Nghien
CLFU- Ky thuat
•7
Nghien cii'u tong hop
thuoc dieu trj ung thu* hydroxyurea
Dat van de
Hydroxyurea (tin khic la hydroxycarbamid) d i dupe tdng hpp lin d i u tiin v i o nam 1869 bdi Dressier.W.F.C v i Stein R. '''', nhung phai din cudi nhu'ng nam 60 cua the ky trude mdi dupe i p dung lim sing trong dieu trj binh bach c i u tuy man [4. 16, 17] Hien nay, hydroxyurea (HU) dupe xic nhin l i thuoc dieu trj binh bach eau tiiy man cd hiiu qua, it dpc v i cd the k i o d i i thdi gian sdng cua binh nhin liu han so vdi Busulfan v i cac thude khie '^' ^' •*• ^' '^\ Ngoii ra, HU cdn dupe sCr dung trong diiu trj u hie td, eareinom budng trung khdng md dupe, HU dupe kit hpp vdi xa tri d i diiu tri ung thu t i bao cd viy (bleu md) d diu v i cd, ngoai trir d mdi. Ca ehi tic dung ehdng ung thu eua HU dupe giai thich l i do HU ire c h i enzym ribonueleotid reductase l i mpt enzym c i n thiit de chuyen c i c ribonueleotid thinh cie deoxyribonucleotid l i tiin chit ein thiit de tdng hpp ADN, h i qua l i HU iec ehi tdng hpp ADN, l i m eho te bao tich luy d pha S. '^^' ^°\ G i n diy, HU edn dupe sir dung trong dieu trj eie benh khdng phai ung thu nhu thiiu miu hdng c i u liim, ting tao tieu cau, tang hdng ciu vd can v i phdi hpp vdi didanosin trong diiu trj HIV/AIDS''^"^°'.
Hydroxyurea l i dupe c h i t dupe ghi trong
Nguyin Quang Dat', Binh Thi Thanh Hdi' Vu Trdn Anh', Hoang Thu Trang', Nguyen Nggc Anh'
Pham Thi Hanh Nguyen', Tran Viet Hiing'
Nguyin Thi Kieu Anh', Biii Thi Hda\ Nguyin Trgng Thong' 'Truang dgi hgc Dugc Hd Npi
^Vien Kiim nghiem thude Trung ucmg
^Trudng dgi hgc YHd Npi
Dupe dien ciia nhieu nude nhu Anh, My, chiu Au, Trung Qudc '^^ " ^^' v i cd trong danh muc thude thiit yeu Vipt Nam ban hinh nam 2005 "'.
Hien nay, hydroxyurea dang dupe diing khi phd biin d nude ta trong dieu trj benh bach ciu tiiy man, mpt benh k h i phd bien trong c i c binh eiia he tao m i u '^' ^'. Nhu c i u ve thuoc HU cho dieu trj la k h i idn va dang hoan toin phai nhip ngoai vdi c i c biit dupe nhu uniroxy, huonhydran (Hin Qude), hydrea (Squibb)...'^'. Vi v i y ehiing tdi thirc hiin de tai nghien eiru xay dung quy trinh tdng hpp hydroxyurea dat tiiu chuan dupe dung, de tien tdi ed the tu san xuat trong nude phuc vu eho nhu c i u dieu trj.
Nguyen lieu va phu'ang phap
Nguyen lieu
Amberiite IRA-410CI resin (Aldrich), kalieyanat, natricyanat, methyl carbamat (Merck), hydroxylamin hydroelorid (Trung Qude), ethanol tuyet ddi (Viet Nam), hydroxyurea chuan USP (My).
