• Nghien ciPU - Ky thuat
4, Tr§n Cam Vmh (1997), "Tac dung cua cay do ngpn trong qua trinh dong mau", Tap chi Y hoc quan su. Hoc vien Quan y, s6 6, trang 7-9.
5 DacieJ.V (1970), Pracf/ca//7aemafo/og>^ Churchill A. 140, Gloncesta Palace, London, pp 270-289.
6. Fraser Murtard J. et al (1967), Animal and laboratory techniques for evaluates blood coagulation
(in: animal and clinical pharmacologic techniques in daigs evaluation, Med. Pub. Inc., Chicago, pp. 250 - 254.
7. WHO (2000), Working group on the safety and efficacy of herbal medicine, Repori of regional office for the Western Pacific of the World Health Organisation
{Ngay nhan bai: 08/06/2014 - Ngay duyet dang: 08/09/2014)
J. Mot SO flavonoid diro'c phan lap tir co seo ga
{Pteris multifida Poir.) thu hai tai Ha Noi
Nguyen Duy Chi', Lai Quang Long^
Thai Nguyen Hiing Thu^*, Nguyen Thai An^
' Vien KN-NC Duac va TTB YT Qudn doi
^Cuc Qudny, Bo QuSc phong
^Truang Bai hoc Duoc Hd Not
* E-mail: [email protected]
S u m m a r y
Three flavonoids kaempferol-3,7-di-O-a-L-rhamnopyranosid (1); kaempferol-3-O-a-L- rhamnopyranosid-7-O-p-D-glucopyranosid (2) and kaempferol-3-O-a-L-rhamnopyranosid -7-0-[a-D- apio-furanosyl -(1-2)-[3~D-glucopyranosid} (3) - were isolated, for the first time, from the ethylacetate extracts of the Pteris multifida Poir by various chromatographic experiments. The structure elucidation of the isolated compounds was done by spectroscopic methods including MS, ID- and 2D-NMR in reference to their literature data.
Keywords Pteris multifida; flavonoids; kampferol.
Dat van de
Co seo ga con cd ten la phuang vT thao....
Cay t h y d n g mpe a nai am thap, moc hoang trong cdc vung ru-ng nui, tren ede khe da, bai ddt hoang .. O Viet Nam, cay phdn b6 khap tu- Bac vdo Nam, toan cay d y g e dung lam thu6e. Theo y hgc CO truygn, eo seo gd d y g c dung de ehua ly, viem t y eung, viem da day, ruot, viem d y d n g tidt nieu... 1^1. Tuy nhien, cde eong trinh nghien euu v§ thanh phdn hda hoc cua cd seo gd tai Viet Nam cdn rdt han ehe. Nhdm gop phdn lam sdng to thanh phdn hoa hgc va tim kigm cdc hoat ehdt cd hoat tfnh sinh hoc trong co seo gd, chung tdi dd tien hanh nghien cuu phan lap ede chat tu- lodi nay.
Nguyen lieu v a phu'O'ng phap n g h i e n CLPU
Nguyen lieu
Mau cdy cd seo gd d y g c thu hai vdo thang 10 ndm 2012 tai Ba Vi (Hd Ngi) Ten khoa hpe dygc TS. D6 Thi Xuydn, Vien Sinh thai vd Tai nguyen sinh vat, Vien Han lam Khoa hoc va Cong ngiie Viet Nam giam djnh Id Pteris multifida Poir. thupc hg Ptendaceae Mdu tieu bdn d y g c lyu try tgi Vien Sinh thai va Tdi nguyen sinh vat, Vien Han lam Khoa hgc vd Cong nghe Viet Nam.
Hda chat, dung moi
Ban mdng trdng sdn Silica gel 60 F^^^ (Merck), RP18 F^^ (Merck); phat hien chat bdng den
50 TAP CHi DU'QfC HQC - 9/2014 (S6 461 NAM 54)
• Nghien ci>u - Ky thuat
t y ngogi d 254 nm vd 366 nm hode dung thuoc thLP la dung d|ch H^SO^ 10%, sdy ndng de hien mdu.
Si> dyng sdc ky cgt pha thudng vd pha dao:
Silica gel co c d hat la 0,040 - 0,063 mm (240 - 430 mesh) vd ODS hodc YMC (30-50 jim, FuJisilisa Chemical Ltd. Nhdt).
