Bước đầu nghiên cứu mối quan hệ định lượng giữa cấu trúc và tác dụng độc tính tế bào của các dẫn chất flavonol và flavanon tổng hợp

Nghien CLFU - Ky thuat<br /> Ket luan only marginal Inhibitory effects against 8 strains<br /> Chung tdi da tdng hgp dugc 7 c h i t gdm 6 of fungi and bacteria tested.<br /> d i n chit A/-(benzothiazol-2-yl)-4-nitrobenzen Tai lieu tham khao<br /> sulfonamid va 1 d i n c h i t A/-(6-methoxybenzo 1. Nguyin Hai Nam, Phan Thi Phuo'ng Dung, Dao<br /> thiazol-2-yl)-4-aminobenzensulfonamid. K i t qua Thi Kim Oanh, Tran Phuong Thao, Nguyin Anh<br /> thir hoat tinh khang khuin, khang n i m eho thiy Ngoc. Tong hgp va tac dung sinh hoc cua d i n chit<br /> benzothiazol. P h i n 1: Cac 2-acylaminobenzothiazol,<br /> ed 4 trong 7 chit (2a, 2d, 2c, 2e) ed hoat tinh<br /> Tap chi Dwac hgc s6 12/2008, 392, 12, 31-35.<br /> khang khuan, khang n i m ; c h i t 2c the hien hoat<br /> 2. Phan Thj Phuo'ng Dung, T r i n Phuccng Thao,<br /> tinh tdt nhit khang duge 2/8 chiing VSV kiem<br /> Nguyin Hai Nam. T6ng hgp va tac dung sinh hoc cua<br /> djnh la Escherichia coli, Staphylococcus aureus d i n c h i t benzothiazol. Phan 2. Cac benzothiazol-2-yl-<br /> vdi gia trj MIC tuang u'ng la 50, 25 pg/ml. cyclopropylcarboxamid, Tap chi Dwac hgc s6 2/2009,<br /> Ld"! c a m c n 394, 2, 29-33.<br /> 3. Phan Thi Phuo'ng Dung, T r i n Phuo'ng Thao,<br /> D i tai duge hoan thanh nhd mgt phin kinh<br /> Nguyin Hai Nam. Tong hgp va tac dung sinh hoc cua<br /> phi tu' Chuang trinh nghien eiru ea ban, Bd dan c h i t 2-phenylbenzothiazol, Tap chi Dwac hgc so<br /> Khoa hge va Cdng nghe (NAFOSTED) c i p ehe 5/2009, 397, 43-47.<br /> PGS. TS. Nguyin Hai Nam. 4. Larry M, Kandel J. Microbiology: Essentials and<br /> Summary Applications. Inc New York. 1996.<br /> A senes of N-(benzothiazol-2-yl)-4- 5. Thao TP, Dung PTP, Nam NH. Design,<br /> synthesis and bioevaluation of several series of new<br /> nitrobenzenesulfonamlds and N-(benzothiazol- 2-acylbenzothiazol derivatives - Pharma Indochina VI<br /> 2-yl)-4-aminobenzenesulfonamld were - The development of Indochina pharmacy in the<br /> synthesized and evaluated for antifungal and context of global economic recession - Hue.<br /> antibacterial activities. All compounds exhibited 12/2009,172-177.<br /> <br /> <br /> <br /> > r<br /> <br /> Biro'c dau nghien cmi moi quan he dinh lu'ong<br /> r r<br /> <br /> giua can triic va tac dung doc tinh te bao cua<br /> ft r f<br /> <br /> cac dan chatflavonolvaflavanontong hop<br /> Thai Khac Minh\ Hoang Thi Kim Dung^<br /> 'BO mon Hoa Duac - Khoa Duac - Dai hoc YDuac TP. Hd Chi Minh<br /> ' Vien Cong nghe Hoa hoc - Vien Khoa hoc va Cong nghe VN<br /> <br /> Dat van de Phu'O'ng phap nghien CLPU<br /> Mgt sd nghien eu'U cho thiy cac flavonoid ty ThCp nghiem doc tinh t§ bao tren dong t l<br /> nhien va tdng hgp cd kha nang chdng ung thu bao ung thip v u MCF-7<br /> theo mgt sd ca c h i trgng dd cd chdng sy tang Phugng phap Sulforhodamine B (SRB) dung<br /> sinh hay ngan chan sy phat trien cua t i bao de danh gia kha nang gay doe t i bao ciia tac<br /> (gay dgc t i bao)'^'. Trong nghien eu'U nay, vdi nhan nghien eu'U. Thu" nghiem dya vao kha<br /> mue dich tim ra cae d i n chit ed hoat tinh khang nang eua SRB, la thude nhudm aminoxanthene<br /> ung thu manh han, 11 d i n c h i t flavonol va mau hdng sang vdi hai nhdm sulfonic g i n tTnh<br /> flavanon dugc tiin hanh tdng hgp'^' va thCr dien vdi protein eiia cac t i bao sau khi 6\ygc ed<br /> nghiem hoat tinh doe tinh tren ddng t i bao ung djnh bing TCA. T i bao 6uac nudi trong dTa 96<br /> thu vu MCF-7. Tren ea s d dd, mdi quan he djnh giing. Sau khi ii 24 gid, t i bao duge xii' ly vdi<br /> lugng giO'a c i u true hda hgc va ddc tinh te bao thude d nhO'ng ndng do khae nhau trong 48 gid.