• Nghien
CIFU- Ky thuat
Tong hop va thu* tac dung khang ung thu*
cua mot so hop chat lai hoa
giira 7-cloro-4-aminoquinolin va 11-azaartemisinin
Le Nguyen Thanh'*, Tran Hfru Giap', Van Thi My Hue-'
' Vien Hoa sinh bien, Vien Han lam Khoa hoc va Cong nghe Viet Nam - Truang Dgi hoc Duac Ha Noi 'E-mail: [email protected]
Summary
Three new hybrid compounds with amine linkage (7a-c) were obtained by reductive amlnation of 11-azaartemisinin aldehyde (4) with 7-chioro-4-aminoquinoiine derivatives (Sa-c). The cytotoxicity of the synthesized compounds against four cancer cell lines including KB (Human epidermic carcinoma), Hep-G2 (Hepatocellular carcinoma), LU (Human lung carcinoma) and MCF-7 (Human breast carcinoma-Michigan Cancer Foundation 7) was evaluated. Ali the tested compounds potentially inhibited all these four cancer cell lines (IC^ range from 4.51 to 16.37 pg/ml). Of them, Ta exhibited the strongest anticancer activity with iC^
value of 4.51 pg/ml on the cancer cell line f/lCF-7.
Keywords: Hybrid, 11-azaartemisinin, 7-chioro-4-aminoquinoline, anticancer, cytotoxicity.
Dat van de
Trong nghien ciru phat triln thule hien dai, phuang phap lai hda la each tilp can mdi diy hipa hen nham thay dii, phat trien eae thulc da bilt thanh thulc mdi. Hgp chat lai hda thdng thudng duge tao thanh bang each gin kit true tilp hay qua ciu nii phin eiu triic cua hai hay nhilu hgp chit d l tao nen mot phan tii' thulc mgi ed hieu qua, dua tren tae dung hiep ding eiia eae hgp phin PI.
Quinolin ia ciu triic di vdng cd nhilu hoat tinh sinh hpe dang quan tam, thudng gap trong thien nhien va duge sii' dung nhilu trong nghien ciru pliat triln thuocP'. Cloroquin la thulc ching sit ret nil tiing ed ciu true 7-elorp-4-aminoquinplin duge phat triln tif hgp ehit tu nhien quinin. Gin day hoat tinh ehing ung thu eua cae din chit cloroquin va cae hgp chit lai hda tCf 4-aminoquinolin da dugc nhilu nhdm khoa hpc nghien ciru, va kit qua da chifng td cac din chit lai hda tif 4-aminoquinolin va cac phin tu- khac nhu artemisinin, sulfonamid
hgp chit alkyl hda ADN, phirc kim loai... ed tac dung ching ung thu dang chu y^'. Oac biet mdt s l thir nghiem d i i vdi hgp ehit lai hda giifa artemisinin va 7-elpro-4-aminoquinplin mang da ehp thay nhilu day ehit nay cd tac dung ire ehl t l bae ung thu rit tit. Cae d i n chit 1-3 ed tae dung gay ddc t l bao vdi IC^^ khoang 0,03-0,08 pIVl tren cae ddng t l bao ung thu sac t l melanoma, ung thu vu l\/ICF-7, ung thu than TK1 ["^i (hinh 1).
Gin day artemisinin, mdt thulc ching sit ret, va eae din chat ciia nd dugc nhilu nha khoa hpe quan tam bdi kha nang khang ung thu rit cd triln vpng i^l Vdi nhtrng tilm nang ching ung thu dang ehii y ciia ea hai din ehit 4-amincquinolin va artemisinin thi viec lai hda hai ciu true phan tif nay cd t h i mang din tae dung hiep ding ire ehl t l bao ung thu. Ciing xu hudng tren, trong nghien ciru nay, mdt s l d i n chit lai hda giti'a 11- azaartemisinin va 7-cloro-4-aminoquinolin dugc tong hgp va thir hoat tinh gay dpe tren mdt s l ddng t l bao ung thu.