Dung moi' n-hexan, cloroform, ethyl acetat, methanol, aceton, nude cdt dat tieu chuan tinh khidt phan tich.
May moc, thiet bj
May do pho cgng h y d n g t u hat nhdn Bruker AM500, mdy do pho khdi luang phan gidi eao Varian FT-CR-MS (USA) hodc LC/MS single quadrupole Agilent 1260 Series (USA) cua Vien Han lam Khoa hgc vd Cdng nghe Viet Nam,
Ket qua va b a n l u a n Chiet xuat va phan lap cdc hap chat Toan cdy Pteris multifida Poir duac thu hdi, rua sach, phai vd sdy khd d 50°C, nghien nhd thu d y g c 2,45 kg bot khd. Bgt nay d y g e ngam chidt 5 lan bdng methanol d nhiet do phong, mdi lan 48 gid. Cde djch chiet d y g c gom lai, loc qua giay Igc vd cat loai dung mdi dudi dp sudt giam thu d y g c 120 g cgn chiet methanol. Can ehiet nay d y g e phdn bo vdo nudc cat vu'a du va tien hanh chiet lan lygt vdi n-hexan, cloroform, ethylaeetat. Cac dieh ehiet n-hexan, cloroform, ethylaeetat d y g e cat thu hdi dung moi d y d i ap sudt giam thu d y a c cdc cdn dich n-hexan (PM-H, 30 g), cloroform (PM-C, 25 g), ethylaeetat (PM-E, 25 g) va phdn nu'dc edn Igi (PM-N, 20 g).
Can ethylaeetat d y g c cho qua cgt silica gel vdi he dung mdi rya giai dicloromethan • methanol vdi dg phdn cgc cua dung mdi tang ddn (ty 20:1 den 0:1), thu d y g c cdc phdn doan F4 (3 g), F5 (2,5g), F 6 ( 5 g ) v d F 7 ( 4 g ) .
Hgp chat 1 (dyge ky higu la PM9) thu d y g c sau khi tinh che phan doan F6 trgn sdc ky cdt pha dao ODS qua rya giai bdng methanol,nydc (1:1) vd aceton.nude (3:7).
Tdch cdc hgp chat trong phan doan F7 (4 g) tren sdc ky cgt pha ddo ODS rCra gial bdng methanol:nydc(1:1), Tiep tye Idm saeh eae phan dogn thu d y g c vdi cpt silica gel rCra giai bang hon hgp ethyl acetat: methanol : nudc (6:1:0,1) thu
d y g c hgp chdt 2 ( d u g c k y hieu Id PM15), vdi cdt pha dao ODS n>a giai bdng methanol.nydc (1:2) de thu d y g e hgp chdt 3 (dyge ky hieu Id PM18)
Xac dinh cau tmc cac hop chat phan lap diFp^
Hgp chdt 1 phan lap d y g c d y d i dang tmh the hinh kim mdu vang nhat. Tren pho khdi luang eua (1) thdy xuat hien pic ion phdn t y m/z 577,5 [M - H]- tuang yng vdi hgp chdt ed edng thyc phdn ti> C^^Hj^O,^. Pho 'H-NMR cua (1) cho 4 tin hieu eua proton tham tai cac vi tri eong hudng 6^ 6,45 (1H, d, J = 2,0 Hz, H-6); 6,77 (1H, d, J = 2,0 Hz, H-8), 7,79 (2H, 6. J = 9,0 Hz, H-2') vd 6,92 (2H, d, J = 8,5 Hz, H-3') gai y vd mgt khung flavonoid dang kaempferol. Ngodi ra cdn quan sdt thay 2 proton anomer dae trung eiia 2 phan t y dudng xudt hien d vj tri cong hydng 5^5,30 ( I N , s, H-1') va 5,54 (1H, s, H-1 ); 2 nhdm methyl bac 3 d y g c nhdn bilt d cae vi tri cgng hydng 6^ 0,81 (3H, d, J = 5,5 Hz. H-6) vd 1,13 (3H, d, J = 6,5 Hz, H-6 ) cho thdy s y cd mat cua 2 rhamnopyranosyl cd cdu hinh a
