» Nghien CLFU - Ky thuat Summary
2-amino-1-(4-nitn3phenyl) propan-1,3-diol from chloramphenicol was synthesized and purified. The structure was identified by UV, IR, Mp and NMR spectroscopic data. Determined by HPLC, the purity of the obtained product was 99.86 %. The content of 2-amino-1-(4- nitrophenyl) propan-1,3-diol was 99.36 % 0.297 by UV analysis. For use as reference substance in quality control of preparations containing chloramphenicol, the product is further studied on the stability to establish the Impurity Reference Standard.
Tai lieu tham khao
1. Nguyen Thj Thu Ba (2007), "Tinh hinh si> dyng khang sinh tai Bgnh vign Hoan My - Da Nang tit thang 01/2007 den thdng 10/2007", Noi San Y Khoa,
B$nh Vien Hoin My, tr. 26 -33.
2. Truang Van Vigt vd cgng sy (2006), "Si> dung khdng sinh tai benh viOn: Khdo sdt tinh hinh tii§n tai ve sd dyng khdng sinh tai mot khoa Lam sdng, Bgnh vien Chy Riy", Y hQC TP. Ho Chi Minh, 10(1), tr. 1 -13.
3. BO Y td (2009), Dupc diSn Vi$t Nam IV, Nhd xuat ban Y hgc.
4. Bg Y te (2002), Du^ diin Vi$t Nam III, Nha xuat bdn Y hgc.
5. D. Gottlieb, H. E. Carter, P. W. Robbins, R. W.
Burg (1962), "Biosynthesis Of Chloramphenicol", University of Illinois, Urbana, Illinois, p. 888-895.
6. G. Fodor, J Toth, E, Kovacs, J. Kiss (2005),
"Synthesis of chloramphenicol", Journal Russian Chemical Bulletin, NewYork, p. 391-399
7. World Health Organization (2006), "General Guidelines For The Establishment, Maintenance And Distribution Of Chemical Reference Substance", Geneva, p. 5-12.
Tong hop mot so dan chat benzo[c][l,9]
phenanthrolin va pyridazino[4,5-c]
phenanthridin tiem nang khang ung thu*
Huynh Thi Ngoc Phuong', Jean-Jacques Helesbreux^, Thai Khac Minh\ Olivier Duval^
'BO mon Hoa Du^c, Khoa Duac, Dai hoc YDuoc Thdnh pho Ho CiiiMinh
^SONAS (UPRES-EA 92), Faculte de Pharmacie.
Universite d'Angers, France
Dat van de
^„ Topoisomerase-ADN (TOP-ADN) la enzym l^d bien, edn thidt cho cac hoat dgng sao chep, phien ma vd tai td hyp ADN ciia td bao '^' ^ l Cd 2 loai enzym topoisomerase chinh:
topoisomerase 1 (TOP-1) va topoisomerase 2 {TOP-2) tiiy thuOc ea chd tac dgng cda chiing, hogc eat dogn lam thdi mdt hoac 2 syi dan ADN. Ca 2 enzym nay ddu la mye tieu quan trgng trong viec phat tridn nhung thudc khang ung thu mdi '^^ T h y c vgy, hogt tinh sinh hgc eua
nhieu tac nhdn khang ung thu dudng nhu tuang quan vdi kha nang ben hda phuc cd thd tdch rdi topoisomerase-AND ''*l Topotecan va irrinoteean, d i n chdt cua campothecin (mgt alkaloid thien nhien) la eae chat de che hgat ddng ciia TOP-1 '•^•^l Daunorubiein vd doxorubicin la nhung thf du dien hinh cua nhung chdt dc chd TOP-2 d u y e s u dung hien thdi trong hda trj lieu ung t h u ^'^^. Ngudi ta ghi nhan phan Idn nhung tac nhdn khang ung t h u bdng Cff chd u c che lopoisomearse d u y c phat trien t d nhung ngudn thien nhien, trong sd nay
TAP fTTT JWXciC HOC - 06/2012 r s 6 434 N A M 521 49