Hinhl : Mdt sd diri chat lal hda giO'a din chit artemisinin va 4-aminoquinolin vdi tac dung khang ung thu
60 TAP CHI DUCK
Nghien
CLFU- Ky thuat
Nguyen vat lieu va phuwng phap nghien
CLPU
Nguyen vat lieu va thilt bj
Hda chat va dung mdi dupc mua tif edng ty hda chat Merck, Aldrich, Trung Quie va su dung khcng qua tinh ehl. Sic ky Idp mdng thue hien tren ban mdng silica gel 60 F^^^ (Merck) va quan sat dudi den UV, bude sdng 254 nm. Phi hing ngoai dugc
ghi tren may Perkin Elmer, Vien Hoa hpc. Phi khii lugng duge ghi tren may LC/MS Agilent 1260 tai Vien Hda sinh bien. Phi cpng hudng tif hat nhan duge ghi tren may Bruker Avanee 500 MHz, Vien Hda hoc vdi TMS lam ehit ehuan ndi, dung mdi CDCI3.
Phu'O'ng phap nghien ciru
Tong hgp hoa hgc: Cac ehit dugc ting hgp theo sa d l sau:
W^m,
MeOH
// \ \ H
rfn "C ^ ^ H 6a-c
NaBHV MeOH
5a-7a: n=3 5b-7b: n=4
5c-7c: n=6 _
^' /a-c" •" 6
Sec a l 1: Tdng hgp cac dan chit lai hda (7a-c) giira 7-cloro-4-aminoquinoliri va 11-azaartemisinin Thir tac dung sinh hgc
Tac dung gay dpc t l bao cua cae chit ting hgp duge thu tren 4 ddng t l bao; KB (Human epidermic carcinoma) - ung thu bilu md; Hep-G2 (Hepatocellular carcinoma) - ung thu gan; LU (Human lung carcinoma) - ung thu phii va MCF- 7 (Human breast carcinoma) - ung thu vu theo phuang phap MTT^ tai Phdng Hda sinh irng dung -Vien Hda hpc-Vien Han lam Khoa hpeva Cdng nghe Viet Nam.
K§t qua nghien cu>u T6ng hgp c h i t lai hoa 7a
Hdn hgp g i m 50 mg hgp chat 4 (0,14 mmol) va 36 mg hgp chit 5a (0,15 mmol) trong 4 ml IVIeOH duge them khoang 50 mg MgSO^ khan va khuiy a 50°C trong khoang 5 gid. Phan irng duge theo ddi bing s i c ky ldp mdng. Kit thiic phan irng thu dugc hgp chit 6a, hgp ehit nay dugc sif dung cho giai doan tilp theo ma khdng can tinh ehl. Lam lanh hdn hgp thu dugc sau phan img din 0°C, them 12 mg NaBH^ va khuiy trong 1 gid, d l qua dem trong tu lanh. Sau dd nang nhiet dp hdn hgp len nhiet dp phdng
va khuiy tilp trong 5 gig. Theo ddi phan img bing sie ky Idp mdng.
