Nghien CIPU - Ky thuat
phu hgp vol tin hieu methyl vinyl a 6_ 2,07 (3H, br s). P h i khoi ESI-MS cua 3 t h i hien ien phan tir tai m/z 281 [M + H]- phti hgp vai cong thirc C.,H.-6^
(M = 280). Tren e a s o cac phan tich tren va s u phti hgp v i so lieu da cong 0 6 ' ° ' ' cho phep xac dinh c h i t 3 la trijuganon B.
Ket luan
Da sir dung p h u a n g phap ngam chiet vai dung moi EtOH 8 0 % va bang phuong phap s i c ky ept phan lap d u g e 3 hgp c h i t tir re cay dan sam trong a huyen Bac Ha, flnh Lao Cai. Xac djnh c i u triic cac h g p c h i t phan lap d u g c thong qua k i t qua do nhiet dp nong chay, goc quay c u e rieng, p h i tif ngoai- kha k i i n , pho k h i i , p h i cpng h u o n g hat nhan va so sanh voi cac d u lieu cong bo ciia cac hgp c h i t lien qua da xac djnh d u g c cau true 3 hgp c h i t phan lap do la: dihydrotanshinon I.
methyldihydretanshineat trijuganon B. Trong do hgp chat methyldihydrotanshinoat l i n d i u tien phan lap d u g e ttr thien nhien.
L&i cam cm: De tai dirge tai tra boi Chuang tnnh Khoa hoc va Cdng nghe phuc vu phat then t)in vUng vung Tay Bic, Dai hoc QGHN, ma s6 di tai: KHCN-TB.05C/13-18.
T a ! lieu t h a m khao
1. So T i t Lai (2005), NhOng cay thuoc va vj thuoc Viet Nam, Nxb. Y hgc. Ha Noi, pp. 818-820.
2. Dai Hui, Xiao Chaoni, Liu Hongbing. Tang Huiru
(2009), .Comnined NMR and LC-MS Analysis Reveals the Metanonomic Changes in Sahria miltionhiza Bunge Induced by Water Depletion", Joumal of Proteome Research, 9(3). pp. 1460-1475.
3. Ikeshiro Yasumasa. Hashimoto Ikuko, Iwamoto Yuka, Mase Izumi, Tomita Yutaka (1990), "Diterpenoids from Sah/ia miltionhiza', Phytochemistry, 30(8), pp.
2791-2792.
4. Onitsuka (.liisuko. Fujiu Mono, Shinma Nobuo, Maruyama Hiromi B. (1983), 'New platelet aggregation inhibitors ft-om Tan-Shen: radix of Salvia miltionhiza Bunge", Chem. Pharm. Bull (Tokyo), 31(5), pp. 1670-5.
5. Sun Jiang Hao, Yang Min, Ivta Xao Chi, Kang Jie, Han Jian, Guo De An (2009), 'Microbial biotransformation of cfyptotanshinone by Cunninghamella eiegans and
;LS application for metalx)!ite identification in rat bile", J.
Asian Nat Prod. Res.. 11 '51. pp. 482^489.
6. Thomson R. H. ^997), Naturally occuning quinones IV reccent advances, Blackie academic &
Professkmal, London, pp. 693-694.
7. Xuezhao L., Houwei L., Masatake N. (1990),
"Tnjuganone A and B: Two new phenanthrenequinones ftrHTi roots of Salvia tnjuga'. Plants Med., 56(1), pp. 87- 88.
8. Lam Thien Phuong, Vu Tong Uyen, Vucfng Bai Kiet Hiiu Vifong, Quan Nhan Quan (2011), -"Phan lap Tanshinone tinh <" et trong Dan sam bing phiro-ng phap s i c -r. cot silicagel ket hgp he ttiing s i c ky phan t)6 nguge dong toe cc cao', Chinese Traditional and Herbal Dnjgs, pp. 466-469.
