-1-yl)quinazolin-4(3H)-on (15c)

Cng thc:

NH

N

(H3C)2N

O


Tin hnh:

Cc bc tin hnh tng hp cht 15ctng tcht 14a, t300mg (1,68mmol)

cht 11; 0,2ml (1,68mmol) 1-naphthaldehyd; 281mg (1,68mmol) NaHSO3 trong 3ml

DMAC. Lc ra ta vi nc, ethanol v ethylacetat.

Sn phm thu c l 317 mg cht bt mu vng m. Hiu sut 60%. (bng

3.1)




45/134

Bng 3.1: Kt qutng hp cc dn cht 14a-k v 15a-c.

TT

K

hiu R1 R2

M

(.v.c)

Hiu

sut (%)

Tnh cht

1 14a 6-CH3 2- CH3 250,30 77 cht bt, mu trng ng

2 14b 6-CH3 3- CH3 250,30 90 cht bt, mu trng ng

3 14c 6-CH3 2-CF3 304,27 48 cht bt, mu vng nht

4 14d 6-CH3 3-CF3 304,27 82 cht bt, mu vng nht

5 14e 6-CH3 2-OCF3 320,27 98 cht bt, mu vng nht

6 14f 6-CH3 3-OCF3 320,27 96 cht bt, mu vng nht

7 14g 6-CH3 2-F 254,26 70 cht bt, mu vng

8 14h 6-CH3 3-F 254,26 90 cht bt, mu vng

9 14i 6-CH3 2-N(CH3)2 279,34 77 cht bt, mu trng ng

10 14j 7-CH3 2-N(CH3)2 279,34 61 cht bt, mu trng ng

11 14k 7-CH3 2-OCF3 320,27 69 cht bt, mu vng nht

12 15a 6-CH3 286,33 76 cht bt, mu vng m

13 15b 7-CH3 286,33 70 cht bt, mu vng m

14 15c 6-N(CH3)2 315,37 60 cht bt, mu vng m

3.2. KIM TRA TINH KHIT, KHNG NH CU TRC

3.2.1. Kim tra tinh khit


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di n tngoi c bc sng 254nm th thy cc cht em thu cho 1 vt gn.

Gi trRfca cc cht 14a-kv 15a-c khi trin khai vi hai hdung mi c tm tt

bng 3.2.

o nhit nng chy

Cc cht 14a-k v 15a-c c kim tra tinh khit bng SKLM ng thi

c tin hnh o nhit nng chy. Kt quo nhit nng chy cho thy: cc

dn cht tng hp c u c im chy r rng, khong chnh lch hp. Kt qucthc tm tt bng 3.2.

Bng 3.2: Gi trRfv Tncca cc dn cht 14a-k v 15a-c

TTK

hiu

R1 R2

Nhit

nng chy

(ToC)

Rf

H dung mi SK

(n-hexan:EtOAc)

1 14a 6-CH3 2- CH3 215-216 0,75 2:1

2 14b 6-CH3 3- CH3 235-236 0,68 2:1

3 14c 6-CH3 2-CF3 195-196 0,58 1:1

4 14d 6-CH3 3-CF3 299-300 0,58 2:1

5 14e 6-CH3 2-OCF3 201-202 0,61 1:1

6 14f 6-CH3 3-OCF3 245-246 0,63 1:1

7 14g 6-CH3 2-F 228-229 0,75 1:1

8 14h 6-CH3 3-F 308-309 0,70 1:1

9 14i 6-CH3 2-N(CH3)2 204-205 0 54 2:1


47/134

Thng qua sc k khi chy SKLM v nhit nng chy ca cc dn cht

c thkhng nh cc cht ny l tinh khit, iu kin o phv thhot tnh

sinh hc.

3.2.2. Khng nh cu trc

3.2.2.1.

Phkhi lng (LC-MS)

Cc dn cht tng hp c ghi ph khi lng theo phng php phun m

in t (ESI-MS) trn my LC-MSD-Trap-SL ti Vin Ha hc cc hp cht thin

nhinVin Hn lm Khoa hc v Cng nghVit Nam. 14 phc ghi cc

phlc 2.1 15.1, bng 3.3.