Phyang phap nghien ciru
Cd 3 phuang phip tdng hpp Hydroxyurea (HU) d i dupe cdng bd:
- Phuang phip cua Dressier, W.F.C v i Stein, R. '^i, Parehure, B.M '"'; HU duac dieu che bing phan irng eua kali eyanat (hoic natri cyanat) vdi hydroxylamin hydroelorid trong dung djch nude;
KOCN H2N-OH.HCI
- Phuang phip eua Graham, P.J '^': HU dupe diiu ehi bing each chuyen nhua trao ddi ion amoni bae 4 tir dang clorid sang dang cyanat v i
HoN-•C-NHOH O
KCl (1)
thue hiin phan Crng cua nhua d dang cyanat vdi hydroxylamin hydroelorid tao ra HU v i anion Cf bj giCr lai bdi nhua amoni b i c 4:
44 T^P CHi DUQC HQC - 7/2009 (SO 399 NAM 49)
Nghien
CLPU- Ky thuat
R4NC1 NaOCN R4NNCO NaCI (2)
R4NNCO H,N-0H.HC1
- Phuang phip eiia Deghenghi R '^', Hengeveld J.E '^°': HU dupe dieu ehi bing phan irng cua ethyl carbamat (hoac methyl carbamat)
HjN-C-NHOH 4- R4NCI (3) O
vdi hydroxylamin hydroelorid trong dung dich NaOH trong nude:
l.NaOH^
2. HCI H2N-C-OC2H5 -f- H2N-OH.HCI
O
Sd liiu edng bd trong cie tii lieu tham khao eho thiy phuang phip ciia Dressier '^' v i Parehure ' " ' cho hieu suit thap (30%) v i cd the tao ra sin phim phu, eie phuang phip eua Graham '^' v i Deghenghi '*' eho hieu suit cao ban (53% v i 42%), rieng phuang phip Graham cd uu diim l i ion Cf bi giir lai bdi nhua trao ddi ion, vi viy d i tinh c h i san phim ban. Tir cac nhin x i t trin, chiing tdi chpn hai phuang phip niy d i tiin hinh khao sit thuc nghiem de xiy dung qui trinh tdng hpp hydroxyurea dat tieu chuin dupe dung.
K i t qua va ban luan
Tong ho>p hydroxyurea (HU) theo phuang phap cua P.J. Graham '°'
Qui trinh tdng hpp HU theo cac phuang trinh phan irng (2) v i (3) neu tren gdm hai budc:
- Budc 1: Cho dung dich natri cyanat tie dung vdi nhua trao ddi anion amoni bic 4 dang clorid (Amberiite IRA-410 dang clorid) de chuyen nhua trao ddi anion tir dang clorid sang dang cyanat.
- Bude 2: Thuc hien phan irng eiia nhua trao ddi anion dang eyanat vdi hydroxylamin hydroelorid, thu dupe hydroxyurea v i anion Cl' bj giir lai bdi nhua amoni bic 4.
Graham P.J '^' d i xuat phuang phip tdng hpp niy vdi qui trinh 2 budc niu tren v i da tien hinh cie phan irng vdi eie dieu kien nhu sau:
dimg 2kg Amberiite IRA-410 dang clorid, 3kg dung dich NaOCN 10% (tuang irng vdi 300g (4,61 moi) NaOCN), dung djch 105g (1,5mol) hydroxylamin hydroelorid trong 400ml nude, phan irng toa nhiit vdi nhiit dd 50-70°C, cd die dung djch phan irng thu dupe dudi i p suit giam d 35°C, thu dupe 90g san pham thd, kit tinh lai tir 100ml nude d 75°C v i siy khd trong binh hiit am chin khdng trin P2OS, thu dupe 60,6g HU cd diem chay 133-136°C, hiiu suit 53%.
H,N-C-NHOH
1-
O
C2H5OH + NaCI (4)
Nghien ciru triin khai qui trinh tdng hpp HU theo phuang phip ciia Graham, trude hit chimg tdi nhin thiy diim ndng chay eua san pham HU (133-136°C) eua qui trinh niu trin thip ban rd ret so vdi cie sd lieu v i diem ndng chay eiia HU d i cdng bd d cic t i i liiu khic l i 139-141°C '^' v i 138-145°C •'^'. VI viy ein tiin hinh khao sit phuang phip tinh c h i cung nhu cic yiu td anh hudng din cie phan irng ciia qui trinh niy nhim thu dupe san phim dat tieu chuin dupe dung v i hieu suit cao. Sau diy l i cic nhin xet v i kit qua khao sat eiia chiing tdi:
- Ciing vdi viic sir dung natri cyanat (NaOCN) de thirc hien phan irng trao ddi vdi anionit nhu qui trinh neu trin eua Graham, chiing tdi da thuc hien phan irng vdi chat ed the thay the la Kalieyanat (KOCN) de so sinh ve cich tien hinh cung nhu ve hiiu suit v i chit lupng san pham.