Kit thuc phan irng, Ipc bd MgSO^, c i t loai dung mdi, chilt bing ethylacetat, Dieh ehilt duge lam khan vdi natri sulphat, Ipc va c i t loai dung mdi dudi ap suit giam. Tinh ehl ein thu duge bing sic ky edt vdi he dung mdi ethyl acetat -methanol (5:1), thu dugc 30 mg ehit 7a la chit ran mau vang nhat, hieu suit 38,4 %, R^. 0,53 (MeOH:
EA=1:5), r-^^. 110-112''C. /R (KBr, v (cm-^)):
3424,70 (v,.„), 1633,71 (v,,„,„„), 'H-/VMR (500 MHz, CDCI3), 5 (ppm): 8,17 (1H, d, J = 5,5 Hz, H-2'), 7,77 (IH, d, J = 9,0 Hz, H-5'), 7,64 (IH, d, J = 2,0 Hz, H-8'), 7,21 (IH, dd, J = 2,0 Hz, J = 9,0 Hz, H-6'), 6,21 (IH, d, J = 5,5 Hz, H-3'), 5,03 (IH, s, H-12), 3,45-3,52 (1H, m, H-13), 3,15-3,31 (3H, m, H-ir, H-13), 3,11 (IH, m, H-9), 2,60 (2H, m, H-15), 2,40-2,50 (2H, m, H-13'), 2,21 (IH, m), 1,45-1,85 (9H, m), 1,10- 1,31 (3H, m), 1,15 (3H, s, 3-CH3), 0,95 (3H, d, J = 7,0 Hz, 9-CH3), 0,82 (3H, d, J = 6,5 Hz, 6-CH3), 0,65-0,90 (2H, m), "C-NMR (125 MHz, CDCy, 5 (ppm): 172,5 (C-10); 152,5 (C-4'); 150,7 (C-2'); 147,9 (C-10');
134,7 (C-7'); 127,8 (C-8'); 124,6 (C-5'); 122,3 TAP CHi Dirac H^nc; - ii/mi 6 rsh 488 NAM 55)
61
• Nghien CCFU - Ky thuat
(C-6'); 117,1 (C-9'); 104,6 (C-3); 97,9 (C-3'); 80,0 (C-12a); 78,5 (C-12); 50,9 (C-5a); 47,2 (C-11');
46,3 (C-13') ; 45,1(C-8a); 41,4 (C-15); 40,1 (C- 13); 37,1 (C-6); 36,1 (C-4); 33,1 (C-7); 32,7 (C- 9)- 26,9 (C-14); 26,9 (C-12'); 24,7 (C-5); 24,5 (3- CH3); 22, 4 (C-8); 19,0 (6- CH3); 12,3 (9- CH3).
ESI-MS: m/z [ M + H f : 557,2 (100%); 559,2 (32%).
T6ng h a p c h i t lai hoa 7b
Chat 7b d u g c tong hgp theo quy trinh t u a n g t u chat 7a, ttr 50 mg hgp c h i t 4 (0,14 mmol) va 50 mg hgp chat 5b (0,20 mmol) trong 6 ml MeOH, 12 mg NaBH^ thu d u g c 40 mg c h i t 7b la e h i t r i n mau t r i n g , hieu s u i t 50,0%. R^ 0,53 (MeOH/
EA = 1/5). P„,.- 280-282''C. IR (KBr, v^^, (em-^)):
3371,02 (v,_,), 1635,83 ( v , , „ , „ , ) . 'H-A/MR (500 MHz, CDCI3), 5 (ppm): 8,34 ( I H , d, J = 5,5 Hz, H-2'), 8,10 ( I H , d, J = 9,0 Hz, H-5'), 7,77 (1H, d, J = 2,0 Hz, H-8'), 7,38 ( I H , dd, J = 2,0 Hz, J = 9,0 Hz, H-6'), 6,51 ( I H , 6, J = 5,5 Hz, H-3'), 5,33 (1H, s, H-12), 3,58-3,64 (1H, m, H-13), 3,40-3,46 ( I H , m, H-13), 3,36-3,38 (2H, m, H-11'), 3,19 (1H, m, H-9), 2,62 (2H, m, H-14'), 2,54- 2,59 (2H, m, H-15), 2,34-1,91 (3H, m), 1,59-1,88 (9H, m), 1,22-1,47 (3H, m), 1,33 (3H, s, 3-CH3), 1,06 (3H, d, J = 7,0 Hz, 9- CH3), 0,96 (3H, d, J = 6,5 Hz, 6- CH3), 0,89-0,97 (2H, m, H-7, H-8). "C-WMR (125 MHz, CDCI3), 5 (ppm): 174,1 (C-10); 152,6 (C-4');
152,4 (C-2'); 149,2 (C-10'); 136,2 (C-7'); 127,6 (C-8'); 125,8 (C-5'); 124,3 (C-6'); 118,8 (C-9');
106,1 (C-3); 99,6 (C-3'); 81,3 (C-12a); 80,1(C- 12); 52,6 (C-11'); 50,1 (C-5a); 47,8 (C-14'); 46,6 (C-8a); 43,8 (C-15); 41,6 (C-13); 38,3 (C-6); 37,6 (C-4); 34,7 (C-7); 34,4 (C-9); 28,3 (C-12'); 28,0 (C-14); 27,1 (C-13'); 26,0 (C-5); 25,6 (3- CH,);
23,7 (C-8); 20,0 (6- CH3); 13,3 (9- CH3). ESI-MS:
m/z [M+H]*: 571,2 (100%) ; 573,2 (32%).