NH

N

O

R1

R2

14a-k

12

34

5

6

7

81'

2'3'

4'

5'

6'

NH

N

O

R1

12

34

5

6

7

8

15a-c


48/134

Bng 3.3: Kt quphn tch phkhi lng ca cc dn cht 14a-k v 15a-c

TTK

hiuR1 R2 M (.v.c) m/z (ESI-MS)

1 14a 6-CH3 2- CH3 250,30 251,1 [M+H]+

2 14b 6-CH3 3- CH3 250,30 249,0 [M-H]-

3 14c 6-CH3 2-CF3 304,27 305,0 [M+H]+

4 14d 6-CH3 3-CF3 304,27 305,0 [M+H]+

5 14e 6-CH3 2-OCF3 320,27 319,0 [M-H]-

6 14f 6-CH3 3-OCF3 320,27 319,0 [M-H]-

7 14g 6-CH3 2-F 254,26 255,1 [M+H]+

8 14h 6-CH3 3-F 254,26 255,1 [M+H]+

9 14i 6-CH3 2-N(CH3)2 279,34 280,1 [M+H]+

10 14j 7-CH3 2-N(CH3)2 279,34 280,1 [M+H]+

11 14k 7-CH3 2-OCF3 320,27 319,0 [M-H]-

12 15a 6-CH3 286,33 287,1 [M+H]+

13 15b 7-CH3 286,33 287,1 [M+H]+

14 15c 6-N(CH3)2 315,37 314,1 [M-H]-

Ph hng ngoi (I R)


49/134

NH

N

O

R1

R2

14a-k

1

234

5

6

7

81'

2'

3'

4'

5'

6'

NH

N

O

R1

12

34

5

6

7

8

15a-c

Bng 3.4: Sliu phIR ca cc dn cht 14a-k v 15a-c

T

T

K

hi

u

R1 R2

Ph IR (KBr), cm-1

NH

(amid)

CH

(aryl)C=O

C=C

(aryl)

1 14a 6-CH3 2- CH3 3055-2928 1682 1453

2 14b 6-CH3 3- CH3 3041-2928 1682 1484

3 14c 6-CH3 2-CF3 3414 3036-2872 1648 1490 -1151

4 14d 6-CH3 3-CF3 3414 3036-2951 1648 1490 -1151

5 14e 6-CH3 2-OCF3 3071-2958 1661 1494 -1577

6 14f 6-CH3 3-OCF3 3086-2958 1661 1494

7 14g 6-CH3 2-F 3019-2877 1680 1443 -1495

8 14h 6-CH3 3-F 3024 2883 1680 1495

9 14i 6-CH3 2-N(CH3)2 3513 2921-2970 1585-1621 1484

10 14j 7-CH3 2-N(CH3)2 3069-2934 1596-1664 1449


50/134


51/134

1H, H5,J1=2,5; J2=2,0); 7,71 (m, 2H, H4, H7);

7,63 (s, 1H, H8,J=8,5); 7,58 (m, 2H, H3, H5);

2,468 (s, 3H, C6-CH3)

6 14f 6-CH3 3-OCF3

12,64 (s, 1H, NH); 8,24 (d, 1H, H5, J=8,0);

8,16 (s, 1H, H2); 7,97 (s, 1H, H7); 7,713 (m,

3H, H8, H5, H6); 7,61 (d, 1H, H4,J=8); 2,472

(s, 3H, C6-CH3)

7 14g 6-CH3 2-F

12,48 (s, 1H, NH); 7,97 (m, 1H, H5); 7,97 (d,

1H, H6, J=1,0); 7,79 (dt, 1H, H4, J1=8,5;

J2=2,0); 7,64 (m, 2H, H7, H8); 7,40 (m, 2H,

H3, H5); 2,47 (s, 3H, C6-CH3)

8 14h 6-CH3 3-F

12,51 (s, 1H, NH); 8,06 (d, 1H, H2, J=8);

8,01 (d, 1H, H5,J=10); 7,96 (s, 1H, H5); 7,67

(m, 2H, H6, H7); 7,62 (m, 1H, H8); 7,46 (m,1H, H4); 2,469 (s, 3H, C6-CH3)

9 14i 6-CH3 2-N(CH3)2

12,74 (s, 1H, NH); 7,94 (s, 1H, H5); 7,85 (dd,

1H, H6,J=8); 7,66 (m, 2H, H7, H8); 7,49 (m,

1H, H4); 7,26 (d, 1H, H5,J=8); 7,15 (m, 1H,

H3); 2,67 (m, 6H, -N(CH3)2); 2,45 (s, 3H, C6-

CH3)