- Lupng NaOCN (hoac KOCN) tdi da ed the thue hiin phan irng trao ddi vdi anionit Amberiite IRA-410 dang clorid dupe tinh tir dung lupng trao ddi eiia anionit niu tren l i 3,4meq/g '^'' v i khdi lupng anionit d i nhdi cpt. Graham '^' d i diing lupng NaOCN bing 2/3 lupng tdi da.
Chimg tdi da sir dung ty l i niy v i khdng khao sit them.
- De phan irng trao ddi ion xay ra nhanh v i hiiu qua cin sir dung dung dich NaOCN bio hda (10%) v i dung djch KOCN bio hda (40%).
- Phan irng cua hydroxylamin hydroelorid vdi anionit d dang eyanat dat kit qua tdt vdi cie dieu kiin phan img: ty l i moi H2N-OH.HCI/NaOCN (hoic KOCN) l i 1:2, ndng dp dung dich nude eiia hydroxylamin hydroelorid l i 20%, nhiit dp phan irng l i 40-60°C.
- Phuang phip tinh ehi HU thich hpp nhit l i kit tinh lai trong hdn hpp EtOH: H2O (5:1).
TAP CHf DUQC HQC - 7/2009 (SO 399 NAM 49) 45
Nghien
CLPU- Ky thuat
Vdi cic dieu kiin phan irng v i cich tinh che niu tren, chimg tdi d i thu dupe hydroxyurea cd diem ndng chay l i 140 - 142°C, hiiu suit trung binh l i 42%. Kit qua x i c djnh c i u triic v i kiem nghiim chit lupng san pham dupe trinh biy d phin sau.
Tdng ha'p hydroxyurea (HU) theo phu'ang phap cua R.Deghenghi '*' va J.H.Hengeveld'"'
Qui trinh tdng hpp HU theo phuang trinh phan irng (4) neu tren dupe thue hiin bdi R.Deghenghi vdi c i c dieu kien phan irng; ty le moi hydroxylamin hydroelorid ; natri hydroxyd : ethylearbamat la 1,2:2:1, nhiit dp phan irng:
25°C, thdi gian phan irng: 3 ngiy de yin, chiit san phim 2 lin bing EtOH, k i t tinh lai trong EtOH, thu dupe san pham HU ed diem ndng chay 139 - 141°C, hiiu suit 42%.
Trong qui trinh tdng hpp thude Zileuton d qui md cdng nghiep, J.E.Hengeveld ''"' v i edng su da thue hien tdng hpp HU d giai doan trung gian vdi phan irng tuang tu phan irng (4) nhung ed mpt sd thay ddi: dung methylearbamat thay eho ethylearbamat, dting dung dich nude hydroxylamin 50% thay eho hydroxylamin hydroelorid, ty l i moi hydroxylamin natrihydroxyd : methylearbamat l i : 1,1:1:1, nhiet dp phan irng 25°C, thdi gian phan irng 4h (khuiy), sin phim phan Crng khdng dupe phin lip m i dung hdn hpp phan Crng trong giai doan sau.
Phin tich so sinh hai qui trinh neu trin, ehiing tdi da lua ehpn eie diiu kien thich hpp de tiin hanh thue nghiim trien khai qui trinh tdng hpp HU theo R. Deghenghi vdi viic diing methylearbamat d i kiem, re tiin ban thay cho ethylearbamat v i khao sat thdi gian phan irng, each tinh ehi san pham. Sau diy l i k i t qua thue nghiim cua chiing tdi:
- Cie diiu kiin phan irng thich hpp l i ty le moi hydroxylamin hydroelorid : natri hydroxyd ; methylearbamat l i 1,2:2:1, nhiet dp phan irng 25°C, thdi gian phan Crng 4h.
- Cich tinh c h i thich hpp l i kit tinh lai san pham thd hai lin: lin thCr nhit trong nude c i t d 50°C v i lin thCr hai kit tinh lai trong hdn hpp EtOH: H2O (5:1). Cieh tinh c h i niy tien hanh dan gian han, tdn it ethanol han so vdi cich kit tinh lai dung EtOH tuyet ddi eua R. Deghenghi, ddng thdi san pham loai dupe ion Cl" theo tieu chuan dupe dien, san pham ed diem chay 140-
142°C, hiiu suit trung binh: 40%. Kit qua xdc djnh eau trCic v i kiem nghiim chat lupng san pham dupe trinh biy d phin sau.