{Ngay nhan bai: 08/01/2016 - Ngay duyet dang: 04/04/2016)
Tong hop va thu" hoat tinh gav doc te bao cua 5-(4'-bromobenzyliden)hydantoin
mi r
va dan chat base Mannich
\'u Tran Anh*. Nguyen Tien Hiep Bo mon Hoa hihi ca - Truang Dgi hpc Duac Hd Noi 'E-mail: [email protected] Summani
A new series of 5-benzylidenhydantoins were synthesized. The compound 5-(4'-bromobenzyliden) hydantoin (^) was obtained from 4-bromobenzaldehyd and hydantoin. The 5-(4'-hromot>enzyliden)hydantoin f l j undenvent Mannich reaction to give 6 Mannich base derivatives (2-7;. The structures of tine syntiiesized compounds were confinned by IR, ''H-NMR, "C-NMR and MS. The cytotoxic effect of the obtained hydantoin derivatives was evaluated on human hepatotic cardnoma cell (Hep-G2), breast adenocardnoma cell line (MCF-7) and prostate cancer cell (PC3). 5 compounds (1 -5y sliowed significant anti-proiiferative activities against Hep-G2 (IC^.= 1.59-4.54 pg/ml). Meanwhile, no cytotoxicity was observed on oOier two cancer cell lines.
Keywords: Hydantoin. 5-(4'-bromobenzyliden)hydantoin, l.'lannich iDases. cytotoxicity.
T.\P CHI DUOC HOC - 4'2016 (SO 480 NAM 56)
Dat van de
Tu- loai bpt bien Hemimycale arabica (Mycalidae) a bien Hing Hal da phan lap duge chit (Z)-5-(4-hydrcxybenzyliden)hydantein, chat nay eiing vol (Z)-5-(4-(ethylthio)benzylidene)- hydantoin eo heat tinh u'c c h i su tang truo'ng va su xam lan cua t i bao ung thu tuyin tiin Net PCS tren in vitro '•^l Lien k i t d6i lien hgp ngoai vong la y i u t i c i u true tae eho hgp chit benzylidenhydantein co kha nang tac dung la tuang tac vai vj tri heat dpng ciia EGFR (thu the cua y i u t i tang truc'ng bleu m6) '"•''•'i. Tiip tuc va phat triin huong nghien ciru v i cac d i n chit 5-arylidenhydantoin ''-"', trong bai bao nay, ehung toi trinh bay k i t qua ting hgp va thir boat tinh gay dpe t i bae ciia 5-(4'-bremebenzyliden) hydantoin va cac d i n chit base Mannich.
So d i ting hgp:
CHO
Nguyen lieu va phuang phap nghien CIPU Nguyen lieu
Cac hoa chat va dung m6i diing trong nghien CU'U d i u nhap ttr eae hang Merck, Sigma-Aldrich, Trung Quic.
Phu'O'ng phap nghien cu'u
Tong hgp hoa hpc: Tong hgp 5-(4'-brpmobenzyliden)hydantoin va dan chat base Mannich theo 2 giai doan i'-^':
f Tong hgp dan chit 5-(4'-bromobenzyliden) hydantoin (1) bang phan irng ngung tu hydantoin vol 4-bromobenzaldehyd.
+ Tong hgp cac d i n chit base Mannich cua chat 1 dugc thuc hien bang phan irng ngung tu chit 1 vai fermol va cac amin bac 1, bae 2 trong dung m6i acid acetic, xiie tac natri acetat khan, nhiet d6 130-135°.
O 3 / R / = \ " V N H •^HCHO + HN,
&• 6' H
EtOH, dun h i i luu 'J e H
-N^„ N 0 Ra V ^
<r-0
^Nv = - N N-CHj
f<2 \ / (2)
(3)
(4)
- Dting phuang phap kit tinh lai de tinh ehi san pham thu ditcic.