10 14j 7-CH3 2-N(CH3)2

12,92 (s, 1H, NH); 8,46 (d, 1H, H5,J=8); 8,21

(d, 1H, H6, J=8); 7,60 (s, 1H, H6); 7,51 (m,

1H, H8); 7,31 (m, 2H, H4, H5); 7,28 (m, 1H,

H3); 2,93 (m, 6H, -N(CH3)2)

11 14k 7-CH3 2-OCF3

10,31 (s, 1H, NH); 8,18 (d, 1H, H6

,J=8); 8,12

(dd, 1H, H5,J=8); 7,61 (m, 2H, H4, H6); 7,51

(t, 1H, H8,J=7,5); 7,42 (d, 1H, H3,J=8); 7,35

(d, 1H, H5,J=8); 2,53 (s, 3H, C7-CH3)


52/134

14 15c 6-N(CH3)2

12,38 (s, 1H, NH); 8,19 (m, 1H, H2); 8,09 (d,

1H, H4,J=8,5); 8,04 (m, 1H, H5); 7,76(d, 1H,

H8, J=6,5); 7,64 (m, 4H, H3, H6, H7, H8);

7,38 (dd, 1H, H5, J1=3; J2=3,0); 7,29 (d, 1H,

H7,J=3,0); 3,05 (m, 6H, 2 (-CH3))

Bng 3.6: Sliu ph13C-NMRca cc dn cht 14a-k v 15a-c

TT K

hiuR1 R2

13C-NMR, (DMSO); (ppm)

1 14a 6-CH3 2- CH3

161,66 (C4); 153,47 (C2); 146,72;

136,29;136,06; 135,67; 134,28; 130,47;129,76; 129,06; 127,20; 125,64; 125,10;

120,69; 20,80 (CH3(C3)); 19,51 (CH3(C2))

2 14b 6-CH3 3- CH3

162,12 (C4), 151,57 (C2); 146,72 (C9); 137,88;

136,23; 135,84; 132,70; 131,82; 128,46;

128,14; 127,32; 125,21; 124,74; 120,68 (C10);

20,94 (CH3(C3)); 20,82 (CH3(C6))

3 14c 6-CH3 2-CF3

161,25 (C4); 151,49 (C2); 146,38 (C8a); 136,87;

135,89; 133,11; 132,39; 130,72; 130,40;

127,30; 126,90; 125,20; 124,87; 122,69;

120,92; 20,85 (-CH3)

4 14d 6-CH3 3-CF3

162,04 (C4); 150,12 (C2); 146,43 (C8a); 136,81;

135,97; 133,75; 131,62; 129,83; 129,53;

127,63; 127,53; 125,27; 124,35; 120,91;

20 86(-CH3)


53/134

7 14g 6-CH3 2-F

161,38 (C4); 160,54; 158,55; 149,055;

146,675; 136,76; 135,82; 132,73; 130,96;

127,34; 125,19; 122,36; 120,82; 116,21;20,83(-CH3)

8 14h 6-CH3 3-F136,69; 135,95; 135,03; 130,74; 130,68;

127,47; 125,26; 123,77; 120,84; 118,16;

117,99; 114,48; 114,29; 20,85(-CH3)

9 14i 6-CH3 2-N(CH3)2

161,17 (C4); 152,88 (C2); 151,86 (C2); 147,26(C8a); 136,22; 135,69; 131,61; 130,59; 127,36;

125,23; 122,17; 120,88; 119,18; 43,70 (-

N(CH3)2); 20,83 (-CH3)

10

14j 7-CH3 2-N(CH3)2

162,01 (C4); 152,35 (C2); 145,29 (C8a); 132,32;

131,29; 128,010; 127,56; 126,29; 124,93;

124,79; 120,17; 119,26; 45,08 (-N(CH3)2);

21,92 (-CH3)

11 14k 7-CH3 2-OCF3

161,95 (C4); 149,26; 149,09; 146,49; 145,96;

132,58; 131,85; 128,97; 127,84; 127,64;

126,76; 126,35; 121,46; 121,31; 118,68; 21,97

(-CH3)

12 15a 6-CH3

161,797 (C4); 152,77 (C2); 146,67 (C8a);

136,44 (C6); 135,70; 133,10; 131,73; 130,24;

128,28; 127,58; 127,24; 126,98; 126,28;

125,17; 125,14; 125,01; 120,91; 20,81 (-CH3)

13 15b 7-CH3

161,75 (C4); 153,63 (C2); 148,81 (C8a); 144,98

(C7); 133,12; 131,70; 130,32; 130,23; 128,29;

128,15; 127,60; 127,08; 126,99; 126,30;

125,68; 125,17; 125,06; 118,78(C4a); 21,31 (-

CH )

3 3 TH HOT TNH GY C T BO UNG TH


54/134

3.3.

