• Nghien CIPU - Ky thuat
Tong hffp va thu tac dung khang tg bao ung thu- cua mot s6 dan chSt moi 2-((2-phenoxyethyl)thio)-
lH-benzo[</|imidazoI
Nguyen Dinh Luyen'", Nguyin Van Hai', Nguyin VSn Giang' Nguyin Xuan Sang', Pham Van Hung', Nguyin Van Manh', Vu Binh Dirimg^
' Tivang Bai hpc Dupc Ha Npi -Hpc Vi4n Quany 'E-mail: ngdiuyentfi^hotmail.com S u m m a r y
a x novel derivatives (Va, Via, Vila, Vb, Vlb, Vllb) of2-((2-phenoxyethyl)thio)-1H-benzo{dJimidazole were synthesized and tested in vitro kir their cytotoxityagain^ human breast adenocarcinoma cell line IMCFT) The 'burconipounds'\na,\m>,\ma,\mshowedrnodBrateactrjty(33.58iig/mL<IC.,<S2S2ua/mL)whiletLiZ onesVaandVbshowedbwacllvity(IC^>100pg/mL).
Keywords: 2-Men:aptobenzimidazole. 2-phenoxyethytthkibenzimidazole. benzirmdazole, anticancer.
thyc hipn nghian ci>u nay vol mgc tiau: (;) Ting hpp mpt s i d i n chit c i a 2-((2-phenpxyethyl) thlo)-1/V-benzo[c(llmidazoi; (li) Thip tac dgng gSy dpc t i bao ung thu vii (MCF7) ciia cac d i n chit t i n g hpp dutjc
Nguyen lieu va p h u n n g phap nghien ciin Nguyen lipu
cac h i a chit d i n g trong nghien cipu c i nguin g i c tip cac hang Merck (Due), Sigma - Aidrich (My) va t i ' Vljt Nam. Tmng Quoc; dgt tiau chuin tinh khiet h i a hpc.
Phuong phap nghien ci>u Tong hgp hoa hgc
Sir dyng cac phuvng phap thyc nghipm eo ban trong hoa hpc hyu co d i t i n g hpp cac chit d y kiin (xem hlnh 1). Theo doi t i i n trien c i a phin ipng bang phypng phap s i c k f lftp ming (SKLM) thyc hipn trin ban mong silica gel 60 F254 Merck vfti cac h i dung m i l khai triin khac nhau- doroform : methanol (9:1) - h i A. dicioromethan : methanol (20:1) - ha B, ethyl acetat n-hexan (7:3) - h i 0 d i xac djnh thfti gian phan i-ng thich hop; quan sat s i c ky do dyfti buftc song 254 nm ciia den tu- ngogi. Si> dgng phuong phap cit, chiit long - ling, chiit ran - ling, k i t tinh,... d i tinh c h i san phim thu dupc.
Dat van d4
Benzimidazol la mpt dj vong quan trong trong nganh Dupc, xuit hian trong cong thipc c i a nhieu dupc ehit nhu; bendamustin (diiu tq ung thu); mebendazol, aibendazol (diet ky sinh tnjng); omeprazol (uc c h i bom proton);
cyanoeobalamin (Vitamin B,,);... cac d i n ehit eiia 1H-benzo[dlimidazol-2-thlol (2MBI) n i l hang cung la m i t nhdm d i n chat dang ehii y c i a di ving benzimidazol vfti nhiiu tac dgng da dupc chiing minh nhu: gay dpc t i bao ung thu «, khang khuin I'l, khang nam I'l, ching vims «!
di$t kf sinh tning <'\ tic che H*/K*-ATPase <",..'.
Trong s i nhiing tac dgng nay, c i mpt su quan tam rit iftn cua eac nha khoa hpc t h i gifti v i viic tim kiim eac d i n chit eo tac dung gay die tren t i bao ung thu. Tgi Viat Nam, cac dan chat t i n g hpp dupc lip sy k i t hop cua khung 2MBi vfti nhdm phenoxy trong m i t s i nghien eipu g i n day cung cho thiy hogt' tinh gay d i e t i bao ung thu dang c h i y. Vi#e tlip tgc nghian cuu ting hpp cao d i n chit mpi lai hoa giu-a 2MBI va nhim phenoxy la mpt huong tiim nang trong viae tim kiim cae phan tip co hoat tinh sinh hpc cao c i t h i phat triin lam thuic, trong do CO nhim thuie diiu tn ung thu. Chlnh vl vay
TAP CHi DirglC H Q C - 9/2OI6 tSb 485 NAM 56)