Xac djnh ciu true cua hydroxyurea tong ha'p du'O'c.
C i u true eua hydroxyurea (HU) tdng hpp dupe bing hai phuang phap niu trin d i dupe x i c djnh bing c i e phuang phip phd IR, 'H- NMR, "C-NMR v i MS. Sd lieu phin tich phd dupe trinh biy d bang 1, bang 2, bang 3. Phd IR eua 3 m i u chit HU tdng hpp dupe (gdm 2 miu HUI, HU8 dupe tdng hpp theo phuang ph^p P.J.Graham v i m i u HU22 duac tdng hpp theo phuang phip R. Deghenghi) phu hpp vdi phd IR cua HU chuan v i deu cd eae dai hip thu d|c trung eho c i e nhdm chCre v i lien kit cd trong phin tCr nhu VQH (3422-3425em'^),VNH (3317- 3318cm''), VNH2* (2821-2823 cm'''), vc=o (1641- 1643em''), yNH2 (1108-1109cm''), VN-O (820- 823em''). Ding chii y l i su xuat hiin eua dai hap thu kha manh d sd sdng 2821-2823em'' dupe biin giai l i dao ddng hda trj cua nhdm ^^^
dugc hinh thinh do su liin hpp glQ'a cie diin tip tu do ciia nguyen tCr Nita vdi cae diin tu n eua nhdm >C=0 d i n tdi eau true phin cue ciia phin tir HU tuang tu nhu phin tu ure ^'^^•^\
HjN—C—NH—OH
: o :
* I
H2N=C—^NH—OH Phd ^H-NMR cua 3 m i u chat hydroxyurea tdng hpp dugc (HUI, HU8, HU22) triing vdi phd ' H - N M R cua HU chuan v i cd d i y du tin hiiu ciia 4 proton thupc 3 dang proton vdi c i c gii trj 5H IS 8,59-8,62ppm (-0H); 8,26-8,30ppm (-NH) vd 6,16 -6,20ppm (NH2) hoin toin phii hpp vdi tSi liiu tham khao •^'''. Phd '^C-NMR eua 3 miu chat HU tdng hpp dupe (HU1, HU8, HU22) triing vdi phd '^C-NMR eua HU chuan v i cd tin hiiu eua nguyen tir carbon duy nhat cd trong phin tCr vdi gii trj 5c = 162,64 -162,83 (C=0 amid) phii hpp vdi t i i lieu tham khao •^^'.
Phd khdi phin giai cao cua 3 m i u chat HU tdng hpp dupe (HUI, HU8, HU22) triing vdi phd khdi eua HU chuan v i deu cd pic ion phin tir (IVI*
= 76,0237 - 76,0255) phii hpp vdi edng thirc dif kien, ddng thdi ed eic pie cua c i e ion manh d§c trung (CO2, HNCO, NH2OH, H2O, NH3) phii hpp vdi sa dd phin manh (xem bang 3).
46 TAP C H i DU'QC H Q C - 7/2009 (SO 399 NAM 49)
• N g h i e n
CLPU- Ky t h u a t
Bang 1: Si lipu phi IR ciia HU ting hgp dugc vd HU chuin Mlu chit Ph6 IR (KBr), c m '
VOH VNH V N H * Vc=o VCJJ YNH, VN.O
HU Chuan 3422,7 3316,7 2819,3 1642,8 1413,3 1108,8 818,9 HU1 3423,3 3317,1 2823,3 1641,7 1409,3 1109,0 820,0 HUB 3422,2 3316,9 2821,4 1643,3 1412,4 1109,4 823,9 HU22 3425,2 3318,0 2821,0 1643,7 1409,6 1108,0 823,9
Bang 2: Si lieu phi 'H-NMA vd '^C-NMR cua HU ting hgp dwgc vd HU chuin
MSu chat 'H-NMR (DMSO-ds), 8„(ppm) "C-NMR (DMSO-ds), Sc(ppm) HU chuan 8,60 (s,1H, OH): 8,27 (s,1H, NH); 6,17 (s,2H, NH2)
HU1 8,61 (s,1H, OH); 8,28 (S,1H, NH); 6,18 (S,2H, NH2) HU8 8,59 (s,1H, OH); 8,26 (s,1H, NH); 6,16 (s,2H, NH2) HU22 8,62 (s,1H, OH); 8,30 (S,1H, NH); 6,20 (S,2H, NH2)