T 6 n g h a p chat lai hoa 7c
C h i t 7c d u g c tong h g p theo quy trinh t u g n g t u c h i t 7a, tif 50 mg h g p c h i t 4 (0,14 mmol) va 55 mg h g p e h i t 5c (0,20 mmol) trong 6 ml M e O H , 12 mg NaBH^ thu d u g e 39,5 mg c h i t 7c la chat r i n mau t r i n g , hieu s u i t 4 7 , 1 % . R^ 0,51 (MeOH: EA /1;8). 7»„^; 290-293''C.
IR (KBr, v^3^ (em-')): 3376,54 (v^.,), 1639,70 (V(._o ^^J. 'H-NMR (500 MHz, CDCI3), 5 (ppm):
8,34 ( I H . d, J = 5,5 Hz, H-2'), 8,10 (1H, d, J = 9,0 Hz, H-5'), 7,78 (1H, s, H-8'), 7,39 (1H, dd, J = 2,0Hz, J= 9,0 Hz, H-6'), 6,50 ( I H , d, J = 5,5 Hz, H-3'), 5,35 ( I H , s, H-3), 3,58-3,62 (1H, m, H-13), 3,42-3,47 (1H, m, H-13), 3,35-3,38 (2H, m, H-11'), 3,20 (1H, m, H-9), 2,52-2,61 (4H, m, H-15, H-16'), 2.36 (1H, m), 1,93-2,03 (2H, m), 1,59-1,87 (7H, m), 1,27-1,60 (9H, m), 1,34 (3H, s, 3- CH3), 1,08 (3H, d, J = 6,5 Hz, 9- CH3), 0,99 (3H, d, J = 5,5 Hz, 3- CH3), 0,89-0,99 (2H, m, H-7, H-8). "C-NMR {^25 MHz, C D C y , 5 (ppm): 174,2 (C-10); 152,7 (C-4'); 152,4 (C-2'); 149,7 (C-10');
136,2 (C-7'); 127,6 (C-8'); 125,9 (C-5'); 124,3 (C- 6'); 118,8 (C-9'); 106,1 (C-3); 99,6 (C-3'); 81,4 (C-12a); 80,2 (C-12); 52,7 (C-11'); 50,3 (C-5a);
47,8 (C-16'); 46,7 (C-8a); 43,9 (C-15); 41,6 (C- 13); 38,4 (c-6); 37,7 (c-4); 34,8 (c-7); 34,4 (e-9);
30,3 (C-12'); 29,3 (C-15'); 28,3 (C-14); 28,1 (C- 13'); 28,0 (C-14'); 26,1 (C-5); 25,7 (3- CH3); 23,7 (C-8); 20,1 (6- CH3); 13,4 (9- CH3). ESI-MS: m/z [M+H]*: 599,3 (100%); 601,2 (32%).