Trgn pho carbon "C-WMR vd DEPT cua (1) xuat hien 27 tin higu carbon, trong dd cd 9 carbon bac 4, 16 carbon bde 3 vd 2 nhdm methyl, Sy chuyen djch vg phia trydng manh cua 2 tin hieu carbon metin tai 6^ 99,52 (C-6) vd 94,70 (C-8) khdng dinh vdng A bi the 2 vi tri 5, 7. Ben canh dd cung quan sat thay 2 tin higu carbon anomer ddc tryng eho hai phan t y d y d n g tai 6^ 101,96 (C-1 ) va 98,53 (C-1 ); 2 nhdm methyl tai cac vj tri edng hydng 6^ 17,50 (C-6 ) vd 17,94 (C-6 ) khdng dmh (1) la mdt kaempferol chya 2 phan t y d y d n g rhamnopyranosyl,
Ket hgp so sanh vdi so hgu pho cOa (1) vdi hgp ehdt kaempferol-3,7-di-O-a-L-rhamnopyranosidi^i thdy hoan todn phu hap tai ede vi tri tuang yng (bdng 1). Cau tnje hoa hoc cua hgp chat 1 dugc khdng dinh lai dya trgn ket qua phdn tich pho hai chidu HMBC vd HSQC. Cac tin hieu proton dyge gdn vdi ede tin hieu carbon tyang yng dya vao pho 2 ehigu HSQC. Trgn pho HIVIBC quan sat thdy tuang tde glya proton anomer 6^ 5,30 (H-1 ) vdi tin hieu carbon 6^ 134,66 (C-3); tyang tdc giya proton anomer 6^ 5,54 ( H - I ) vdi tin hieu carbon 6^ 161,80 (C-7). Do dd, (1) dyge xac dmh Id cd edng thue phdn t y C^^Hj^,^ (M= 578), cd tgn Id kaempferol -3,7-di-O-a-L-rhamnopyranosid hay cdn cd tdn la kaempferitnn va cd eau true nhy d hinh 1 TAP CHI DUQC HQC - 9/2014 (SO 461 NAM 54)
• Nghien cii'u - Ky thuat
Bang 1 ; Do- lieu phi NMR cua hq/f.
C 2 3 4 5 6 7 8 9 10 r 2' 3' 4' 5' 6' 1"
2"
3"
4"
5"
6"
1 - 2'"
3"' 4'"
5'"
6'"
•6,.
158,3 135,0 178,0 161,5 100,0 162,3 95.0 156,6 106,3 121,0 131,2 116,0 160,7 116,0 131,2 102,4 70,9 70,6 72,2 71,7 18,0 99,3 70.8 70,6 71,2 70,3 18.5
^c"
157.89 134.66 178.02 161.80 99.52 161.80 94.70 156.22 105,88 120.48 130.79 115.48 160.19 115.48 130.49 101.96 70.76 70,31 71,23 71.23 17.50 98.53 70.76 70,76 71.23 70.31 17,94
S„","
6,45 (d, 2.0) 6,77 (d. 2,0)
7.79 (d. 9.0) 6,92 (d. 8.5) 6.92 (d. 8.5) 7.79 (d. 9.0) 5,30 (s) 3.16(ovedap) 3.43 (overlap) 3.31 (m) 3.31 (m) 0.81 (d. 5.5)
5.54 (s) 3.16 (ovedap) 3.16 (ovedap) 3,31 (m) 3.63 (m) 1.13 (d. 6.5)
1 chat 1 HMBC (H^CI
5.8,10 6,7.9.10
2.4' 1.4'
3
7
^ do trong DMSO-d^ '125 MHz. "500 MHz. \ kaempferitnn do trong CDpD'^'
Hap ehdt 2 phdn lap d y g c d y d i dang chdt rdn mau vdng Trgn pho khdi lygng eua (2) thdy xudt hign pic ion phdn ti> m/z 595,1 [M + H ] M y a n g yng vdl hgp ehdt cd cdng thye phan tCr C^^H^fi^^
Quan sdt trgn pho ^H-NMR va ^^C-NMR cua (2) thdy s y t y a n g ddng vdi (1) vg edu true phan t y Pho 'H-NMR cua (2) eho bon tin higu cua proton tham tai 8^6,51 ( I H , d, J = 2,0 Hz, H-6,);