- Dung sac ky lap mong (SKLM) de theo doi phan irng va so bp xac dinh dp tinh khiit.
Xae djnh ciu triic eiia cac chit ting hop duge bang cac phuang phap pho {IR, 'H-NMR
">C-NMR, HSQC, HMBC, MS).
Thir boat tinh gay dpe t i bap ung thu thep phuang phap SRB I'l tai Vien Hoa hoe cac hgp chat thien nhien - Vien Han lam Khoa hpc va Cong nghe Viet Nam.Thee phuang phap SRB, cac chit CO IC^„< 5 pg/ml dugc coi la co hoat tinh.
Thyc nghiem, l<et qua va ban luan Sac ky lap mong (SKLM) duge thuc hien tren ban mong silicagel Kieselgel 60F Nhiet dp 48
2-7
(5)
(6)
(T)
nong chay dugc de tren may EZ-Melt. Phi /Rdugc ghi tren may Perkin Elmer. Pho 'H-NMR, '^C-NMR dugc ghi tren may AVANCE Spectrometer AV500 (BRUKER, Du'e). Pho MS dugc ghi tren may Autospec premier va LTQ Orbital trap.
Tong hop hoa hgc
Tong hgp 5-(4'-bromobenzyliden)hydantoin (1) Che vae binh c i u 9,25 g (0,05 moi) 4-bremobenzaldehyd; 5,00 g (0,05 mel) hydantoin;
16,4 g (0,1 mel) natri acetat khan va 52,5 ml acid acetic bang. Hon hgp phan irng dugc khuay d i u , dun hii luu, duy tri nhiet dp phan U'ng 6' 130-135°. Phan irng kit thue sau 4 gia.
Thep dpi phan img bang SKLM vol he dung moi dicleromethan:methanol (12:1). Kit tiia thu dugc TAP CHI D t r g c HOC - 4/2016 (SO 480 NAM 56)
Nghien
CLFU- Ky thuat
dugc ara nhiiu lin bang nuac cit eho d i n khi hit acid acetic, sau do rira bing con lanh. Kit tinh trong dung m6i EtOH/DMF (15:4). Khoi lugng san pham la 3,56 g tinh the mau trang. Hieu suit: 26,7%. Nhiet dp nong chay: 295-297°C, R, = 0,74 (TLC, silicagel 60 F^^, he dung moi CH^CI^:
CH30H(12:1)).
IR (KBr, v _ (em-i): 1767 (v,,,„); 1735 (v„,„);
1664 (v^ J. 'H-NMR (500 MHz, DMS0-d6), 5 (ppm), J (Hz): 11,27 (s; 1H; N3-H); 10,58 (s; 1H;
N,H); 7,56 (m; 4H; H^.^^,,.); 6,37 (1H, s, -CH=).
"C-NMR (125 MHz, DMSO-dg), 5(ppm)): 165,38 (-C^=0); 155,62 (-€2=0); 121,45 (C,,); 132,24 (C,); 131,60 (C,,,.); 131,21 (C,.,,); 128,54 (C^);
106,80 (-CH=). LC-IWS: [M-H]- (tinh toan: 266,08 [C,„H^BrN20J, tim thiy m/z (%) = 264,93 (100).
rdng hgp 5-(4'-bromobenzyliden)-3- morpholinomethylhydantoin (2)
Cho vao binh ciu 0,51 g (0,0025 moi) chit (1), them 15 ml EtOH, khuiy 6' nhiet dp phong cho phan tan deu trong 15 phut. Cho tiip 0,21 ml fermol (0,0025 mel HCHO) va 0,0025 mel morpholin , 3-4 gipt CH3COOH, khuiy a nhiet dp phong trong 1 gio. Sau do dun each thuy nang din nhiet dp tai 85°C thi them tiep DMF vao ttr tu' de hin hgp tan hoan toan. Sau do, tiip tue khuiy va giu- nhiet dp phan irng a 85°C, thai gian phan irng la 5 gia. San phim thu dugc la 0,71 g tinh the mau vang , hieu suit 77,8%. Nhiet d6 nong chay: 232-233°C, R, = 0,78 (CH2Cl2:CH30H (12:1)).