Hoat tinh khang t l bao ung thu*
Trong nghien eifu nay, eae c h i t tong hgp d u g c thif tSe dung gay dpe tren 4 ddng t l bao ung t h u : KB, Hep-G2, LU va MCF-7. K i t qua hoat tinh gay dpe t l bao ciia cac c h i t d u g c t h i hien 6' bang 1
Bang 1 : Kit qua thii' hoat tinh gay ddc ti bao ciia cac chit 7a-c
Hop chit
GiatrilC^(yig/ml)
KB Hep-G2 LU MCF-7
Ta 7b
7c
11,13
14,88
15,17
14,68
16,37
14,99
7,87
4,51
12,42 14,56
15,95
Ellipticin 0,31 0,38 0,41 0,34
Cac chat d u g c eoi la ed hoat tinh khi I C „ <128 ng/ml.
62 TAPCHI DUO ;/~i I I r v / - ' f l / I A l z : /Orf-v Acta HT 1 m - - ^ .
Nghien
CCFU- Ky thuat
Ban luan
Cae hgp chit lai hda dugc tdng hgp ttf d i n chit 11-azaartemisinin aldehyd 4 >^i va cac hgp chit 4-aminoquinolin 5a-c '^' bing phan irng amin hda khCr. Qua trinh gdm hai giai doan: giai doan diu la phan irng cdng hgp ai nhan vao nhdm carbonyl giCra 4-aminoquinolin 5a-c vdi d i n ehit aldehyd 4 tao hgp chit imin 6a-c, tilp theo la qua trinh khu hda nhdm chirc imin bing NaBHy MeOH tao hgp chat amin 7a-c. Nhu vay hai hgp phin 11-azaartemisinin va 4-aminoquinolin da dugc lai hda vgi nhau qua c i u nil amin vdi dp dai maeh carbon khac nhau, hieu suit phan ipng 38,4-50%. C i u true ciia cac chit tong hgp duge khing dinh bing eae dti' lieu p h i IR, NMR CH va "€) va ESI-MS. Tren p h i 'H-NMR ciia hgp chat lai hda 7a thiy xuat hien eae tin hieu cpng huang cua nhan quinolin a vi tri 5„ la 8,17 (IH, d, J = 5 , 5 H z , H-2'), 7,77(1 H, d, J =9,0 Hz, H-5'), 7,64 (IH, d, J = 2,0 Hz, H-8'), 7,21 (IH, dd, J = 2,0 Hz, J = 9,0 Hz, H-6'), 6,21 (IH, d, J = 5,5 Hz, H-3'). Ngoai ra edn ed eae tin hieu dac trung cua khung artemisinin nhu nhdm cetal 5^ la 5,03 (IH, s, H-12), 3,11 (1H, m, H-9), va 3 nhdm methyl 5„ la 1,15 (3H, s, 3-Me), 0,95 (3H, d, J = 7,0 Hz, 9-Me), 0,82 (3H, d, .J = 6,5 Hz, 6-Me). Cac tin hieu eiia mach nhanh amin d 5„ la 3,45-3,52 (1H, m, H-13), 3,15-3,31 (3H, m, H-ir, H-13), 2,60 (2H, m, H-15), 2,40-2,50 (2H, m, H-13'). Tren phi "C-NMR thiy xuit hien 30 tin hieu carbon bao g i m 9 tin hieu carbon vdng quinolin a vting tham, 15 tin hieu carbon cua khung 11-azaartemisinin va 6 tin hieu carbon c i u nii. Tren pho khii ESI-MS eho thiy tin hieu cua 2 pic m/z [M+H]* 557,2 (100%) ; 559,2 (32%) la phu hgp vdi edng thire phan tif va khing dinh su cd mat cua nguyen tii' Cl trong phan tii'. Tuang tu cau triic hgp chit 7b va 7c cung dugc khang dinh bang cae p h i NMR, MS.