• Nghien cu-u - Ky thugt
/a, ra I na.Hh
a-CHj—CH,—o
NH(X>CH, NHCO
Hinh 1: Scdo tSnghop cac chat cua 2-({2-phenoxyethyl)thio)-1H-benzo[d]imidazol
I. ..
tfuvc Sv dgng phuong phap SKLM vfti cae diiukiin nhu da trinh bay ft phan Phuong phap nghlin cipu, mgc Ting hpp h i a hoe va phuong phap do nhiat dO nong chay Iran may EZ-Melt.
Dya v i o hp s i luu glu R, khai triin vfti cac hp dung m i l khac nhau va khoang gia trj nhipt dp ning chay d i so bp danh gia dp tinh khiet c i a san phim.
Xac dinh ciu triic cia cic chat tong hifp dtn?c
C i u tnic cua cSc dan chit dupc xac dinh bing cac phuvng phap: pho khol luvng (MS), p h i hing ngogi (IR), p h i cing huftng tip hgt nhan proton CH-NMR) va " 0 ("C-NMR). P h i khii luvng dupe ghi tgi Phing Phan tich, Kiem nghipm va Tuong duvng sinh hpc, Vi$n Cpng nghp dupc phim quic gia, tren may LO-MS/MS Agilent 1290/6460 vfti c h i d i do ESI. P h i hing ngoai duvc ghi tgi B i min Hia hoc vo co, Khoa Hia hoc, Tnrong Dpi hpc Khoa hpc ty nhien - Ogi hpc Quoc gia Ha Nil, Iran may Shimadzu vfti ky thuat vien nan kail bromid trong viing 4000 - 400 cm-'. P h i cing huvng tip hgt nhan proton va " 0 dupc ghi tgi Phing thl nghipm Hia dupc, Khoa Hoa hpc, Trijftng Dgi hpc Khpa hpc ty nhian - Bgi hpc Quic gia Ha N i l , tren may Bmker 500 MHz Ascend su dgng dung m i l la D,0 hcSc CD,OD, chit chuin n i l la tetramethylsilan.
T*P CHf DUtJC HQC - 9/2016 ( S 6 485 NAM 56)
Ia,IIa,Va,Vla,yiIa:R = -ll lb, lib, n, Vlb. WB: R = <:i^
T/ii> hoat tfnh giy dgc te bio ung thw cua t:ic din chit tong /ipp ifu^pc
Thip tac dgng gay dpc te bap ung thu vu (ding MCFT) cua cae d i n ehit Va, Vb, Via. Vlb, Vila, Vllb tai Phing Thu nghipm sinh hpc, VIpn Cong nghi sinh hpc, VIpn Han lam Khoa hpc va C»ng nghp Viet Nam theo phuong phap SRB c i a A. Monks va OS. cing b i nam 19911=).
Kit qua va ban luan K i t qua nghien ci>u
Tong hgp hoa hgc, kiim tra dg tinh khiet va xac djnh ciu true sin pham
Tdng hgp 1H-benzo[d]imidazol-2-thiol (lla):
Thyc hian theo phuong phap cua J. A. VanAllan va 8. D. Deacon f vfti 10,82 g (0,10 moi) o-phenylendiamin (la); 5,60 g (0,10 moi) kail hydroxyd; 100,0 mL ethanol; 15,0 mL nuftc eat;
6,2 mL (0,10 moi) carbon disulfld. San phim thu dupc la tnh the hlnh phien mong, trong suit, mau vang nhgt Khol lupng (m) = 12,20 g. HiSu suit (H)
= 81,22%. (?,= 0,35 ( h i A); 0,15 (ha B); 0,57 (h$
0). Nhlit dd nong chiy (T"J = 301-c - 304°C MS (ESI), m/z: 148,8 ([M-Hf).
Tong hgp 5-methyl-1H-benzo[d]imidazol- 2-thiol (lib). Theo quy trinh nhu ting hpp chat lla, thay o-phenylendlamin (la) bang 4-methyl- o-phenylendiamin (lb) vfti ciing s i moi. S i n phim thu dupc la tnh t h i hinh kim, mSu nau m = 12,84g. H = 78.16%. R, = 0,37 (hp A)- 0 21 (ha B); 0,75 (ha 0). r = 291 "C - 293°0; MS (ESI) m/r. 162.8 ([M-H]).