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phdi kd ddn fagaronin (1) vd nitldln (2), cd hai duyc chidt tdch td lodi Zanthoxylum hg Rutaceae'^'"'. Hai hyp chdt ndy thd hiOn dOc tinh td bdo vd tdc dOng nhu chdt dc ehd TOP-1 d ndng dO thdp vd dc chd TOP-2 d ndng dO cao '^^•^*'. Nhung thd nghiOm in vivo tidn Idm sdng dd phdt hign hogt tinh khdng ung thu mdu cua fagaronin d lodi ggm nhdm ''^'. Tuy vgy nhdng thd nghigm ndy dd nhanh chdng ddng lgi vl cdu tnic nita bgc 4 hgn chd tinh thdm ngi bdo ciia thudc, Nhdm chdc iminium ciia nhdng alkaloid ndy ddu tidn duyc gid djnh id cdn thidt cho hogt tinh sinh hgc, sau dd cdc tdc gid Bisagni vd JanIn d3 chl ra rdng cdc chdt tuang ddng nitldln khOng chda diOn tich cung cd thd tdc dOng nhu chdt dc chd topoisomerase vd thd hlOn dOc tinh td bdo ddng kd '^°'. Dya trdn nhgn djnh ndy nhdm nghlOn cdu LaVoie vd cOng sy dd phdt tridn nhung chdi luang ddng cdu tnic benzo[/]phenanthridin ddy hda hgn thd hiOn dOc
tinh td bdo mgnh vd tdc dyng dc ehd TOP-1 ddng kd, trong sd ndy vdi chat thd hign hogt tfnh khdng ung thu in vivo hiOu qud nhu ARO- 111(3), ARC-31(4) •^^•^^'. Cling vdi djnh hudng ndy, vigc thay thd vdng tham A ctia nhdn benzo[c]phenanthridin khfing chda nita bgc 4 bdng mOt vdng pyridin hay pyridazin cd thd thd hiOn hpat tfnh dc chd TOP-1 nhu trong intoplicin (5), tdc nhdn cd tdc dgng dc chd cd TOP-1 Idn TOP-2 '"• ^*K VI vgy trong nghidn cdu ndy chiing tdi sd tdng hyp cdc ddn chdt benzo[c][1,9]phenanthrolin vd pyridazino[4,5- c]phenanthridin vdi hy vgng tim ra nhung chdt tuang ddng benzo[c]phenanlhridin (BCP) mdi khOng chda nhdm iminium trong cdu triic ddng thdi vdi vigc dua mgt hogc hai nita vdo vdng A se Idm ldng dign tfch dm trgn khung BCP.
Nhung cdi thlgn vd mgt cdu tnic ndy hy vgng mang lgi tdc dgng di)c tfnh td bdo vd tdc dOng dc chd TOP-1 gia tang.
AnC 111 (topovaO (3) ARC-31 (4) Intoplicine (5)
Hinh 1: Cdc benzo[e]phenanthridin thiin nhiin va cie ehit tuong ddng
Nguyen li^u va phu'O'ng phdp
Nguygn ligu
Tdt cd nhung hda chdt vd dung mOi diing trong nghign edu cd duyc tu cdc nhd cung cdp Acros, Aldrich, Alfa Aesar, Avocado vd Fisher Chemicals. Didm chdy duyc xdc djnh trdn mdy Electrothermal 8100, phd IR duyc do trdn mdy Bruker FT IR spectrophotometer Vector 22, phd
^H-NMR vd ^^C-NMR duyc do tren mdy GSX 270 WB spectrometer vd Bmker Avance DRX 50 spectrometer, phd khdi LRIVIS duyc xde djnh trgn may Esquire 3000 Plus Bruker Daltonics spectrometer tai cdc phong thf nghjem cua Khoa Duac, Trudng Ogi hgc Angers, Phdp.
Phuong phdp
Tdng hgp hda hgc: cdc dan chdt
benzo[c][1,9]phenanthrolin vd pyridazino[4,5- e]phenanthriclin duyc tdng hyp theo sa dd 1.
- ThO- nghiim sinh hgc: thd nghigm dgc tinh td bdo in vitro ciia edc chat tdng hap duye duyc thyc hiOn trSn ddng td bao L1210 (murine leukemia cells) theo phuang phap 'microcuiture tetrazolium assay" ^^\
Tiin trinh "docking": duyc thyc hign chii
ydu nhd cac phdn mdm dudi 0dy:
PDB files: http:/AwAW.pdb.org.