6,76 ( I H , d, J = 2,0 Hz, H-8), 7,82 (2H, d, J = 9,0 Hz, H-2); 6,97 (2H, d, J = 8,0 Hz, H-3) ggi y vd mgt khung flavonoid dang kaempferol. Ngoai r a 2 proton anomer d 6H 5,42 ( I H , d, J = 1,5 Hz, H - r ) v a 5 , 0 9 ( I H , d, J = 7,0 Hz, H-1 ) cung vdi 1 nhom methyl 6^ 0,96 (3H, d, J = 6,0 Hz, H-6 ) vd mgt nhdm oxymetilen 6^ 3,74 ( I H , m, H-6"a), 3,95 ( I H , dd, J = 2,0/ 12,0 Hz, H-6"b) cho thdy s y tdn tai cua 1 phdn tCp d y d n g rhamnose vd 1 phan t y d y d n g glucose
Tren pho carbon "C-NMR va DEPT cOa (2) xudt hien 27 tin hieu carbon, trong do co 9 carbon bdc 4, 16 carbon bae 3, 1 nhdm metilen va 1 nhdm methyl. Ddc biet s y chuyen djch ve phia t r y d n g manh cua hai tin hieu carbon 5,, 100,86 (C-6) vd 95,82 (C-8) dae tryng cho viec vdng Abi thd 2 vj tri 5, 7 bdi 2 nguyen t y oxy. Bgn egnh do eung quan sat thdy 2 tin hieu carbon anomer tai 5^103,48 (C-1") va 101,58 ( C - f ) ; 1 nhdm methyl tai vj tri 6^, 17,64 (C-6"); mpt nhdm oxymetilen tai 62,46 (C-6"). T y cac di> kien tren eho phep ta di/
doan ve mgt kaempferol dinh 2 d y d n g . Cde tin hieu proton d y g c gdn vdi cdc tin hi|u carbon t u a n g y n g d y a trgn k i t qua phdn tich pho hai chieu I^SQC Tren pho edng hydng ti>
hat nhan hai chieu HMBC quan sat thay tucng tae giya tin hieu proton ^^^ 5,42 (1H, d, J = 1,5 Hz, H-1") vdi tin hieu carbon 6^ 136,46 (C-3); giua tin hieu proton 6^ 5,09 ( I N , d, J = 7,0 Hz, H-1") vdi tin hieu carbon 5^ 164,66 (C-7) eho phep khang djnh 2 phan t y d y d n g ndi vdi carbon C-3 va C-7
H i n h 1 : Cdu (rue ctia (1), (2) va(2) TAP CHI DUQC HQC - 9/2014 (SO 461 NAM 54)
• Nghien ci>u - Ky thuat
Hinh 2: Cdc tuang tac HI\/IBC cua {^). (2) va{3)
So sdnh vdi so lieu pho cua hgp chat 2 vdi kaempferol 3-0-a-L-rhamnopyranosid -7-0-|3- D-glucopyranosid'^' (bang 2) thay hoan toan phu hgp t^i cac vi tri t y a n g yng. T y do cd the khang djnh (2) ehinh la kaempferol-3-O-a-L- rhamnopyranosid-7-p-D-glucopyranosid, cd cdng thye phdn t u C^-^H^p^^ (M = 594) va cd cau true nhy d hinh 1.
Bang 2: DO" li$u pho NMR cua hop chit 2 C
2 3 4 5 6 7 8 9
• « j
159,7 136,4 179,7 162,7 100.8 164.6 95.7 158,0
S j "
159,85 136.46 179,80 162.80 100.86 164.66 95.82 158.00
5„"
6,51 (d. 2.0) 6.76 (d. 2.0)
HMBC (H^a
5.7,8.10 6.7.9.10
10 1' 2' 3' 4' 5' 6' 1"
2"
3"
4"
5"
6"
1 "
2'"
3'"
4'"
5'"
6'"
107.6 122,3 132.0 116.5 161.7 116.5 132.0 103.4 71.2 72.1 73,1 71.8 17.6 101,5 75.1 78.0 72.1 78.3 62.4
107.69 122.42 132.02 116.57 161.75 116,57 132,02 103.48 71.27 72.07 73,17 71.89 17.64 101.58 74,71 77.81 72.12 78.36 62.46
7.82 (d, 9.0) 6.97 (d, 8.0) 6,97 (d. 8,0) 7,82 (d, 9,0) 5,42 (d. 1,5) 3,36 (m) 3.74 (m) 3.36 (m) 3.74 (m) 0.96 (d. 6.0) 5.09 (d. 7.0) 3.52 (m) 3.54 (m) 3.36 (m) 3.54 (m) 3.74 (m) 3,95 (dd. 2.0/12.0)
2,4' 1'.4' 1'.4' 2.4' 3.5"
4". 5"
7
" do trong CDpD, '125 MHz. °500 MHz.