THHOT TNH GY C TBO UNG TH

Thhot tnh gy c tbo trn mt sdng tbo ung th ngi c tin

hnh ti Phng Ha sinh ng dngVin Ha hcVin Hn lm Khoa hc v Cng

nghVit Nam.

Ti phng Ha sinh ng dng (Vin Ha hc), 14 dn cht do nhm nghin cu

tng hp c 14a-k v15a-c c thhot tnh gy c tbo trn cc dng t

bo ung th ngi theo phng php MTT. Cc dng tbo ung th c sdng l:

KB (Human epidemic carcinoma) ung th biu m; Hep G2 (Hepatocellular

carcinoma) ung th gan; LU (Human lung carcinoma) ung th phi v MCF-7

(Human breast carcinoma)ung th v.

Kt qu thhot tnh gy c tbo ca 14 dn cht tng hp c trnh

by bng 3.6.Kt qucho thy dn cht 14c,14e, 14g, 14h, 14i, 14k, 15a-cc hot tnh c

chtrn cbn dng tbo ung th ngi, ring cht 14ikhng c hot tnh trn t

bo ung th phi.

Trong ng lu l dn cht 15cc hot tnh tt trn cbn dng tbo ung

th nng IC50 = 0,0510,5 g/ml.

Bng 3 7: Kt qu th hot tnh gy c t bo ca 14a-k v 15a-c trn 4 dng t


55/134

Bng 3.7: Kt quthhot tnh gy c tbo ca 14a-k v 15a-c trn 4 dng tbo ung th ngi

TTK hiu

chtR1 R2

Gi trIC50(g/ml)

KB Hep-G2 LU MCF7

1 14a 6-CH3 2- CH3 >128 nt nt nt

2 14b 6-CH3 3- CH3 >128 nt nt nt

3 14c 6-CH3 2-CF3 4,48 5,81 62 74

4 14d 6-CH3 3-CF3 >128 Nt nt nt

5 14e 6-CH3 2-OCF3 1,18 1,36 2 25,33

6 14f 6-CH3 3-OCF3 >128 nt nt nt

7 14g 6-CH3 2-F 29,17 24,8 104 29,25

8 14h 6-CH3 3-F 0,32 0,5 7,21 21,11

9 14i6-CH3

2-

N(CH3)2 0,84 5,27 8 >12810 14j 7-CH3

2-N(CH3)2

>128 nt nt nt

11 14k 7-CH3 2-OCF3 70,4 32 104 >128

12 15a 6-CH3 3,92 5,8 11,69 16,64

13 15b 7-CH3 14,85 20,75 30 30,62

14 15c 6-N(CH3)2 0,051 0,096 0,125 0,5

CHNG 4: BN LUN


56/134

CHNG 4: BN LUN

4.1. VTNG HP HA HC

4.1.1.

Tng hp dn cht trung gian 2-aminobenzamid vkhng nh cu trc

Tng hp 2-amino-5-methylbenzamid 4

NO2

COOH

NO2

COCl

NH4

OH

Diclomethan CONH2

CH3

NH2

CONH2

H3C H3C H3C

NO2

SOCl2

H2, 10% Pd/C

CH3OH

1 2 3

4

Tng hp 2-amino-5-methylbenzamid 4tacid 5-methyl-2-nitrobenzoic 1 qua

3bc. u tin acid 1 c hot ha bng tc nhn thionylclorid v unhi lu

50oC trong 4h thu c sn phml benzoylclorid 2. Sau hp cht2 tip tc phn

ng vi dung dung dch NH4OH nhit 0oC trong dung mi DCM thu c hp

cht 3(hiu sut 82%). Cui cng hydro ha nhmNO2ca 3 vi xc tc 10%Pd/C nhit phng thu c hp cht 2-amino-5-methylbenzamid 4, phn ng c hiu

sut cao 94%.