Dock 6.2: htlpy/'dock'.compbk).ucsf.edu/'DOCK_&
ChemBioOffice 2008: http://www.cambridge soft.com/software/ChemBioOffice/
Chimera: http;//wvvw.rbvi.ucsf.edu/chimera/
TAP CHl.Dirqc HQC - 06/2012 (S6 434 NAM 52)
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JX X£
So* do 1 : Quy trinh tdng hg/p din ehit benzo[c][1,9]phenanthrolin va pyridazino[4,5-c]phenanthridin.
Sidu kign phan dng: (i) di^ng ct,i Dean-Stari<, toluen, hdi iuu 18-24h; (ii) methanol, NaBH4, nhidt dd phdng;
(Hi) LDA/THF -78oC/5h, sau do di d nhiet do phong trong 16h
Ket qua
Tdng hyp hoa hgc
Cde imin (6), (7), (8) d u y c tdng hap bang each dun hdi luu dung djch chda cde amin tuang dng vd 2-bromoveraldehyd trong toluen, nude tgo thdnh trong qud trinh phdn ung d u y e igai lign lye bang each s d dyng bg dyng cy Dean-Stack. Higu sudt imin (7) thu d u y c la cao nhdt (91%), didu ndy cd thd giai thich do s y hien dign eiia nhdm ethoxy d vj tri para so vdi nhdm amin lam gia tang tfnh ai nhan ciia nhdm amin. Phd ^H-NMR cua cae imin tdng hyp d u y c ddu xudt hign mgt singlet t u y n g ung vdi proton ciia nhdm imin d 5=8,85ppm; 8,81 ppm;
8,87ppm t u y n g dng ldn l u y t vdi (6), (7), (8).
Sy khd cde imin (6), (7), (8) thdnh cdc amin thu cap tuang dng (9), (10), (11) d u y c thyc hign bang edeh cho cdc imin phan dng vdi NaBH4 trong dung
moi methanol d 0°C Viec phan tfch phd ^H-NlylR eua cac amin thu duye sau khi finh khidt hoa cho thdy singlet tuang dng vdi H ciia imin bidn mdt, ddng thdi eo s y xudt hien singiet tuang ung vdi 2H nhdm benzyl [5=4,54ppm, 4,49ppm, 4,57ppm tuang dng idn luyt vdi (9), (10), (11)]. San phdm amin sau khi tinh chd cd hieu suat 53%, 77%, 98%
tuang dng Idn luyt vdi (9), (10), (11).
Ve mat ca chd phan dng, s y ddng vdng ngi phan t d cac amin (9), (10), (11) dd tgo eae ddn chdt phenanthrolin va phenanthridin luang dng (12), (13), (14) d u d i s y hien dign eiia LDA bao gdm 3 giai dgan: lithium hda amin d -78 C;
thdnh Igp benzyn trung gian; ddng vdng nOi phan t d d nhiet dO thudng (Sa dd 2). LDA d u y c didu che ngay trudc khi s d dyng t u diisopropylamin vd n-butyllithium/hexan d 0 C.
Higu sudt thu d u a c Id 43%, 30%, 43% tuang ung Ian l u y t vdi (12), (13), (14).
OC2H5
H3CO ^ ^ ^ ^ + CH3
(15) (16) Hinh 2: Cie imin twong ung cOa hg-p chat (12), (13)
T^P CHI Dir<?C .HOC - ^iZm (SO 434 NAM 52)
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H3C0'
H3C0
So* d6 2: Co chi ddng vdng mdi phin ttr cic amin dwiri tic dung cua LDA DO l i ^ u v i p h i cua (12), (13), (14)
8,9'Dlmethoxybenzo[cJ[1,g]phenanthrolin (C,8H,4N202 = 290,0) (12)
Ch4t r i n va dinh hlnh, v i n g nSu. IR v 1616, 1499, 1158 c m ' . 'H-NMR (270 MHz: CDCI3) 6 10,61 (s, 1H); 9,28 (s, 1H); 8,75 (s.e, 1H);
8,53(d; J = 9,0 Hz; 1H); 7,84 (d; J = 9,0 Hz; 1H);
7,80 (s, 1H); 7,72 (d, J = 5,0 Hz; 1H); 7,37 (s, 1H); 4,17 (s, 3H); 4,10 (s, 3H). "C-NMR (67,5 MHz; CDCI3) 6 153,3; 151,1; 150,4; 149,3;
144,7; 140,5; 135,9; 128,3; 125,2; 124,7; 122,9;
121,2; 120,1; 107,3; 101,3; 56,2; 5 6 , 1 . LRMS [M*Hf theo tfnh t o i n ly thuydt CiBHisNaOi:
291,10; thi/c t l do du-gc: 291,0.