162,69 (C=0) 162,72(0=0) 162,64(0=0) 162,83(0=0)
Bang 3; Si lieu phi khii Iwgng cua HU ting hgp dugc vd HU chuin
m/z (ty le cifang do % )
76,0279 (M*; 3,30); 44,0023 (CO2; 71,29); 42,9960 (HNCO; 13,76);
33,0057 (NH2-OH; 100,00); 17,9989 (H2O; 2,96); 17,0074 (NH3; 8,06) HU chuan
76,0237 (M*; 4,36); 44,0294 (CO2; 70,94); 43,0253 (HNCO; 18,42);
33,0508 (NH2-OH; 100,00); 18,0759(H2O; 2,95); 17,0885 (NH3; 8,32) HUI
76,0255 (M*; 3,45); 44,0163 (CO2; 72,00); 43,0118 (HNCO; 15,69);
33,0304 (NH2-OH; 100,00); 18,0421 (H2O; 4,28); 17,0536 (NH3; 7,42) HU8
76,0247 (M*; 3,45); 44,0164 (CO2; 66,65); 43,0152 (HNCO; 14,70);
33,0292 (NH2-OH; 100,00); 18,0457 (H2O; 2,73); 17,0533 (NH3; 6,85)
Kiim nghiem chit lup'ng cua hydroxyurea tdng hofp dugc theo BP 2005
Chiing tdi da giri 4 miu hydroxyurea tdng hap dupe de kiim nghiim theo BP 2005 tai Vien Kiem nghiem thude Trung uang (miu HU1A) v i tai Trung t i m Khoa hpe edng nghi dupe (Trudng Bai hpc Dupe H i ndi) (3 mau: HU06- 08, HU07-08, HU08-08). Kit qua l i ea 4 mau giri kiim nghiem diu dat yeu ciu chit lupng theo BP 2005 [phieu kiem nghiem sd 905 (ngiy 11/11/ 2008) eua Vien Kiim nghiem thude Trung uang v i cic phieu kiem nghiem sd 07/08-NC (ngiy 07/11/2008), sd 08/08-NC (ngiy 12/11/2008), sd 09/08-NC (ngiy 14/11/2008) ciia Trung tim Khoa hpe edng nghi dupe (Trudng dai hpe Dupe Ha Ndi).
Thir dpc tinh d p cua hydroxyurea tdng hgp du'gc
- Noi tien hanh thir. Viin Kiem nghiim thude Trung uang.
- Phuvrng phap: Cin cir v i o cie t i i lieu sau:
+ Qui trinh thir dde tinh cap ciia Vien kiim nghiim thude Trung uang.
+ OECD guidelines for testing of chemicals.
Acute oral toxieity-fixed dose procedure OECD 420,2001.
TAP CHi DU'QC HQC - 7/2009 (SO 399 NAM 49)
- Ddi tupng nghiin ciru: mau hydroxyurea dai dien (HU1A).
- Ddng vat thi nghiim: Loii: chupt nhit trang gidng Swiss; can nang 18-22g; sd lupng: 70 eon.
Ngudn gdc cung cip: Vien Ve sinh dich te Trung uang.
- Cie tiin hinh v i kit qua dupe trinh bay d Phieu phin tich sd 39G135 (21/01/2009) cua Vien Kiem nghiem thude Trung uang.
Kit qua thu dpe tinh cip miu HU1A cho thiy:
liiu khdng gay chit chupt la 7,500g/kg; liiu gay chit 100% sd chupt thir nghiem l i 30,000g/kg.
Dua trin sd lieu thuc te, tinh dupe LD50 eua Hydroxyurea trin chudt nhit tring l i (17,1189 ± 1,4451) g/kg theo dudng udng.
Thuc nghiem
Diim ndng chay dupe xic dinh trin miy do diim chay hien sd Electrothermal, phd IR dupe ghi tren miy Perkin Elmer. Phd ' H - N M R v i '^C- NMR dugc ghi trin miy Bruker AV500. Phd MS dugc ghi tren may Autospec Premier (Waters).