• Nghien CIPU - Ky thuat
Tong hqp N-(4-(2-ck>roethoxy)phenyl) acetamid (IV) Cho 1,00 g (6,6 mmol) N-(^
hydroxyphenyi)acetamld (///); 9,12 g (66 mmol) kali carbonat; 50,0 mL acetonitril vao binh non dung tich 100 mL. Khuiy h i n hpp trong 1 gift.
D i chat l i n trong binh ling xuong, ggn phan djch trong^vao binh n h i gipt Dung 30,0 mL acetonitril chuyen phan chat r i n c i n lai trong binh non vao binh phan ipng hai eo dung tieh 250 mL.
Them vao binh phan ung 10,5 mL (0,13 moi) 1,2-dlcloroethan. Vipa dun h i l luu vipa nho tip tip dung dich /V-(4-hydroxyphenyl)acetamid trang acetonitril ft Iran vao binh phan ring. Dun hoi luu trong 20_gip. Sau khi phan ung k i t thuc, eat chan khing h i n hpp phan ung den c i n . Diing 100.0 mL dldpromethan va 30,0 mL nuftc c i t d i chuyin hen hpp cin sang binh ggn dung tich 250 mL, l i e cho tan h i t chit r i n . Rua pha huu eo 3 lan bang dung d|ch natri hydroxyd 10%, m i l l i n 30,0 mL.
Rua Igl bang nuftc c i t d i n pH = 7 Thu lay pha hipu CO, lam khan bang natri sulfat khan. Loc loai bo chit lam khan, cat chan khing djch Ipe den can. K i t tinh Igl c i n trong dung dich ethanel 10%.
Lpc l i y tnh t h i . n>a bing ethanol 10% ignh say tinh t h i ft 60°C den k h i . san pham thu dupc la tnh t h i hinh kim, trong suit, khing mau hogc anh hing. m = 1,19 g. H = 84,65%. R = 0 59 ( h i A); 0,49 (hp B); 0,47 ( h i C). P = 124»c - 126»0. MS (ESI), m/z: 211.8 ([M-H])!"
T6ng hvp 2-((2-(4-acetamidophenoxy)ethyi) thio)-1H-benzo[d]imidazol (Va): Cho 0 45 g (3.0 mmol) ehit lla; 0,12 g (3,0 mmol) natn hydroxyd; 0,25 g (1,5 mmol) kail lodid va 35 0 mL acetonitril vao binh c i u hai co dung tich 100 mL Khuiy hon hpp ft 60-O trong 1 gift. Them 0,32 g (1,5 mmpi) chat IV vao h i n hpp phan Ung dun hoi luu trong 15 gift. Sau khi phin ung k i t thuc cat Chan khing h i n hpp d i n c i n . Ripa c i n 3 iiri bang dung djch natri hydroxyd 10%, m i l l i n 20 riiL. Rua igi bang nuftc c i t d i n pH = 7. Tiip tuc ma can 3 lan bing dicioromethan. m i l l i n 20 mL. Ket tinh lai can trong methanol. Loc, ru^a tua bang methanol Ignh, s i y k h i ft 60-0. san phim thu dupc la b i t mau tring hoi xam. m = 0 40 g- , h - % , t^''°- " ' ° ° ' ^ ^ ' " * * ' • " ' ^ (1? B); 0,31 (heC). r.„=239"C-242-C.IUSfeS/l ^ 4 - 3 2 7 8 Cfi.OD), 6 (ppm): 2,10 (3H, s, H-10'); 3,64 (2H 6,83 (2H, d, J = 9,0 Hz, H-2', H-6'); 7 2 1 (2H m H - 5 , H - 6 ) ; 7 , 3 9 ( 2 H , d , J = 9 , 0 H z , H - 3 ' H : 5 ^ ;
7,48 (2H, br.s, H ^ , H-7). "C-NMR (125 MHz, CDjOD), S (ppm): 23,53 (0-10'); 32,69 (C-7')- 68.48 (0-8'); 115.76 (0-4, C-7, 0-2', C-6'); 123,00 (0-5, C-6, C-3', 0-5'); 123,38 (CA'); 133,26 (0-8 0-9); 156,56 (0-2, C-1'); 171,45 (0-9').