12-Ethoxy-8,9-dimathoxybenzo[c][1,91 phenanthrolin (C2oH,8N203 = 334) (13)
Chat r4n v6 djnh hlnh, v i n g n i u . IR v 1617, 1498, 1144 c m ' . 'H-NMR (270 MHz; CDCI3) 6 10,53 (s, 1H); 9,11 (s, 1H); 8,72 (s.e, 1H); 8,13 (s.e, 1H); 7,57 (s, 1H); 7,52 (s, 1H); 7,32 (s, 1H);
4,34 (q; J = 7,0 Hz; 2H); 4,16 (s, 3H); 4,09 (s, 3H); 1,66 (t; J = 7,0 Hz; 3H). "C-NMR (67,5 MHz; CDCI3) 6 153,0; 152,1; 160,4; 148,6;
148,3; 143,6; 135,9; 130,63; 127,6; 123,2;
122,1; 107,4; 107,3; 101,3; 101,3; 100,7; 64,3;
56,2; 5 6 , 1 ; 14,7. L R M S f / U + H f theo tinh t o i n ly thuyet C2oH,9N203: 335,13; thifc t4 do du'Q'c:
335,1.
8, g-Dimethoxypyrifiazino [4,^]phenanthridin (C,7H,3N302 = 291,0) (14)
C h i t r i n va dinh hlnh, v i n g n i u . IR (CHCI,) V 1609, 1506, 1161 c m ' . ' H - N M R (270 MHz;
CDCIa) 8 10,88 (s, 1H): 9,70 (s, 1H); 9,42 (s, 1H); 8,88 (d; J = 9,0 Hz; 1H); 8,05 (d; J = 9,0 Hz; 1H); 7,96 (s, 1H); 7,51(s,1H); "C-NMR (67,5 MHz; CDCI3) 8 153,7; 152,2; 151,2; 150,1;
148,1; 138,5; 128,5; 127,9; 127,1; 126,0; 125,0;
123,6; 123,4; 107,6; 101,6; 66,4; 56,3. LRMS [M+Hf theo tinh t o i n ly t h u y i t C,7H,4N302:
292,10; t h v c t l do d u y c : 292,0.
Thu> nghlgm sinh h p c
Ket q u i thi> nghl$m s o bo dOc tinh te b i o in vitro cua c i c c h i t tu'ong ddng BCP tong hp'p (12) (13) (14) thi/c hl#n tren d6ng t l b i o L1210 (murine leukemia cells) theo phirong p h i p
"Microcuiture tetrazolium assay" dLrcc ghl trong b i n g 1. K i t q u i cho t h i y c i c d i n c h i t (12), (13), (14) d i u ca IC50 t h i p hon fagaronin. C i c h e p c h i t (12), (13) cung ca IC50 t h i p hon c i c d i n c h i t ca c i u tn^c iminium (15), (16) tu'ong Crng (Hlnh 2); trong dd hp'p c h i t (12) cd ICso t h i p n h i t .
B i n g 1 : KSt qui ddc tinh tS bio in vitro cOa cic BCP tSng hop
Hvp chit Fagaronin
(12) (13) (14) (15) (16)
L1210 ICxdiU) 6,40 2,90 4,72 3,40 10,40 5,79
T^P CHf n i r n r H O T _ ntn«,-, / s 6 434 NAM 52)
m N g h i e n C I F U - Ky t h u a t Md h i n h " d o c k i n g "
3B
Hinh 3: (A) Mo hinh bieu diin kha ning gin kit d mirc do phan tO- trong khong gian 3 chiiu cua (12) v&i phuv hop ADN/TOP-1. (B) M6 hinh bieu diin kha nang gin kit 2D cua (12)
v&i phuc hap ADN/TOP-1 T d edu true tinh thd tia X cue phdc
ADN/TOP-1: indenoisoquinolin (pdb 1SC7) thugc "Ngan hang d u lieu protein"
(www.rcsb.orq). v| trf tac dgng d u y c xac d|nh Id lat ca cdc acid amin xung quanh trung tam khdi cau ban kinh 6.5A; tam khdi cau chfnh la nai gan kdt phan t d indenoisoquinolin vdi ADN/TOP-1 (xac djnh bdng chuang trinh MOE).