"Sj, cua kaempferol-3-0-a-L-rhamnopyranosid-7-P-D- glucopyranosid do trong CDfiD '^'
Hap chdt 3 phan lap d y g e d y d i dang chdt rdn mau vang. Trgn pho khoi lygng cua (3) thay xuat hien pic ion phan t y m/z 725,1 [M - H]'tyang yng vdi hap chat cd cdng thdc phdn t y C^^H^fi.^^
Quan sat tren pho 'H-NMR vd '^C-NMR cua (3) thdy sy tyang dong ve cau true phdn t i i eua hgp chat 2.
Pho ^H-NMR cua (3) cho bon tin higu cua proton tham tai 6^ 6,48 (1H, d, J = 2,0 Hz, H-6,);
6,75 ( I H , d, J = 2,0 Hz, H-8); 7,83 (2H, d, J = 8,0 Hz, H-2); 6,96 ( 2H, d, J = 8,0 Hz, H-3) cho thay ddy eung la mgt hgp chdt flavonoid dang kaempferol. Ngoai ra, 3 tin higu proton anomer quan sat thay d eae V! tri cgng hudng 6^5,42 ( I H , d, J = 1,5 Hz, H-1 ); 5,16 ( I H , d, J = 7,5 Hz, H-1 ") v d 5 , 4 7 ( 1 H , d, J = 1,5 Hz, H-1 ), 1 nhdm methyl bde 3 tai vi tr( cpng hydng 5^ 0,96 (1H, d, J = 6,0 Hz, H-6") eho thdy trong 3 phdn t y d y d n g thi cd 1 phan t y dudng rhamnose. T y a n g t y hap chdt (2), s y ehuyen djch vd phia trydng manh cua 2 tin hieu carbon methyl 8^ 100,70 (C-6) va 95,73 (C-8) cho thay vdng A cung h\ the 2 vi tri 5, 7, Sy xuat hign eua 2 tin higu carbon oxymetilen tai cae vi tri cdng hudng 8^ 75,42 (CH^) va 65,86 (CH^)
T.\P CHi DUQC HQC - 9/2014 (S6 461 NAM 54)
• Nghien CLFU - Ky thuat
cung 1 tin hieu carbon bae 4 tai vi tri b^ 80,70 (C) eho phep d y doan s y cd mat cua 1 phan t y d y d n g apiofuranose. Cac tin hieu proton d y g c gan vdi tin hieu carbon t u a n g y n g d y a vao kdt qua phdn tieh pho hai chidu HSQC. So sanh v d i sd lieu pho cua hgp ehdt 2 thi dd ddng nhan thay s y sai khac chu yeu xay ra d cde tin higu carbon oxymethin eua phdn t y dudng glucose.
S y chuyen djch ve phia t r y d n g ydu eua tin hieu carbon oxymethin S^. 78,26 (so vdi 74,72 (C- 2") eua hgp ehdt 2 ggi y s y cd mat cua d a n vi d y d n g apiofuranose tai vj tri C-2'. Vj tri lien k i t cua d y d n g rhamnose tai vj tri C-3 d y g c khang dmh d y a vdo t y a n g tde giua proton 5^ 5,42 (H-1") vdi tin hieu carbon 8^ 136,46 (C-3); cua d y d n g glucose tai vi tri C-7 do t u a n g tdc giua proton 6j, 5,16 ( H - 1 ) vdi carbon 8^, 164,53 (C-7).
Ben canh do, tren pho HMBC cung quan sat thdy t y a n g tdc rat rd giua proton 6^ 5,47 (H-1 ') vdi tin hieu carbon 6^ 78,26 (C-2"). Didu ndy eho phep k h i n g dmh phdn t y d y d n g apiofuranose lien ket vai carbon d vj tri C-2 cua d u d n g glucose.