Tdng hcfp 2-((2-(4-acetamidophenoxy)ethy!) thlo)-5-methyl-1H-benzold]imklazoi (Vb): Theo quy trinh nhy t i n g hpp chat Va. Thuc hipn vfti 0,46 g (3,0 mmpI) chat ;/li; 0,12 g (3,0 mmol) natri hydroxyd; 0,25 g (1,5 mmol) kali lodid; 35,0 mL acetonitril va 0,32 g (1,5 mmol) chat IV. san pham thu dupc la b i t mau nau hope tnh the hlnh kim mau nau. m = 0.40 g. H = 76,43%. (? = 0 32 (hp A); 0,13 (hp B); 0,41 (ha 0). P = 166«C - 168'<;
MS (ESI), m/z:. 339,9 ([M-HJ). 'H-NMR (500 MHz CDjOD), 6 (ppm): 2.12 (3H, s, H-10'); 2,44 (3H s H-11');3,61 (2H,t,J = 6,0Hz, H-7');4,29(2H t J
= 6,0 Hz, H-8'); 6,82 (2H, d, J = 9,0 Hz, H-2', H-6')- 7,06 (1H, d, J = 8,5 Hz, H-6); 730 - 737 (2H m' H-4, H-7); 735 (2H, d, J = 9,0 Hz, H-3', H-5')- 9 75 (1H, s, NH). »C-NM/?(125 MHz, CD,OD), 6 (ppm)- 20,38 (0-11'); 22,37 (C-10'); 31,57 (C-7'); 67 24 (0-8'); 114,60 (0-4, 0 - 7 C-2', C-6'); 122,10 (0-5 C-6, 0-3', 0-5'); 123,57 (0-4'): 131,56 (0-8 C-9)-' 155.18(0-1', C-2); 170,86 (0-9').
Ting hi?p 2-((2-(4-aminophenoxy)ethyl)thki)- 1H-benzo[dlimidazol dihydrociorid (Via): Hia tan 0,33 g (1,0 mmpI) ehit Va via 30,0 mL methanei trong binh c i u hai c i dung tieh 100 m L Tham 5,0 mL (50 mmol) add hydrodoric dgc vao hon hpp phan ung. Dun h i l luu b i n hpp trong 4 gift. Sau khi phan ipng k i t thuc, c i t chan khong b i n hpp d i n can. K i t tinh igi c i n trong methanol. Lpc lay tinh t h i , nia bang methanol Ignh, s i y ft 50"O din k h i . SSn phim thu dupc la tnh t h i hlnh phlin mong, mau hoi hong; m = 0,25 g; H = 76 88%
fi, = 0,54 (hp A); 0,41 (hp B); 0,51 (ha 0) vfti diiu kien ho amonlac dgc tmVc khi khai triin- r = 275 -C - 277»a MS (ESI), m/z: 285,8 ([M-HCI-Cl]').
IR (KBr), v „ ^ (em-'): 2476 - 2706 (N'H), 3035 vi 3072 ( C - H „ ) , 2980 (C-H.,), 1620 (C=N), 1514 (C=C J , 1257 (C-O). 'H-NMR (500 MHz, D O) 5 (ppm): 3,82 (2H, t, J = 5,0 Hz, H-7'); 4,53 (2H t J = 5,0 Hz, H-8'); 6,73 (2H, dd, J, = 2,5 Hz J = 7 d Hz, H-2', H-6'); 715 (2H, dd, J,= 2,5 Hz, j ' = 7,0 Hz, H-3', H-5'); 7,56 - 7,68 (4H, m, H ^ , H-5 H-6 H-7). "C-NMR (125 MHz. D,0). 6 (ppm): 33.12 (C- 7'); 6760 (C-8'); 113,06 ( 0 4 , 0-7); 115,35 (C-2' 0-6'); 123,04 (C-4'); 124,03 (0-3', 0-5'); 126 01 (C-5, 0-6); 131,92 (0-8, 0-9); 14947 (O-i'l- 15718(0-2).