Sn phm 4c khng nh cu trc bng phcng hng tht nhn proton1H-NMR. Trn ph 1H-NMR ca hp cht 4 thy: pic rng ca nhm amid v tr

7,65-7,34ppm; cc H ca vng thm xut hin v tr 6,96-6,59 ppm; proton ca

nhm aminNH2xut hin vtr 6,30 ppm; v pic nhmCH3xut hin vtr 2,13

ppm. Dliu ph1H-NMR ca hp cht 4 ph hp vi ti liu tham kho c [22,

tng hp 2-amino-4-methylbenzamid 6, tin hnh thy phn 2-amino-4-


57/134

g p o e y be d 6, y p o

methylbenzonitril trong mi trng kim KOH/ EtOH, phn ng c un hi lu

90oC, cho hiu sut 73 %.

Sn phm 6 c khng nh bng ph cng hng t ht nhn proton 1H-

NMR. Trn ph1H-NMR ca hp cht 6cng cho thy: proton ca vng thm xut

hin v tr 7,26-6,47 ppm; proton ca nhm CH3xut hin v tr 2,26 ppm. D

liu ph1H-NMR ca hp cht 6 ph hp vi ti liu tham kho c [22,23].(bng

4.1, phlc 1.2)

Tng hp 2-amino-5-(dimethyl amino)benzamid

NO 2

COCl

NH4OH

Dicloromethan

NO 2

CONH2

(H3C)2N

NH 2

CONH2

Cl

NO 2

Cl ClCOOH

SOCl2

(H3C)2N

NO 2

CONH2

H2, 10% Pd/C

CH3OHDMF, 1100C

NH(CH3)2

7 8 9

10 11

Qa trnh tng hp 2-amino-5-(dimethyl amino)benzamid 11gm 4bc. Phn

ng hot ha acid 7v amin ha 8 tng tkhi tng hp 2, 3 thu c hp cht 9.

Tip tc tin hnh phn ng tha nhm dimethylamin vo hp cht 9 trong dung

mi DMF, phn ng c tin hnh trong bnh kn. Phn hn hp phn ng c un

nng 110oC, thu c hp cht 10. Hiu sut phn ng cao 96%. Sau khha

nhmNO2ca hp cht 10bng phn ng hydro ha vi xc tc 10%Pd/C nhit phng thu c 2-amino-5-(dimethyl amino)benzamid 11. Hiu sut phn ng 72%.

Sn phm thu c 11 khng nh bng phcng hng tht nhn proton 1H-

h 1 h h h h i h id

Bng 4.1: Ph1H-NMR ca cc dn cht trung gian 4, 6, 11


58/134

g g g , ,

TT Cht CTCT 1H-NMR (DMSO; (ppm), J(Hz))

1 4

CH3

NH2

CONH2

7,65-7,34 (2H, -CONH2); 6,96 (dd, 2H, H4,6,

J=3,0); 6,59 (d, 1H, H3,J=8,5); 6,30 (s, 2H, C2-

NH2); 2,13 (m, 3H, C5-CH3).

2 6 H3C NH2

CONH2

7,26 (m, 1H, H6,J=3,5); 6,49 (s, 1H, H5); 6,47

(d, 1H, H3,J=8,0); 2,26 (s, 3H, C

4-CH

3).

3 11

(H3

C)2N

NH2

CONH2

7,72-7,00 (s, 2H, -CONH2); 6,91 (d, 1H, H6,

J=2,5); 6,81 (dd, 1H, H4,J=9); 6,61 (d, 1H, H3,

J=3,5) 5,87 (s, 2H, C2-NH2); 2,75 (m, 6H, -

N(CH3)2).

4.1.2.Tng hp dn cht trung gian aldehyd thmvkhng nh cu trc

NCH3H3C

OHCOHC

F

NH(CH3)2

K2

CO3

, DMF, 1100C

12 13 Hu ht cc aldehyd thm trong lun vn ny u c sdng trc tip khng

qua xl g thm. Tng hp thm dn cht 2-(dimethylamin)benzaldehyd bng phn

ng thnhm dimethylamino vo o-flourobenzaldehyd vi cht xc tc kim K2CO3

trong mi trng DMF 1100C. Phn ng cho hiu sut 92%.