IR (KBr, v _ (cm-'): 1768 (v,,,J; 1713 ( v „ , J ; 2815 (V(,J; 1655 (v^,.^). 'H-NMR (500 MHz, DMS0-d6f, 5(ppm), J(Hz)): 7,59 (m; 4H; H^.^^.^.);
6,51 (1H, s, -CH=); 4,35 (s, 2H, -N-CH^-N);' 3,54 (m, 4H; Hj.^..); 2,50 (m; 4H; H^.^,). "C-NMR (125 MHz, DMSO-dg), 5(ppm)): 164,C)6 (-0^=0); 155,76 (-0^=0); 132,06 (C,.); 131,63 (C^^,); 131,33 (C^,,.);
126,99 (C3); 121,72 (C,.); 108,11 (-CH=); 65,97 (03.3.); 59,87 (NCHjN); 50,313 (C^.^.). LC-MS: [M- H]-(tinh toan: 365,21 [C,3H,gBrN303], tim thay m/z (%) = 363,96 (100).
Tong hgp 5-(4'-bromobenzyliden)-3- piperidinomethyl hydantoin (3)
Cho vao binh ciu 0,67 g (0,0025 mel) chit (1); 0,21 ml fermol (0,0025 moi) HCHO va 0,21 g (0,0025 mel) piperidin, tiin hanh nhu chit (2), thai gian phan irng la 5 gia. San pham thu duge la 0,74 g tinh the mau vang, hieu suit 81,5%, nhiet do nong chay 220-223°C. R, = 6,6 (CH^Cl^: CH3OH (14 :1)).
IR (KBr, v _ (cm-1: 1767 (v,,,„); 1716 {v^J;
2940 (VgJ; 1662 {v^_J. 'H-NMR (500 MHz, DMS0-d6f, 5(ppm), J(Hz)): 7,57 (m; 4H; Hj^^.^,);
6,48 (1H, s, -CH=); 4,34 (s, 2H, -N-CH^-N); ' 2,50 (m; 4H; H^.,.,); 1,46 (m; 4H; H^,^,); 1,31 (m; 2H; H,.).
"C-NMR (125 MHz, DMSO-d^), 8(ppm)): 165,06 (-C,=0); 155,96 (-0^=0); 132,142 (C,.); 131,46 (03,5.); 131,19 (C,.,,); 127,17 (C^); 121,72 (C,.);
107,85 (-CH=); 60,70 (NCH^N); 51,16 (Cy,,..);
25,41 (Cy.^.); 23,32(C^,.). LC-MS: [M-H]'(tinh toin:
363,24 [C^3H,gBrN30J, tim thiy m/z (%) = 361,91 (2);
-o
; (264,90 (95).Tong hgp 5-(4'-bromobenzyliden)-3-(N- methylpiperazino)mefhylhydanfoin(4)
Cho vao binh c i u 0,67 g (0,0025 mel) chit (1); 0,21 mi formol (0,0025 moi) HCHO va 0,25g (0,0025 mel) N-methylpiperazIn, tien hanh nhu chit (2), thai gian phan irng la 5 gio". San pham thu dugc CO khii lugng la 0,605g tinh the mau trang, hieu suit 64,0%, nhiet d6 nong chay 238-240°C, R,
= 0,76 (CH2Cl2:CH30H (12:1)).