Qua trinh docking d u y c thue hien bang each s u dung chuang trinh docking DOCK 6.2 tren cae hyp chat (12), (13), (14). Cdu dang tdi u u nhat cda hyp chdt (12) khi d u y c "dock" vao vj tri tac dong d u y c bleu d i i n d hlnh 3. Kdt qua eho thdy nhd vao ban chat phang cCia he dj vong, h y p chat (12) da ien vao ADN d vi trf G11/C112 va A113/T10, va tao d u y e eac IiSn kdt TT-TT vdi guanin G11 va adenin A l l 3 . Ngoai ra, hgp chat (12) eon tao d u y c lien kdt hydro vdi acid amin Arg364 cua topoisomerase-1.
Ban luan va ket luan
T u kdt qua t h u dgc tfnh td bao chung toi s a bd nhan thdy rang viec thay the vdng tham A cCia nhan benzo[c]phenanthridin khong chua nita bgc 4 bang mgt vong pyridin hay pyridazin CO the lam gia tang ddc tfnh td bao [cac dan chdt phenantholin (12), (13) va phenanthridin (14) ddu ed doe tfnh td bao manh han fagaronin tren ddng te bao L1210]. Didu nay phCi hyp v d i djnh hudng lue ddu, s y tang dien tfch am trong phan t u se lam lang dOe tinh td bdo. Mgt khac kdt qua s a bg ve doe tfnh td bao nay cijng cho thay IC50 cCia h y p chdt (12) va (13) cung thdp
han dang ke so vdi cac iminium tuang ung (15) vd (16), dieu nay phu h y p v d i nhgn djnh eua mgt sd lac gia la s y hien dien cda nhdm iminium ed the can trd s y hap thu qua mang td bao cda nhung tac nhdn nay d i n den hgat tinh kem hay that thudng '''^•''^^ mac du cung cd nhung quan diem cho rdng nhdm iminium trong cdc chat tuang ddng BCP can thiet eho hoat tinh ^^~^\ Ket qua docking eho thdy khung di vong eua cae chdt phenanthrolin va phenanthndin tdng h y p d u y c CO xu hudng nam d vj trf song song vd xen vdo giua eac cap base G11/C112 va A113/T10 cua cau trtjc ADN va han chd kha nang gan ket eua ADN vdi TOP-1. Mac du eae d i n chat nay eung cd kha nang tao lien kdt v d i TOP-1 d eac acid amin nhu Asn352, Arg 364, Asn772, nhung ket qua docking cho thay xu hudng gan kdt ro rdt cua eae chdt (12), (13), (14) len ADN nhieu han la tren TOP-1. Nhu vay nhung chat nay ed le la nhung chat d c chd ADN/TOP-1 gay dgc tinh td bao theo c a chd kim ham hoat tfnh TOP-1 (suppressor).
Summary
Promoted by the fact that the topoisomerases are promising targets of anticancer dmgs, and of those expressing a topoisomerase-targeting activity, the synthetic analogues of alkaloid family of benzo[e]phenanthridine (BCP) are well studied, this work focused on development of a way to obtain the BCP analogues with 1 or 2 nitrogen atoms in the cycle A, with or without ethoxyl groups in position 12. The following three
TAP CHi DirOC HOC - 06/2012 (SO 434 NAM 52)
• Nghien ciru — Ky thu^t
compounds 8.9-dimeU}oxybenzo[c][1.9]phenanthn^in (12), 12-ethoxy-8.9-dimethoxy benzo[c][1,9]
phenanthrolin (13), 8.9-dimethoxypyridazino[4,5- c]phenanthridin (14) were synthesized by cyclization via intermediates of benzyne. In vitro cytoxicity tests on L1210 cell line showed these compounds were more potent than fagaronin. a natural BCP containing an aromatic cycle A in structure.
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