<br /> (QSAR) duge xay dyng. Sau dd, t i bao dugc cd djnh b i n g TCA 50% va<br /> <br /> <br /> 28 TAP CHi DirpC HOC - 12/2010 (SO 416 NAM 50)<br />  Nghien CLFU - Ky thuat<br /> nhudm vdi SRB 0.2%. Tong lugng protein t i PEOE (Partial Equalization of Orbital<br /> bao dugc nhudm phan anh sd lugng t i bao Eleetronegativitie - phuang phap can bing tu'ng<br /> sdng sau khi xii' ly vdi hoat chit, va dugc danh phin orbital dien tich am). Trong phuang phap<br /> gia bing phuang phap do mat do quang (OD) d PEOE, dien tich 6ufac chuyen ddi giCra cac<br /> bude sdng 492 nnv . Thir nghiem duge thye nguyen tir trong lien k i t d i n khi dat trang thai<br /> hien tai phdng thi nghiem sinh hge phan tu', Bd can bing'®'.<br /> mdn Di truyin, Trudng Dai hgc Khoa hgc T y Dien tich to po be mat phan circ phan tie<br /> nhien TP. Ho Chi Minh. (TPSA)<br /> Phu'O'ng phap Hoa tin Dien tieh fd pd b i mat phan eye phan tii'<br /> Phin m i m MOE (Molecular Operating (TPSA - topological polar suri'aee area) duge<br /> Environment, version 2007.06) dugc sir dung xae djnh bing tdng dien tieh b i mat eua cac<br /> d i xay dyng edng thire khdng gian eua 11 d i n manh c i u triic phan cyc'^'. TPSA da irng dung<br /> chit'"'. Tdng sd 184 thdng sd 2D md ta c i u true thanh edng trong xay dyng QSAR eua cae d i n<br /> phan tir dugc tinh toan. chit resveratrol chgn lge tren cyclooxygenase'^'<br /> Mdi quan he dinh lu'ang glu>a c i u true va cung nhu dy doan tinh t h i m eua cac d i n chit'^'.<br /> tac dung sinh hoc QSAR He so phan bo dau nw&c (logP(o/w))<br /> Gia trj dgc tinh t i bao IC50 (pM) duge chuyen Thdng sd logP xae djnh kha nang phan bd<br /> ddi thanh gia tri log(1/lC5o) dung trong xay dyng eua phan tir giO'a 2 he n-oetanol va nude. He sd<br /> phuang trinh QSAR. Phan tieh 'QSAR-ngiu duge sir dung nhu la mgt thdng sd xae djnh kha<br /> nhien' (QSAR-Contingeney) tren phin m i m nang di chuyen eua thude xuyen qua cac mang<br /> MOE duge sir dung de phan tieh sa bd mdi t i bao'"'<br /> quan he giO'a 184 thdng sd md ta phan tir va Dw&ng kinh phan tu' (diameter)<br /> hoat tinh sinh hge'"'. Phan tieh binh phuang tdi Dudng kinh phan tir xac djnh la gia trj Idn<br /> thiiu tirng phin (Partial Least Squares PLS) nhit trong eae khoang each giO'a 2 nguyen tir<br /> dugc tiin hanh tren cac thdng sd md ta phan tir trong phan tir'^'<br /> va duge danh gia cheo bing phan tich Leave-<br /> So Iwg'ng cac lien ket co kha nang quay<br /> One-Out (LOO)'^'.<br /> (opr_nrot)<br /> Thong s6 mo ta phan tie dung trong xay Cae lien k i t ed kha nang quay duge xac djnh<br /> d y n g phu'ang trinh QSAR va su" dung nhu la thdng sd md ta c i u true phan<br /> Tuxrng quan dien tich am tirng phan Q tir'^°'<br /> (Q_PRC-)<br /> K§t qua va ban luan<br /> Q_PRC thugc nhdm thdng sd dien tich tu'ng<br /> phin. Q_PRC xae djnh bing ty sd giua dien tieh Doc tinh t i bao<br /> am nhd nhit eiia nguyen tu' / vdi tdng dien tich K i t qua ddc tinh t i bao tren ddng t i bao ung<br /> am tu'ng phin ciia phan tir''*' ^\ thu vu MCF-7 eua 11 d i n c h i t flavonol va<br /> Tong dien tich be mat van der Waals phan flavanon duge trinh bay d bang 1.