IR (KBr, v _ (cm-i): 1767 (v,,,„); 1718 (v^,„);
2946 (Vj,„); 1665 (v^.^,). 'H-NMR (500 MHz, DMSO-d6f, 5(ppm), J(Hz)): 7,57 (m, 4H, H^.^^.^,);
6,48 (1H, s, -CH=); 4,35 (s, 2H, -N-CH^-N);' 2,'50 (m, SH, H2,.3.,3,.g,.); 2,12 (s, 3H, CH3). "C-NMR (125 MHz, DMSO-dg), 5(ppm)): 165,36 (-0^=0);
155,69 (-0^=0); 135,13 (C,.); 133,64 (C^.); 129,01 (C3); 128,25 (Cj.,.); 106,43 (-CH=); 61,46 (NCH^N);
54,20 (Cj-j.,); 49,97 (C^,.,..); 40,09 (CH3). LC-MS:
[M-H]- (tinh toan: 378,25 [C^^H^^BrN^J, tim thiy m/z (%) = 377,05 (34).
Tong hgp 5-(4'-bromobenzyliden)-3- pyrrolidinomefhylhydanfoin (5)
Cho vae binh ciu 0,67 g (0,0025 mel) chit (1); 0,21 ml formol (0,0025 mel) HCHO ya 0,18 g (0,0025 moi) pyrrolidin, tiin hanh nhu chit (2), thai gian phan irng 5 gia. San phim thu dugc la 0,65 g tinh the mau vang, hieu suit 74,4%, nhiet do nong chay: 224-227°C, R,= 0,74 (CHCI3: MeOH (9:1)).
IR (KBr, v^ (em-'): 1767 (v,,,„); 1713 (v„,„);
2971 (V;,J; 1660 (v^..^. 'H-NMR (500 MHz, DMSO-de;^ 5(ppm), J(Hz)): 7,56 (m; 4H; H^.^.^.^);
6,43 (1H, s, -CH=); 4,46 (s, 2H, -N-CH^-N);' 2,50 (m; 4H; H^..^..); 1,63 (m; 4H; H^.^.). "C-NMR (125 MHz, DMSb-dg), 5(ppm)): 164,99 (-C^=0); 155,91 (-C,=0); 132,12 (C,,); 131,60 (C^^,); 131,20 (C,.,.);
127,17 (C5); 121,66 (C^.); 107,92 (-CH=); 55,53 (NCH^N); 49,81 (C^.^,.); 23,34 (C3.,,..). LC-MS: [M- H]-(tinh toan: 349,21 '[C,3H,3BrN30J, tim thiy m/z (%) = 264,9 „-cH,-fQ] (100).
Tong hgp 5-(4'-bromobenzyliden)-3-(4"- methoxyphenylamino)methylhydanfoin(6)
Che vae binh ciu 0,67 g (0,0025 moi) chit (1); 0,21 ml fennol (0,0025 mel) HCHO va 0,31 g (0,0025 mel) p-anisidin, tiin hanh nhu chit (2),
TAP CHl DLTOC HOC - 4/2016 (SO 480 NAM 56) 49
Nghien - Ky thuat
thai gian phan irng 5 gio. San pham thu duge la 0,62 g tinh the mau vang, hieu suit 61,8%, nhiet do nong chay. 234-237°C, R, = 0,85 (CH^CI, : CH30H(14:1)).
IR (KBr, v„,„ (cm-'): 1771 (v^^^o): '''"''' (^c4=o);
2946 (Vj,J; 1665 {v^_^). 'H-NMR (500 MHz, DMSO-d6:^ 5(ppm), J(Hz)): 10,82 (s; 1H; N, H); 7,58 (m; 4H; H^,^,,.); 6,79 (m; 2H; H^,^..); 6,71 (m; 2H;
H .„.); 6,38 (1'H, s, -CH=); 6,16 (m; 1H; NH); 4,87 (s, ^H, -N-CH,-N); 3,66 (s; 3H; OCH3). "C-NMR (125 MHz, DMSO-d,), 5(ppm)): 164,07 (-C,=0);
155,12 (-C,=0); 151,08 (C,.,); 139,765(0,.); 131,98 (C,); 131,60 (C3,,.); 131,37 (C,.,.); 126,88 (C^);
121,78 (C,.); 114,35 (C,.,.): 113,77 (C,..,,.); 108,30 (-CH=); 55,20 (OCH3); '4S,54 (NCH^N). LC-MS:
[M-H]-(tinh toan: 401,24 [C,3H,gBrN303], tim thiy m/z (%) = 399,95 (100).