Tdng hgp hydroxyurea theo phuang phap Graham P.J '''
Cin 500g nhua trao ddi ion Amberiite IRA.410 dang clorid, nhdi vio edt thuy tinh cd kich thude 90x4 em. Cho chay qua cpt dung djch
47
Nghien
CLFU- Ky thuat
ciia 73,46g (1,13mol) NaOCN trong 660ml nude cat (hoac dung djch cua 91,65g (1,13mol) KOCN trong 138ml nude cat) de chuyin nhua tir dang clorid sang dang eyanat. Sau dd rua cpt bing nude cit de loai NaCI (hoac KCl) v i NaOCN thira (hoac KOCN thira). Tiep dd cho chay qua edt dung dich eua 39,26g (0,565 moi) hydroxylamin hydroelorid trong 150 ml nude cit d khoang 15°C.
Mpt vimg phan irng ndng (khoang 40-60°C) phit triin d gin phia diu edt. Tdc dp nhd gipt dung dich hydroxylamin hydroelorid dupe diiu chinh sao cho viing phan irng ndng d cpt ludn d khoang 40-60 C.
Tiip dd cho nude cit chay qua cpt. Sau khoang 2h, khi viing phan irng ndng lan din hai phin ba cpt thi lay djch hirng v i thir phan irng vdi dung djch FeCij 10%, khi thay xuit hiin miu tim thi bit dau hirng san phim. Tiep tuc eho nude cit chay qua edt din khi viing ndng din cudi edt. Sau dd cho nude eit chay nhanh qua cpt din khi liy hit dich thoat chua san pham HU. Thu dupe khoang 1000 mi dung djch HU. Cd die djch hirng bing cat quay din khi xuit hien tiia trong binh eat. Dd phin cdn lai trong binh cit ra cdc, lim lanh din 0°C. Lpc hilt din kiet nude, kit tinh lai trong hdn hpp EtOH : H2O (5:1). Lpc hut, siy khd san pham trong tu siy chin khdng d 60°C trong 3gid. Thu dupe 19,4 g san phim, hieu suit 45,4%. San pham HU l i chit kit tinh tring, d i tan trong nude, khd tan trong EtOH, cd diem ndng chay 140-142°C.
Torjg hgp hydroxyurea theo phirong phap Deghenghi R.™.
Cho 37,5 g (0,5mol) methylearbamat vio dung djch chira 41,7 g(0,6mol) hydroxylamin hydroelorid v i 40g (Imol) natri hydroxyd trong 150 ml nude cit trong binh 3 cd dung tich 500 ml. Khuiy trpn hdn hpp phan Crng d nhiit dp 25°C trong 4 gid. Lim lanh dung dich rdi trung hoi bing HCI dac. Cit quay loai nude eua dung djch d i p suit thip vdi nhiit dp 50-60°C. Phin can thu dupe, ehiit vdi 150 ml EtOH 90°. Lim lanh djch ehiit d 0°C. Lpc hut thu dupe san pham thd. Kit tinh lin 1 trong nude cit d 50°C. Lpc hilt. Kit tinh lin 2 vdi hdn hpp EtOH : H2O (5:1). Lpc hiit Siy khd san phim trong tu siy ehin khdng d 60°C trong 3gid. Thu dupe 14,26 g san pham, hiiu suit 40%. San phim HU l i chit kit tinh tring, d l tan trong nude, khd tan trong EtOH, ed diem ndng chay 140-142°C.
K i t luan
- D i tdng hpp duac hydroxy urea dat tiiu chuan dupe dung theo Dupe dien Anh 2005 (BP 2005) bing hai qui trinh tdng hpp vdi hieu suit 40-50%.
- C i u true h o i hpc cua san pham dupe xic dinh bing c i c phuang phip phd IR, 'H-NMR, '^C-NMR v i MS.
- Da thir dpe tinh c i p ciia hydroxyurea tdng hpp dupe v i x i c djnh LDso trin chupt nhit tring l i (17,1189 ±1,4451 g/kg) theo dudng udng.
Summary
Study on the synthesis of the anticancer drug Hydroxyurea.
Hydroxyurea (HU) was synthesized by two methods; first, by converting a quaternary ammonium anion exchange resin from the chloride form to the cyanate form with sodium cyanate (or potassium cyanate) and reacting the resin In the cyanate form with hydroxylamin hydrochloride; secondly, by reacting methyl carbamate with hydroxylamin hydrochloride and sodium hydroxide in aqueous solution. The structure of synthesized hydroxyurea has been confirmed by IR, 'H-NMR, '^C-NMR and mass spectroscopy. The quality of synthesized hydroxyurea was controlled and meets the requirements of BP 2005. The acute toxicity ol synthesized product was tested with the result is determining the oral LD50 of Hydroxyurea is (17.1189+ 1.4451)g/kg In mice.