V l tae dung sinh hpc, eae chit tong hgp 7a-c diu the hien hoat tinh ire c h i kha t i t ddi vdi t i t ca cac ddng t l bao ung thu thir nghiem vgi IC^^
trong khoang 4,51-16,37|ig/ml, tuy nhien d i u y l u han so vdi ehit chuin ellipticin. Mdi hgp ehit lai hda ed hoat tinh chpn Ipe tren cac ddng t l bao ung thu khac nhau. Chit 7a t h i hien kha nang ifc e h l chpn Ipc tren ddng t l bao ung thu vii MCF-7 (ICjo = 4,51 ng/ml), manh han 3-4 lin so vgi cac ddng t l bao ung thu khac. Hgp chat lai hda 7b lai cd tae dung manh nhit tren ddng
t l bao KB (IC^Q = 7,96 ng/ml), trpng khi irc c h i cac ddng t l bao HepG-2, LU, MCF-7 y l u han vgi gia trj IC^^ = 12,42-14,68 ng/ml. Hgp chit 7c lai ed tae dung chpn Ipc tren ddng t l bao ung thu phoi LU vo'i ICjj = 7,87ng/ml. Kit qua nay ehp thiy eae ehit iai hda ting hgp duge d i u ed trien vpng v l tac dung khang ung thu, nhung ehua thiy ed m l i quan he giO'a kha nang gay dpe t l bao va dp dai phin eiu ndi giifa hai hgp phin 11-azaartemisinin va quinolin.
K§t luan
Trong nghien ciru nay 3 din ehit lai hda mdi (7a-c) giifa 11-azaartemisinin va 7-cloro-4- aminoquinolin da duge tong hgp qua ciu nil amin bing phan irng amin hda khii'. Ciu triie eiia cac chit nay diu dugc khing dinh bing cac phuang phap phi.
Kit qua thif hoat tinh gay ddc t l bao eua cac chit tong hgp dugc tren 4 ddng t l bao ung thu ngudi (KB - ung thu bilu md; Hep-G2 - ung thu gan; LU - ung thu phoi va MCF-7 - ung thu vii) cho thiy ca 3 hgp chit lai hda 7a-c diu cd hoat tinh irc ehl kha t i t t i t ea eae ddng t l bao ung thu thir nghiem. Trong dd hgp chit 7a t h i hien kha nang ifC ehl manh nhit tren ddng t l bao ung thu vu MCF-7 vdi IC3„ = 4,51 ng/ml.
Tai lieu tham khao
1. Meunier B. (2008), "Hybrid molecules with a dual mode of action: dream or reality?", Ace. Chem. Res., 41(1), 69-77.
2. Solomon V. R., Lee H. (2011), "Quinoline as a privileged scaffold in cancer drug discovery". Current Medicinal Chemistry, 18(10), 1488-1508.
3. Srivastava V., Lee H. (2015), "Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents", European Journal of Phanvacoiogy, 762, 472- 486
4. Zhang H., Solomon V. R., Hu C, Ulibarri G., Lee H. (2008), "Synthesis and in-vitro cytotoxicity evaluation of 4-aminoquinoline derivatives", Biomedicine &
Phannacotherapy 62, 65-69.
5. Lombard M. C, N'Da D. D., Breytenbach J.
C, Smith R J, Lategan C. A. (2011), "Synthesis, in-vitro antimalarial and cytotoxicity of artemisinin- aminoquinoline hybrids", Bioorganic & Medicinal Chemistry Letters, 21, 1683-1686.
6. Lai H. C, Singh N. R, Sasaki, T (2013),
"Development of artemisinin compounds for cancer treatment". Invest New Dmgs, 31, 230-246.
7. Scudiero, D. A., Shoemaker R. H., Kenneth D.
P., Monks A., Tierney S., Nofziger T. H., Currens M. J., Seniff D,, Boyd M. R. (1988), "Evaluation of a soluble tetrazolium/formazan assay for cell grovrth and drug TAP r w t n i r o r HQr -1 riiMt, r^h 488NAIV156)
63
• Nghien CIFU - Ky thuat
sensitivity in culture using human and other tumor cell lines". Cancer Res., 48, 4822-4833.