TAP CHi DlTQC HQC - 9/2016 ( S 6 485 NAM 56)
• Nghien CIFU - Ky thuat
Tdng hgp 2-((2-(4-aminophenoxy)ethyt)thio)- 5-methyl-lH-benzo[d]imidazc^ dihydrociorid (Vlb):
Theo quy trinh nhu- tong hgrp chat Via. Thi/c hi^n v6i 0.34 g (1,0 mmol) diat Vb, 30,0 mL methanol;
5,0 mL (50 mmol) acid hydrodoric dac. San phim thu diroc la bflt mau trlng hoi xam ; m = 0,24 g ; H = 73,28%. R, = 0,56 (he A ) ; 0,42 (he B ) ; 0.63 (he C) voi di^u ki^n ha amonlac dac tniac khi khai trien ; P ^ = 283'C - 285'*C. MS (ESI), m/r. 300,0 {[M-HCI-CIT); 297,9 ([M-2HCI-Hr). IR (KBr), v (cm'); 2571 - 2804 (N*H). 3059 ( C - H ^ ) . 2868 \ ^ 2902(C-HJ.1612(C=N).1510va1566(C=C )
1255 (C-O). ' Tong hap 2-((2-(4-aminophenoxy)ethyl)lhio)-
1H-benzo[d]lmidazol (Vila): Cho 0,33 g (1,0 mmc^) chit Va; 30,0 mL ntrac c i t va 5.0 mL (50 mmol) acid hydrodoric dgc vao binh cau hai co dung tfch 100 m L Dun hoi lu-u h6n hap trong 5 gia. Sau khi phan i>ng ket thiic, lam Ignh ben ngoai khoi phan u-ng bang nu'oc d^. Trung h6a hon hgp phin LPng bing dung dich natn carbonat 20% den pH = 7 thiy xuat hi$n ket tua. Lpc lay k i t tua, ket tinh lai trong dung djch methanol 70%. Lpc thu dnh the, n>a Igi bing niro-c cat, s l y a 50'C d i n kho. San phim thu du'p'c Id tinh the hinh philn m6ng. mdu hai h6ng; m = 0.21 g; H = 73,39%.
R, = 0,54 (h§ A): 0,41 (h? B); 0,51 (hp C). 7*
= 135<<; - 137-^:. MS (ESO. m/z: 286,0 ([M+H]*™
283,9 ([M-H]). IR (KBr). v ^ (cm '): 3332 va 3427 (N-H), 3047 ( C - H ^ ) , 2854 vd 2926 (C-H ) 1622 (C=N), 1508 vd 1587 ( C = C ^ ) , 1234 (C- 0). 'H-NMR (500 MHz, CD^OD). 6 (ppm): 3.58 {2H, t, J = 6.0 Hz, H-7'); 4,20 (2H, t. J = 6.0 Hz H-8'); 6,64 - 6,69 (4H. m, H-2', H-3', H-5', H-G');
7,18 (2H. m, H-5, H-6); 7,46 (2H, br.s, H ^ , H-7).
TSng hpp 2-((2-(4-amlnophenoxy)ethyl)thio)- 5-methyl-1H-benzo{d}lmidazol (Vllb): TTieo quy trinh nhu' tong hp-p chit Vila. Thyc hi§n vai 0.34 g (1,0 mmol) chat Vb. 30.0 mL nuac c i t vd 5,0 ^mL (50 mmol) acid hydrodoric dac.
San phim thu du^c la bpt mau trlng xam m = 0,21 g. H = 70,27%. fi, = 0,56 (he A); 0 42 (h# B); 0,63 (he C). T'^ = 114°C - l i e - C MS (ESQ. m/r. 300.0 ([M+H]*); 297,9 ([M-H]) IR C^O. v ^ (cm-'): 3367 (N-H). 3005 (C-H ) 2935 ( C - H J . 1620 (C=N), 1510 (C=C ) S (C-O). 'H-NMR (500 MHz, CDpD). 5 (ppmV 2 43 (3H. s. H-11); 3,56 (2H, t. J = 6,0 Hz, H-7')- 4 ' l 9 (2H, t J = 6.0 Hz. H-8'); 6,65 - 6,69 (4H m H-2' H-3-, H-5'. H-6'); 7,02 (1H. d, J = 8,0 Hz,'H-6)i
T ^ P CHI DU(?C HQC - 9/2016 (SO 485 NAM 56)
7.31 (2H. br.s, H-4, H-7). "C-NMR (125 MHz, CD3OD), S (ppm): 21,62 (C-11'); 32.92 (C-7');
68,99 (C-8'): 116,84 (C-4, C-7. C-2', 0-6'); 118,08 (C-5, C-6, C-3', C-5'); 142,20 (C-8, C-9. C-4');
153,04 (C-2, C-1').