Tal lieu tham khao
1. Bo Y t i , Danh muc thude thiit yiu Viet Nam l§n thu- V, Tap chi Dugc hoc (2005), 8, tr. 2-3, 30-36 .
2. D6 Trung Bam, Thuoc chira ung thu, Nxb Yhoc Ha Wp/(1995), tr.139-141.
3. Nguyen Ba Dire, Hoa chat dieu trj benh ung thir, Nxb Yhgc Ha Ngi (2003), tr.202-208.
4. NguySn Anh Tri, Dieu tri cac b#nh ac tinh co quan tao mau, Nxb Yhgc Ha Npi (2004), tr.104-109.
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Tong hop va doc tinh te bao
cua 2,3-diphenylpropenal va dan chat
Nguyen Hai Nam
Bg mon Hoa Dirge & Trung tdm NCPT thuoc mdi (C3D) Tru&ng dgi hgc Dugc Hd Ngi
Dat van de
Combretastatin A-4 (CA-4, hinh 1) l i mdt c h i t chuyen hda dupe p h i n l i p tO' c i y liiu c h i u Phi - Combretum caffrum '''. CA-4 ire e h i q u i trinh tdng hpp td chirc spi hinh dng ciia t i b i o , qua dd cd t i c dung ire e h i s u p h i t trien ciia c i c t i b i o ung thu.
Thir nghiim eho t h i y CA-4 cd dde tinh ddi vdi h i n g loat t i b i o ung thu v i ed t i c dung chdng ung thu in vivo. Hiin CA-4 dang dupe p h i t trien d giai doan thCr l i m s i n g pha II.
Trong chuang trinh nghien ciru tdng hpp c i c d i n c h i t eiia CA-4 '^•^' chiing tdi chu y d i n nhdm d i n c h i t propenal cd cdng thirc chung t r i n hinh 1.
D i n c h i t (£)-3-(4-methoxyphenyl)-2-(3,4,5- trimethoxyphenyl)propenal ed dpe tinh k h i manh ddi vdi mdt sd te b i o ung t h u n h u B16, HCT116, A431. Khich l i bdi k i t qua n i y chiing tdi d i tdng hpp mdt d i y d i n c h i t propenal tuang t u v i thu' t i c dung uc e h i t i b i o ung t h u eiia chiing. B i i b i o n i y edng bd k i t qua thu d u p e tir nghiin cCru t r i n .
HjCQ-
0CH3
OCH3 D/c Propenal Hinh 1: Ciu true cua CA -4 vd din chit 2,3-
dlphenylpropenal
Nguyen lieu va phu'ang phap Dung moi, hda c h i t va dung cu
C i e hda c h i t v i dung mdi thdng thudng dupe n h i p tir cdng ty Merck hoic Sigma-Aldrich v i dupe sir dung tore tiip khdng ed tinh c h i gl t h i m . Nhiet dp ndng chay dupe do b i n g m i y do diem chay nhiet dien. S i e ky cpt dupe tiin hinh vdi silica gel Merck 70-230 mesh. S i e ky Idp mdng sir dung ban mdng nhdm tring s i n silica gel GF-254, quan s i t dudi den tir ngoai d bude sdng 365 v i 254 nm. Phd hdng ngoai dupe ghi bing may Perkin-Elmer, hiiu chinh dua v i o pie 1600 em'' eua polystyren. Phd cpng hudng tir hat nhan ' H v i '^C dupe ghi bing may Bruker AV-300 dung DMSO-de hoac CDCI3 l i m dung mdi. Dp chuyin djch hda hpc (5) dupe bieu thj bing dan vj p h i n triiu (ppm), l i y mdc l i pie eiia c h i t chuan ndi tetramethylsilan (TMS). Phd khdi lupng dupe ghi b i n g m i y khdi phd HP-5989B-MS.
Tdng ho>p cac d i n c h i t
C i c dan c h i t 2,3-diarylpropenal d u p e tdng hpp theo s a dd 1.
S a d d 1 : (a) (Ac)20, TEA, reflux, 12 h; (b) Mel,
T/lP CHI DU'QC HQC - 7/2009 (SO 399 NAM 49) 49