8. Le Nguyen Thanh, Tran HCru Giap, Van Thj My Hue, Nguyen Thj Minh Hang, Nguyin Van Hting, Chau Van Minh (2014), "Tong hgp cac d i n chat acid va aldehyd ciia 11-aza-artemisinin", 7ap chi Nghien cuu
duuc va Thdng tin thudc, 5 (6), 227-230.
9. Le Nguyin Thanh, Nguyin Anh Dung, Nguyin Thi Minh Hang, Van Thj My Hue, Nguyin Trung Kien (2015),
"Tong hgp mot so dSn chat 4-aminoquinolin irng dung trong phat trien thuoc diiu tri s6t ret". Tap chi Nghien cUu duuc va Thdng tin thudc, 6 (1), 21-25.
{Ngay nhan bar 27/09/2016 - Ngay phan bien: 27/10/2016 - Ngay duyet dang: 02/12/2016)
K h a o s a t t a c d o n g . . . (nip theo trang 5I)
Tac dong cua NIVIDA va cac c h i t chdng co giat o" cac lilu khac nhau tren t l bao t h i n kinh hdi hai ma sau khi gay dpc b i n g NIVIDA
Lo trang Lo trang
L6NL197 5 m g ; K g L o N L 1 9 7 12.6nng;Kg
Lo NL197 25 mg/Kg Lo IML197 SO mg/Kg
Hinh 1: Ti bao hdi hai ma nhudm eresyl violet a vat kirih xl00
NMDA lam t i n thuang t l bao d vung d i i thi, t l bao hat (Granule cell) va t l bao thap (Pyramidal cell). Mpt s l t l bao bi co cum, khdng nhin rd ttrng te bao, khdng rd nhan va t h i NissI, mang t l bao bi t i n thuang rd ret, b i t mau s i m ,
NL197 l i l u 12,5 mg/kg va 25 mg/kg + NMDA:
nhin rd td'ng t l bao, s l t l bao bi co cum, b i t mau s i m it han Id benh, NL197 l i l u 50 mg/kg + NMD:
te bao khong bi co cum, edn mang, nhan va the NissI rd rang, DZP + NMDA: nhin rd ttrng t l bao, sd te bao bj co cum, b i t mau s i m it han id benh, '
Ket luan
Khi gay eo giat bang NMDA l i l u 75 mg/kg, NL197 6' eae l i l u thir nghiem cd tae dpng lam giam tf ie tif vong xudng d i n 40%.
NL197 d cac l i l u khao sat cd tac ddng c h i n g oxy hda.
Qua quan sat vi hpc, NL197 12,5; 25; 50 mg/
kg va DZP 5 mg/kg ed tae dpng bao ve t l bao than kinh, NL197 50 mg/kg t h i hien tae dpng bae ve tren t l bao t h i n kinh t i t han DZP.
Ghi chiJ: Nghien ciru nay duuc hd trg tai chinh bdi Vien Kiim nghiem thudc Tp. Hi Chi Minh cho di tai: "Nghien ciru tac dung duuc ly thin kinh cua NL197, Din xuit cua 4(3H)-quinazolinon".
Tai lieu tham khao
1 .Nguyin Ngoc Vinh (2006), Nghien ciru ting hgp cac d i n chit mdi ciia dj vong 4(3H)-quinazolinon co tac dung sinh hpc, Luan an Tien sT Duuc hoc, Bai hoc Y D u g c T R H l C h i M i n h .
2. Nguyin Xuan Dung, Vo Phiing Nguyen, Nguyen Ngoc Vinh (2008), "Boc tinh c l p va tac dong dugc ly ciia d i n xuit 4(3H)-quinazolinon", 7ap chi Yhoc TP Hd Chi Minh, 12(1), tr. 94-100.
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{Ngay nhan bar 14/10/2016 - Ngay phan bien: 15/11/2016 - Ngay duyet dang: 02/12/2016)
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