Sn phm thu c 12 khng nh bng phcng hng tht nhn proton 1H-

NMR. Trn ph 1H-NMR ca hp cht 11 cng cho thy: proton ca nhm CHO

xut hin vtr 10,21ppm; cc proton ca vng thm xut hin vtr 7,76-7,04; v

chung l phn ng ngng tcc dn cht 2-aminobenzamid v cc aldehyd thm c


59/134

un nng 150oC trong mi trng N,N-dimethylamin sau c tinh chthu sn

phm. Phng php ny c la chn v:

- Nguyn liu v cc hp cht aldehyd thm ban u sn c, a dng.

- Phn ng tin hnh ddng, hiu sut phn ng cao.

- Sn phm thu c hu ht l cc cht kt tinh trong nc, chcn lc ra,

dtinh ch.

C chphn ng xy ra theo s 4.1 di y:

R1

NH2

NH2

O

RH

O

R1

N

NH2

O

R

R1

HN

NH

O

R

R1

N

NH

O

R

NaHSO3

1617 18

19

DMAC

-H2O

S 4.1: C chtng hp cc cht 2-aryl-4-quinazolinon

u tin phn ng cng hp i nhn vo nhm carbonyl ca hp cht aldehyd,

tip theo c sloi nc to thnh cht 17.

Sau , cht 17ng vng to vng 6 cnh bn to thnh cht 18 trong dung

mi N,N-dimethylacetamid, cui cng di tc dng oxy ha ca NaHSO318 dehydro

ha tch hydro to thnh vng quinazolinon bn 19 [1,22,23,27].

Tng hp cc dn cht 2-aryl-4-quinazolinon theo phng php ca Hour M J

4.2.

VXC NH CU TRC


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4.2.1.

Phhng ngoi( IR)

tin hnh o ph hng ngoi ca 14 dn cht tng hp c. Qua nghin

cu phca cc cht, chng ti nhn bit c cc di hp thc trng ca cc

nhm chc v lin kt ca cc cht tng hp c. Kt qubin gii phc trnh

by bng 3.4. Sau y l mt snhn xt chung:

Ph hng ngoi ca 14 cht 14a-k v 15a-c u c xut hin di hp th

mnh tng ng vi dao ng nhmNH amid nm trong vng t3513-3414

cm-1

ph hp vi dao ng ha tr ca nhm amin bc 2 b nh hng bi

nhm carbonyl. Tuy nhin trn ph hng ngoi ca mt s cht khng xut

hin di hp thmnh ny iu ny c thgii thch nh sau, do pic ca nhm

amid c tnh cht t v thp nn c thdo trong qu trnh ophbbqua.Trn phhng ngoi cng xut hin di phc trng ca nhm -CH c

trng c trnh by bng 3.4 v phlc 2.2 15.2.

Trn phhng ngoi ca 14 dn cht tng hp c u xut hin di hp

thca nhm C=O amid 1680-1585 cm-1.

Trn 14 phca 14 dn cht 14a-k v 15a-ctng hp c u xut hin

di hp thc trng ca cc nhmCH thuc vng thm 2880-3159 cm-1.

Nh vy, qua vic xc nh sc mt ca cc nhm thc trng, s bc

thnhn thy phn ng tng hp xy ra. Tuy nhin, khng nh chc chn cu

trc ca cc cht th cn thm d liu ca phkhi lng v phcng hng thtnhn.

Di y l hnh nh minh ha phhng ngoi ca cht 15c.


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Hnh 4.1: Phhng ngoi ca cht 15c

4.2.2.

Phcng hng tht nhn proton (1H-NMR)

Ph1H-NMR cho thy cc tn hiu c trng ca cc proton v slng proton

tng dng ca 14 dn cht tng hp c ghi qua sliu vdch chuyn ha hc ,

bi, hng sghp cp J, v cng ca cc pic c trnh by bng 3.5. Sau

y l bin gii vmi quan hcu trc phn tv ph1H-NMR ca cc cht tng

hp c. Ph1H-NMR cho thy tn hiu ca proton H-N3( tn hiu t, cng yu)

CHNH CH

C=O

Sau y l phcng hng tht nhn 1H-NMR minh ha ca hp cht 15c.


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a)

-N(CH3)2

-NH

b)


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Hnh 4.2: a)Ph1H-NMR; b) Ph1H-NMR dn rng ca cht 15c

4.2.3.

Phcng hng tht nhn 13C (13C-NMR)

14 dn cht tng hp (I-XIV) c ghi ph13C-NMR. Kt quphn tch

phc trnh by bng 3.6 cho thy cc cht c ghi phc scarbon v dich

chuyn ha hc ca cc vtr carbon trong cng thc phn tph hp vi cng thc

dkin.