Tong hgp 5-(4'-bromobenzyliden)-3-(4"- methylphenylamino)mefhylhydanfoin(7).
Cho vao binh ciu 0,67 g (0,0025 moi) chit (1); 0,21 ml formol (0,0025 mel) HCHO va 0,27g (0,0025 mel) p-teluidin, tiin hanh nhu chit (2), thoi gian phan u'ng 5 gia. San pham thu duge la 0,84 g tinh the mau vang chanh, hieu suit 87,2%, nhiet do nong chay. 243-245°C, R,= 0,92; he dung m6i H p : A c O H : M e O H = 5:1:4.
IR (KBr, v^,^ (cm-'): 1762 (v,,,„); 1715 (v„,„);
2919 ( v ^ J ; 1662 (v^.^)- 'H-NMR (500 MHz, DMS0-d6:^ 5(ppm), J(Hz)): 10,831 (s; 1H; N,H);
7,58 (m; 4H; H^.^^,,.); 6,901(m; 2H; H3.5.); 6,74 (m;
2H; H2", 6"); 6,33(m; 1H; NH); 6,50 (1H, s, -CH=);
4,89 (s, 2H, -N-CH^-N); 2,174 (s; 3H; CH3). "C-NMR (125 MHz, DMSO-dg), 8(ppm)): 164,03 (-C^=0);
155,08 (-0^=0); 143,55 (C,.,); 131,98(0,.); 131,615 (C3,,,); 131,27 (C3.3.); 129,34 (C,.,.); 126,879 (C^);
125,73 (C^..); 121,79 (C,,); 112,72 (C^..,.); 108,32 (-CH=); 48,00 (NCH^N); 20,01 (CH3). LC-MS: [M- H]-(tinh toan: 385,24 [C,3H,gBrN30J, tim thiy m/z (%) = 383,95 (100).
Cac chit (1 -7) deu duge xac djnh ciu triie bang eae phuang phap pho hong ngoai, pho khii va pho cpng huong ttr hat nhan 'H-NMR va 'K-NMR. So lieu phi thu dugc che thiy cac chit diu co dai hip thu dac trung che cae lien kit dien hinh treng phan tir, xuit hien day dii cac tin bleu cua cac vj tri proton va carbon phti hgp vai eOng thirc du kiin.
ThCp hoat tinh gay doc t i bao ung thu' ngu'O'i Tai Phong sinh hpc thuc nghiem, Vien Hoa hpc cae hgp chit thien nhien, Vien Han lam Khea hpe va COng nghe Viet Nam, 7 chat ting hgp duge ttiir hpat tinh gay dpc te bac tren cac dong t i bao te bao ung thu gan Hep-G2, t i bao ung thu vu MCF- 7, t i bae ung thu tiin Net tuyin PC3 theo phuang phap SRB P=i, chit doi ehiiu la elliptiein. 5 chit
(2-6) CO tac dung itc ciie dong t i bao ung thu Hep-G2 vo'i IC^, liri lugt la 4,54; 2,89; 2,86; 1,59 va 3,73 pg/ml. 2 chit la chit 1 va chit 7 kh6ng co boat tinh vo'i 3 dong t i bao thir nghiem.