Bang 3: Dir lieu pho NMR cua hap chit 3
c
2 3 4 5 6 7 8 9 10
r
2' 3' 4' 5' 6' 1"
2"
3"
4"
5"
6"
1'"
•i.
159,8 136.4 179,7 162.8 100.6 164.4 95.7 158.0 107.6 122.3 132.1 116.5 161,7 116.5 132.1 103.5 71.2 72.1 73.1 71.8 17.6 100.1
« / • •
159.89 136.46 179.81 163.00 100.70 164.53 95.73 158,12 107,90 122.39 132.04 116.59 161,81 116.57 132.04 103.48 71.29 72.13 73,17 71,90 17.65 100,18
V
6.48 (d. 2.0) 6.75 (d. 2.0)
7,83 (d. 8.0) 6 96 (d. 8.0) 6.96 (d. 8.0) 7.83 (d, 8,0) 5,42 (d.1.5) 4.24 (dd. 1.5.3.0)
3.97 (d.1.5) 3.44 (m) 3.65 (m) 0.96 (d. 6.0) 5.16 (d. 7.5)
HMBC (H^C)
5.7.8,10 6.7,9.10
2.4' 1',4 1'.4' 2.4' 3
7 2'"
3'"
4'"
5'"
6'"
1"' 2'-' 3-"
4,-, 5'"'
78.2 78.6 72.1 78.4 62,4 110,8 78.1 80.7 75.4 65.4
78.26 78.76 72.13 78.41 62.40 110.89 78,15 80,70 75,42 65.86
3,71 (m) 3,43 (m) 3,36 (m) 3,64 (m) 3,74(m) 3 97 (d 1 51 5,47 (d, 2.0) 4.05 (d.10.0) 3,83 (d, 10.0) 4.05 (d. 10.0) 3.56 (brs)
2'
* do trong CDpD, " 125 MHz. " 500 MHz, \ cua kaempferol-3-0-a-L-ihamnopyranoside-7-0-[a-D-apio- furanosyl-(1-2)-^-D-glucopyranoside do trong CDpD fJ
So sdnh vdi s6 lieu pho cua hgp chat 3 vdi 3-0-a-L-rhamnopyranosid-7-0-[a-D-apio- furanosyl-(1-2)-3-D-glucopyranosid'^i thdy hoan todn phu h g p tai ede vi tri t y a n g dng (bang 3).
Vdy (3) ehinh Id kaempferol-3-O-a-L-rhamno pyranosid-7-0-[a-D-apio -furanosyl -(1-2)-p-D- glueopyranosid ed edng thue phan t y C^^^^p^^
(M = 726) va cdu true n h y d hinh 1.
Ket luan
Ba h g p chat kaempferol-3,7-di-0-a-L- rhamnopyranosid ( 1 , PM9), kaempferol-3-0- a-L-rhamnopyranosid-7-O-p-D-glucopyranosid (2. PM15) vd kaempferol-3-O-a-L- rhamnopyranosid-7-0-[a-D-apio-furanosyl-(1-2)- p-D-glucopyranosid] (3, PM18) da d y g e phan lap t y eo seo ga thu hdi tai Hd Ndi. Cdu true hoa hpc cua Chung d y g c xac djnh bdng cac phyang phap pho khdi l y g n g , pho cgng h y d n g tilF hat nhan mgt chieu va hai chidu. Day Id lan ddu tien 3 hgp chat nay d y g e phan lap tu" loai Pteris multifida Poir..
Tai lieu tham khao
1. V6 Van Chi (2012), Tir dien cay thuoc Viet Nam.
Nha xudt ban Y hoc, lap 1, tr 541.
2. M M Marzouk, S. A Kawashty, N. A. M. Saleli and Abdel Salam M. Al-Nowaihi (2009), "A new kaempferol trioside from Farsetia aegyptia", Chemisry of Natural Compound, 45 (4), 483-486.
3. Yung-Husan Chen, Fang-Rong Chang, Yih-Jer Lin, Lisu Wang, Jinn-Fen Chen, Yang-Chang Wu, Ming-Jiuan Wu (2007), "Identification of phenolic antioxidants from Sword Brake fern (Pteris ensiformis Burm.)", Food Chemistry. 105, 48-56.
(Ngay nhan bai- 01/07/2014 • Ngay duyet dang: 08/09/2014)
TAP CHI DU^QC HQC - 9/2014 (SO 461 NAM 54)