Tac dung gay ddc te bao ung thw Tren dong t l bao ung thu vu {MCF7): bon chit Via, Vila, Vlb, Vllb the hign hoat lire a mi>c do trung binh vcri gia tri IC^^ l l n lu'Ot la 52,52 MQ/
mL(146,58nM);33,69^g/mL(118.04^lM); 33,58 pg/mL (90,20 jiM) vd 35.08 ng/mL (117.17 ^iM).
Dan chit V& va Vb the hipn hogt lye yeu vai IC
> 100 MQ/mL {> 305,43 fiM vd > 292,89 ^M). Chit d6i chiJng du-ong elliptidn hoat dpng on dinh trong thi nghiem. Cac k i t qua tren la chfnh xac vai fi > 0,99.
Ban luan Ve tong hop hoa hgc
Kh6 khan lan nhit gap phai khi thyc hipn phan iJng S-atkyI hoa tong hgp cac ddn chit Va va Vb la sy tgo thanh cua cdc san pham phy (dupc d y doan la san pham W-alkyl hda hogc S.W-dialkyI hoa) doge quan sdt trgn s i c ki do bdn m6ng.
Cac sdn phim phu cd hp s6 lu-u giO R, r l t gan vd'i san phim chinh, dieu ndy ndi lgn rang cdc san phim phy co 66 phan eye g i n gilng nhy sdn p h i m chinh, do dd se khd c6 ( h i tdch khoi sdn phim chlnh n l u cht dya vdo bi^n phap k i t tinh Igi thdng thy^rng, dac bipt Id khi san pham phy da dyac tgo thanh vd-i mot lypng dang k l . Chung tdi da loai dygc cac sdn phim phy tao thanh vd lu'png du' tdc nhdn alkyl hoa bing cdch XLF li h6n hpp sau phdn Ong vdi kiem NaOH va sau do chiet vdi CH^CIj. Cac k i t qud thu duoc nhy sau: cdc chit lla hoac lib duge dung dy so vdi tdc nhdn alkyl hda IV theo ty Id moi Id 2 : 1;
chit hogt hda natri hydroxyd va chit xijc tac kali iodid dyac dung vdi lu-gng vu'a du, t / Ip moi cua Chung lan lygt so vdi chit lla (hogc lib) vd chit /VId 1 ; 1; d i l u kipn t i l n hdnh phdn yng Id dun hdi lyu trong dung mdi acetonib-il trong thai gian 15 gid.
Ve cau true cac san phim
Pho MS cua cdc san pham deu cho cdc pic ion phan ti> tyang yng vdi khdi lugng phan tir va ^cdng thyc phan ti> cua tCfng chit d y kiln.
Pho 'H-NMR cua d i a l Va chija cac tin hi#u dgc tnjng cho cdc proton trong phan t i j , trong dd, tin hieu singlet cr 2,10 ppm Id tin hipu cua 3 proton
• Nghien ci>u - Ky thuat
trong nhom acetyl, 2 tin hi$u triplet * 3,64 ppm va 4,30 ppm la tin hieu cua cac proton trong 2 nhom methylen 4 vi tri 7' va 8' co tuong tac spin-spin v6i nhau, tin hieu cua cac proton trong 2 nh§n thom xuat hi#n ilSy aO trong vung 6,82 din 7,48 ppm.
Pho "C-NMR cua chit Va cung chiia cac tin hieu aac thing cho cac nguyen t i i cartjon trong phan tii. Cac chat Via va Vila thu diigo t i i chat Va sau phan ling deacetyl hoa. Phan ling duioc chiing minh xay ra thOng qua sir v i n g mat cua tin hieu singlet * t r u i n g manh dac tn/ng cho cac proton trong nhom acetyl tren pho 'H-NMR cua cac chit Via vi Vila, tren ph6 "C-NMR cua chat Via cung khong quan s^t thay tin hieu cua 2 carton Irong nhom acetyl n^y Cau tnjc cua ciSc chit Via va Vila con dipoc chuing minh thong qua pho IR v6i sv xuit hi#n van h i p thg cua cac nh6m chiio dac tnj-ng Dan chit Vila l6n tai d dang base, du.|?c chiing minh thong qua cac van h i p thg * 3427 va 3332 cm-' dac tning cho dao dpng hoa tri cOa lien ket N-H. D i n chit Via t i n tai 4 dang muii duvc chiing minh thong qua cac vin hap thg trong khoang 2706 d i n 2476 cm-' dac tru'ng cho dao 6t>na hoa tri cua nhom N--H. C i c d i n chit Vb, Vlb. Vllb khac bi#t v4l cac dSn chit Va, Via Vila * vi tri ciJa nhom the methyl tren nhan 2MBI dieu nay 6v!,c chiing minh thong qua sy xuit h«n them 1 tin hiju singlet o tnrong manh tren ph6 'H-NMR vi 1 tin hieu * t r u i n g manh ti«n pho "C-NMR da do cda cSc d i n chit nay.