Nhan xet sa bo ve moi lien quan cau truc- tac dung
K i t qua thir nghiem cho thiy base Mannich cua 5-(4'-bromebenzyliden)hydantoln co the mang lai boat tinh iec che t i bao ung thu. So sanh vol cac k i t qua da thu dugc truo'e day i'- '21, anh huo'ng cua nhom t h i aminomethyl a N-3 khong dong d i u , khOng co tinh qui luat. Ve anh huo'ng eua cac nhom t h i tren vong aryl, so sanh vol cac d i n chit 5-arylldenhydantoin khac va cac dan chit base Mannich ciia chiing ma chung toi da tiin hanh nghien ciru va c6ng b i k i t qua "-'^i thi CO the nhan xet rang cac nhom t h i hiit dien tir (-Cl.-NOJ a hgp phan aryllden la y i u to eau true da gop phin mang lai heat tinh ire c h i te bao ung thu gan Hep-G2 {\C^= 0,38-5,0 ) pg/ml. Kit qua thuc nghiem thu dugc cung khang djnh them ring nhom the hut dien tip -Br trong vong aryl da gop phan mang lal hoat tinh khang t i bao ung thu gan nguai Hep-G2.
Ket luan
Da tong hgp dugc 5-(4'-bromobenzyliden) hydantoin va 6 dan chat base Mannich (2-7) trong do 6 chit (2-7) chua thiy e6ng b i trong cae tai lieu tham khao dugc.
Kit qua thir boat tinh gay dpc t i bap ung thir cho thiy 5 chit la cac chit 2 (10^^ = 4,54 pg/ml), chat 3 (IC^o = 2,89 pg/ml), chit 4 (IC^^ = 2,86 pg/
ml), chit 5(IC3„- 1,59 pg/ml), chit 6 (IC3„= 3,73 pg/ml) CO boat tinh gay dpe t i bap ung thu gan Hep-G2. Ca 7 chit deu khOng CP hpat tinh ire chi t i bap ung thu tuyin tiin liet PC3 va t i bao ung thu bleu mo vii MCF7.
Tai lieu tham khao
1. Kirk Othmer (1966), Encylopedia of chemical technology, 2"", vol. 11, pp. 141 - 164.
2. G. Billek (1962), "Condensation of aromatic aldehydes with hydantoin", Monatsh. Chem., 92, p. 352- 360.
3. Beverly A. Telcher (1997), Anticancer dmg development guide: Preclinical screening, clinical trials, and approval, Humana Press, Totowa, New Jersey, 59-74.
4. Carmi C. et al. (2006), "5-Benzylldene-hydantoins as new EGFR inhibitors with antiproliferative activity", Bioorganic & Medicinal Chemistry Letters, 16, 4021- 4025.
5. Houghton P. et al. (2007), "The sulphorhodamlne (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity". Methods 42, 377-387.
50 TAP CHi DirOC HOC - 4/2016 (SO 480 NAM 56)
Nghien
CLFU- Ky thuat
6. Mudit M., Khanfar M. et al. (2009), "Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products", Bioorg. Med. Chem., 17(4), 1731-1738.
7. Zuliani V , Carmi C. et al. (2009), "5- Benzylidene- hydantoins: Synthesis and antiproliferative activity on A549 lung cancer cell line", European Journal of Medicinal Chemistry, 44(9), 3471-3479.
8. Vu Trin Anh, Binh Thi Thanh Hai, NguySn Quang Dat, Doan Thi Hiru (2008), "Tong hgp va thir hoat tinh sinh hgc ciia mpt s6 dSn chat 5-arylidenhydantoin", Tap chi Ducyc hoc, thang 12, tr. 36-39.
9. Vu Trin Anh, Dinh Thj Thanh Hai, NguySn Quang {Ngay nhan bai: 31/01/2016 -
Dat va Trin Thj Oanh (2009), "Tong hgp va thir hoat tinh sinh hgc cua 5-(o- va p-clorobenzyliden)hydantoln va dSn chat base Mannich", Tap chi Duc/c hoc, thang 12, tr 3 8 - 4 2 .