Nguyn t carbon nhm C=O (amid) l C4 c tn hiu cng hng trong vng

H2

H4

H5

H8

H3 6 7 8

H5

H7

Sau y l ph13C-NMR minh ha ca hp cht 15c.


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a)

-CH3

b)


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Hnh 4.3: a)Ph13C-NMR; b) Ph13C-NMRdn rng ca cht 15c

4.2.4.

Phkhi lng (MS)

khng nh thm vcu trc ca 14 dn cht 14a-k v 15a-c chng ti

tin hnh ghi phMS (LC_MS) ca cc dn cht ny.

Sau y l v dphn tch phkhi lng xc nh sph hp gia CTPT

d kin v CTPT ca cht 15c tng hp c. Cht 15c c CTPT d kin l

C20H17N3O tng ng vi skhi l 315,37. Trn phxut hin pic [M-H]-cng

l ht khi 314 (H h 4 4) Nh b h th ht 15 khi

C4 C5


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Hnh 4.4: Phkhi lng (MS) ca cht 15c

Tcc kt qughi ph thu c c thnhn thy 14 cht tng hp c u

xut hin pic phn tc cng phn t ln, khi lng ion phn tph hp vi

khi lng phn tdon ca cht dkin.

Tm li d liu ph thc nghim cho php khng nh cu trc cc hp cht

tng hp dy 14a-k v 15a-c ng nh d kin v l sn phm tinh khit T cc

[M-H]-

[M]

4.3.

VHOT TNH KHNG TBO UNG TH

D t kt th h t t h kh t b th b 3 7 th h th


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Da trn kt quthhot tnh khng tbo ung th bng 3.7 c thnhn thy

mt smi lin quan gia cu trc v tc dng gy c trn bn dng tbo ung th

thnghim nh sau:

Bng 3.7: Kt quthhot tnh gy c tbo ca 14 dn cht trn 4 dng tbo ung th ngi.

TTK hiu

chtCTCT

Gi trIC50(g/ml)

KB Hep-G2 LU MCF7

1 14aNH

N

CH3

H3CO

>128 nt nt nt

2 14bNH

N

H3C

O

CH3

>128 nt nt nt

3 14cNH

N

CF3H3C

O

4,48 5,81 62 74

4 14dNH

N

H3C

O

CF3

>128 nt nt nt

5 14e NHN

H3C

O

OCF3

1,18 1,36 2 25,33

6 14f N OCF3 >128 nt nt nt

9 14i N 0 84 5 27 8 >128


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9 14iNH

H3C

O

NMe2

0,84 5,27 8 >128

10 14jNH

N

O

H3C

NMe2

>128 nt nt nt

11 14kNH

N

O

H3C

OCF3

70,4 32 104 >128

12 15aNH

N

H3C

O

3,92 5,8 11,69 16,64

13 15bNH

N

O

H3C

14,85 20,75 30 30,62

14 15cNH

N

Me2N

O

0,051 0,096 0,125 0,5

Ellipticin 0,31 0,35 0,45 0,53

Cc dn cht c hot tnh th u c tc dng trn c4 dng tbo ung th c

bit c p ng tt nht trn dng tbo ung th biu mKB trong c dn

cht 15cc hot tnh mnh nht vi IC50= 0,051g/ml.Hu ht cc dn cht c cha nhm thF trn vng phenyl thvtr C2ca

vng quinazolinon nh: -F, -OCF3, -CF3 u c hot tnh gy c trn cbn

Tng tnh vy, dn cht 14ev 14fcho thy nhm th-OCF3vtr C2c

hot tnh sinh hc cao IC = 1 18 g/ml; 1 36 g/ml; 2 00 g/ml; 25 33 g/ml


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hot tnh sinh hc cao IC50= 1,18 g/ml; 1,36 g/ml; 2,00 g/ml; 25,33 g/ml

tng ng vi bn dng tbo ung th biu m, ung th gan, ung th phi, ung

th v, cn vtr C3li khng c hot tnh sinh hc. Khi so snh vi ti liu

tham kho [22] nhm th-OCF3vtr C2c hot tnh khng tbo ung th

da trn chut v trn ngi cao nng IC50= 0,35 v 0,47M.