Vi tic dgng giy d^c ti bio ung thir So sanh cac kit qua trong nghign cu-u c i a minh V6I cac kit qua trong cac nghien ciiu khac vi t6ng hg.p va thii tac dung gay doc t« bao ung
«iu. cua cac d i n chit c6 c i u tnjc tuong tv (BOi Thl Thu Hiin (2014). T6ng hpp va thii tac dung sinii hpc cua m6t s6 d i n chit 2-[(4-phenoxybutyl)
» n ; , - ; ^ ' ; ? " ' ' " " " ' f °'" ™ ' ' 3 ' V ' " ^ i Ngan (2015). Nghijn o i u ting hp.p va thii tac dung sinh hpc m61 so dan chit 2-phenoxybutylbenzimidazo|- - Kh6a luan tot nghijp Dime sT, Trirtng Bai hoc Du<?c Ha NOi), Chiing t6i nJt ra nhiing k i t lujn ban d i u ve s j , lien quan gl&a c i u tnic va lac dung lic ChS te bao ung thi, vO (ddng MCFT) ciia do d i n chat ket hop gliia khung 2MBI »a nhom phenoxy nhii sau;
- NhOm methyl (-CH,) ft vj tri so 4 trSn khung 2M81 thudng lam tang hoat \vc.
- cac nhom I h i amino (-NH,), amonio (-NH,*), methoxycarbonyl (-C0OCH,) a vi tri para tren nhan phenoxy cho hoat \vc t i t han so v4l cac nhom the acetamido (-NHCOCH,), cartjoxy (- COOH) ft Cling vi tri.
- Oau noi g i m 4 nguyen t i i carbon giiia hai nhan thom cho hoat luc t i t hen cau n i l g i m 2 nguyen tii carton.
Ket lulin
1. Da ting hop 6voo 6 d i n chit mffl cua 2-((2-phenoxyethyl)thio)-1H^)enzoMimldazol(Va Via, Vila. Vb, Vlb, Vllb). O i u tnic ciia cac san phim duo'c xac * h bing phuong phap phan tich cac pho IR, 'H-NMR, "0-NMR va MS.
2. Da thii tac dgng gay dOc t i bao ung thu' vii (MCFT) cDa 6 d i n chat tong hpp dupc. D i n chat Va vi Vb the hien hoat \vc y i u vfti 10^ > 100 pg/
mL (> 305,44 pM va > 293,17 pM tuftng ling), bin d i n chat Via. Vila, Vlb. Vllb t h i hiOn hoat Ipc t i t hPn vol gia tri IC„ trong khoang 33,58 - 52,52 pg/
mL (90,20 - 146,58 pM).
Tai li^u t h a m khao 1. Anandarajagopal K, at al. (2010), "Synthesis anti-injammaloiy and antimicrobial evalualion of 2-mercaptob8nzlmldazolB denvatives". intematkmal Joumal of Chemical end Anelytkial Science 1(91 pp. 214-216. ' '' 2. Monks A. et al. (1991), •Feasibility of a higMux anticancer drag screen using a dlvsise panel of ajllured human tumor cell lines", Joumal of National Cancer institute, 83(11), pp. 757-766.
3. Moore T. W. et al. (2013), -Asymmetric synthesis of host-directed inhibltois of myxovlmses-, SeJsleih Joumal of Organk: Chemistry, 9, pp 197-203
4. Sweelman S. c. (2009). Marimdale The Complete Dmg Reference 36" edition. Phamiaceutlcal Press London.pp.157.pp. 1753.
5. VanAllan J. A . Deacon B. D (1950)
•2-mereaptobenzimlda2ole-. Organic Syntheses. 30. pp' 6 Vedula M. S. et al. (2003). -New slyiyl sullbnes as anlicancer agents'. Eumpeen Joumal of Medianel Chemistry, 38. pp. 811-824.
^Ngiynhan bii: 22/06/2016 - Ngay duyet ding: 01/09^016)
T*P CHi DirOC HQC - 9/2016 ( S 6 485 NKM 5 ^