10. VQ Tran Anh (2014), "Tong hgp va thir hoat tinh khang te bao ung thu cua 5-(3'-fluorobenzylidenhydanto in) va dan chat base Mannich", Tap chi Duac hoc, thang 2, tr. 41 - 44.
11. D6 Thj Thu Hang, Vu Tran Anh (2012), "Tong hgp va thCr hoat tinh khang te bao ung thu cua mgt so d i n chat 5-(3'-bromobenzyliden)hydantoin va dan chat base Mannich", Tap chi Duac hoc, thang 10, tr. 4 5 - 4 8 .
Ngay duyet dang: 04/04/2016)
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T o n g h o p v a t a c d u n g ... (TUp theo trang 42)
So vol tac dung dpc te bao ciia cae d i n chat quinazolinon, hgp c h i t dang c i u sinh hpe treng cac nghien ciru truac day 1'°', boat tinh eiia cac d i n c h i t quinazolinamin la y i u ban. Co the khi ehuyen tir nhom 0 = 0 cua quinazolinon sang nhom C-N, kha nang boa tan ciia cae hgp chat quinazolinamin thay doi nen lam giam heat tinh cua day c h i t nay
Ket luan
N h u vay ehung toi da tong hgp d u g e 5 d i n c h i t 6-methyl-2-(naphthalen-1-yl)-4-quinazolinamin mai (10 a-e). C i u true eae hgp c h i t d u g c xae djnh bang phuang phap pho cpng huang ttr hat nhan, php k h i i .
Cac c h i t 10 a-e the hien boat tinh gay dpc t i bao trung binh, y i u hay khOng co boat tinh tren 4 dong t i bao ung t h u nguai la t i bae ung t h u b i i u m6 KB, t i bae ung t h u gan Hep-G2, t i bao ung t h u phoi LU, t i bae ung t h u vii MCF-7, t h i p hon n h i i u se vol c h i t d i i ehd'ng ellipeitin, Hgp c h i t 10b CO boat tinh t i t n h i t chpn Ipe tren dong t i bae ung t h u vu MCF-7 voi IC^^ la 14,85 pg/ml.
Tai lieu t h a m k h a o
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3. Peng W., Tu Z. - C , Long Z. J., Liu Q., Lu G. (2016),
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(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents", European Journal of Medicinal Chemistry, 108, 644-654.
4. AlafeefyA. M., Ahmad R., Abdulla M. etal (2016),
"Development of certain new 2-substituted-quinazolin- 4-ylaminobenzenesulfonamide as potential antitumor agents", European Joumal of Medicinal Chemistry, 109, 247-253.
5.Xu L., RussuW.A. (2013), "Molecular docking and synthesis of novel quinazoline analogues as inhibitors of transcription factors NF-KB activation and their anti- cancer activities", Bioorganic & Medicinal Chemistry, 21, 540-546.
6. Le N. T, Yang S. H., Khadka D. B. etal. (2011),
"Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase I inhibitors with molecular modeling", Bioorg. Med. Chem., 19, 4399-4404.
7. Thanh L.N., Giap T H., Dung N. A. ef a/. (2015),
"Synthesis and biological evaluation of 2- aryl-4- aminoquinazolines as antitumor agents". Tap chi Hda hoc, 53 (2E), 56-60.
8. Van Thj My Hue, Chu Van Toan, Le NguySn Thanh (2016), "Tong hgp va doc tinh t§ bao ung thu ciia mgt so dSn chat thS 4-quinazolinamin", Tap chi Nghien cUu Duuc va Thong tin Thudc, (dang in).
9. Scudiero D. A., Shoemaker R. H., Kenneth D. P. et al. (1988), "Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines". Cancer Research., 48, 4822-4833.
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(Ngay nhan bai: 03/03/2016 - Ngay duyet dang: 04/04/2016 )
TAP CHI DtrOfC HOC - 4/2016 (SO 480 N A M 56)
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