Ngc li dn cht 14hnhm th-F vtr thC3li c hot tnh cao hn

trn cbn dng tbo ung th so vi dn cht 14gc nhm th-F vtr C2.

So snh vi ti liu tham kho [22] dn cht 6-pyrolidinyl-2(2-substituted

phenyl)-4-quinazolinon c nhm th-F vtr 2 cng c hot tnh trn 2 dng

tbo ung th da ngi v chut trn tng s6 dng ung th thnghim

nng IC50= 0,51 v 0,75

M.

Cc dn cht 15a-cc nhm thnaphthalen vtr C2ca vng quinazolinon

u c hot tnh sinh hc cao trn cbn dng tbo ung th ngi. Tng t

khi so snh vi ti liu tham kho [33] cho thy dn cht 2-(napthalen-1-yl)-6-

pyrolidinyl-quinazolinon cng c tc dng rt tt trn 6 dng tbo ung th:

ung th da, ung th phi, ung th gan, ung th vm hng, khi u c tnh vi

nng IC50= 0,033-1,350 M.

T3 cp dn cht 14cv 14k, 14iv 14j, 15a v 15bcho thy nhm th-CH3

vtr C6c tc dng gy c tbo ung th tt hn so vi vtr C7ca vng

quinazolinonDn cht 15c c nhm thdimethylamin v tr C6 c hot tnh sinh hc rt

cao cao IC50= 0,051 g/ml; 0,096 g/ml; 0,125 g/ml; 0,5 g/ml tng ng vi

Nh vy, kt quthhot tnh gy c tbo ung th ca cc dn cht 14a-k

v 15a-c cng vi vic so snh vi cc dn cht c cng b trong cc ti liu


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v 15a-c cng vi vic so snh vi cc dn cht c cng b trong cc ti liu

tham kho c, c thcho thy:

Nhm thvtr C6cho hot tnh ca dn cht tng hp c cao hn vtr

C7.

Nhm thnaphthalen vtr C2ca vng quinazolinon cho hot tnh gy c

cc tbo ung th cao.

Dn cht c nhm thdimethylamin vtr C6c hot tnh sinh hc cao.

Hu ht cc hp cht tng hp c c tnh chn lc trn dng tbo ung th

KB tbo ung th biu m, tbo hay c sdng trong cc nghin cu

thhot tnh sinh hc.

Vtr nhm th2 v 3 trn vng 2-phenyl khng c tnh quyt nh n hottnh gy c tbo ung th ca cc hp cht tng hp c.

KT LUN V KIN NGH

KT LUN


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KT LUN

Tnhng kt qunghin cu trnh by trn, c thrt ra mt skt lun

nh sau:

1. tng hp c 14 dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c). Trong

c 13 cht 14b-kv 15a-cl cc cht mi, cha thy cng btrong cc ti liu tham

kho c. Tt ccc cht tng hp c u c kim tra tinh khit bng sc k

lp mng v o nhit nng chy. Cu trc cc dn cht tng hp c xc nh

bng cc php o ph hng ngoi IR, ph cng hng t ht nhn (1H-NMR, 13C-

NMR), phkhi lng (MS). Kt qu thu c cho php kt lun cc cht tng hp

c c cu trc ng nh dkin.

2.

thhot tnh gy c tbo ung th ca 14 dn cht tng hp c vi 4dng tbo ung th ngi l tbo ung th biu m KB, tbo ung th gan Hep

G2, tbo ung th phi LU, tbo ung th v MCE 7. Kt qucho thy c 9 dn

cht trong 14 dn cht tng hp c c hot tnh sinh hc trn c4 dng tbo ung

th ngi. c bit hp cht 15c c hot tnh khng tbo ung th rt tt nng

IC50= 0,051

g/ml trn tbo ung th da, IC50= 0,096

g/ml trn tbo ung th gan,

IC50= 0,125g/ml trn tbo ung th phi, IC50= 0,5g/ml trn tbo ung th v.

KIN NGH

Tcc kt qunghin cu trn nhm nghin cu xin c mt sxut nh

sau:

Tip tc thsng lc hot tnh gy c tbo ca cc dn cht tng hp c

t d t bo ng th khc nha : ng th i trng ng th d d

TI LIU THAM KHO

TING VIT


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Documents

Tổng Hợp Và Thử Hoạt Tính Kháng Tế Bào Ung Thư Của Một Số Dẫn Chất 2-Aryl-4-Quimazolinon