<br /> CLTC PEOE (PEOE_VSA_POL) R4.<br /> PEOE_VSA_POL thugc nhdm thdng sd dien<br /> tich tirng phin. Tdng eua dien tich b i mat van<br /> der Waals (vdW) eiia cae nguyen tCr cd trj tuyet<br /> ddi cua dien tieh tu'ng phin PEOE Idn hgn 0.2.<br /> Dien tich b i mat vdW duge tinh toan dya vao<br /> bang tra tuang irng. Dien tieh tung phin cua<br /> nguyen tir dugc xae djnh theo phuang phap<br /> <br /> Bang 1 : Ciu true hoa hoc va ddc tinh ti bao tren ddng ti bao MCF-7 cua cac dan chit<br /> Ten n Ri R2 R3 R4 Rs X ICso(pM)^ Log(1/ICso)<br /> 1" 2 OH H H H H H 129 -2,11<br /> 2 2 O-CH3 CH3 CH3 CH3 CH3 H 209 -2,32<br /> 3 2 0- C(=0)CH3 C(=0)CH3 C(=0)CH3 C(=0)CH3 H 84 -1,92<br /> <br /> <br /> TAP CHi DUOC HOC - 12/2010 (SO 416 NAM 50) 29<br />  Nghien CLFU - Ky thuat<br /> Ten n FU Rs X ICso(pM)^ Log(1/ICso)<br /> C(=0)CH3<br /> <br /> 0-C(=0)- C(=0)- C(=0)- C(=0)-<br /> C(=0)-C2H5 49 -1,69<br /> C2H5 C2H5 C2H5 C2H5<br /> 0-CONH- CONH- CONH- CONH-<br /> CONH-C4H9 36 -1,56<br /> C4H9 C4H9 C4H9 C4H9<br /> 6 2 OH CH3 CH3 CH3 CH3 H 275 -2,44<br /> 7" 1 H H H H CH3 H 124 -2,09<br /> CONH-<br /> 8 1 H H CONH-C4H9 CH3 H 113 -2,05<br /> C4H9<br /> 9 1 H H H H CH3 Br 153 -2,18<br /> 10 1 H H H H CH3 01 197 -2,29<br /> 11 1 H C(=0)CH3 C(=0)CH3 C(=0)CH3 CH3 H 21 -1,32<br /> 3 lin thw nghiem; "Quercetin; '^Hesperetin.<br /> Gia trj IC50 xac dinh theo phwang phap SRB, tien hanh<br /> M i l quan he djnh lu'ang glira c l u true va trinh 3, bang 3). Phan tieh Leave-One-Out<br /> tac dung - Phu'ang trinh QSAR so- bo (LOO) duge t i i n hanh vdi muc dich danh gia lai<br /> Tdng cdng 184 thdng sd md ta phan tir dugc cac phuang trinh va k i t qua trinh bay d bang 3.<br /> tinh toan. Bang 2 trinh bay k i t qua tinh toan eua Kit qua phan tieh eung cho thiy sd lieu eiia ciu<br /> 6 thdng sd md ta phan tir dung trong xay dyng true 11 n i m ngoai miin gia trj tuyin tinh so vdi<br /> phuang trinh QSAR. Phan tieh 'QSAR-ngiu cac sd lieu edn lai cua ea sd du" lieu. Loai bd gia tri<br /> nhien' dugc t i i n hanh vdi muc dich phan tich sa cua c i u true 11 nay, phuang trinh 4, 5 va 6 dugc<br /> bd mdi quan he giO'a l i n lugt tu'ng tham sd eua xay dyng va k i t qua eho thiy mire do tuang quan<br /> 184 thdng sd vdi tae dung doe tinh t i bao eua tuyin tinh giua dgc tinh t i bao va thdng sd md ta<br /> 11 .din chit flavonol va flavanon. K i t qua phan phan tii' la r^ > 0.84. Do thj d hinh 1 biiu diin mdi<br /> tich eho thiy 3 thdng sd ed mdi tuang quan tdt tuang quan giua gia trj hoat tinh sinh hoc<br /> vdi hoat tinh sinh hge la tuang quan dien tieh [log(1/IC5o)] va gia tri cac thdng sd md ta phan tir<br /> am tu'ng phin Q Q_PRC- (r = 0,79, r^ = 0,62, thu duge tir phuang trinh 1-6 eiia 11 hoac 10 din<br /> phuang trinh 1, bang 3), dien tieh fd pd b i mat chit nghien eu'U. Tuy nhien, phan tieh tuang quan<br /> phan eye phan tCr TPSA (r = 0,68, r^ = 0,45 giO'a 3 thdng sd md ta phan tir nay eho thiy ed sy<br /> phuang trinh 2, bang 3), va tdng dien tich b i tuang quan cheo manh (trj tuyet ddi eua r > 0,96,<br /> mat van der Waals phan eye PEOE bang 4). Do dd khdng t h i k i t hgp 3 thdng sd nay<br /> PEOE_VSA_POL (r = 0,71, r^ = 0,51, phuang trong eung mgt phuang trinh QSAR.<br /> <br /> B a n g 2: Gia tri thdng sd md ta phan tCr dung trong xay dwng phwang trinh QSAR<br /> Ten Log(1/ICso) Q_RPC- TPSA (A^) PEOE__VSA_POL (A') logP(o/w) Diameter (A) opr_nrot<br /> <br /> 1 Q -2,11 0,1379 127,45 114,99 2,03 10 1<br /> 2 Q9 -2,32 0,1734 72,45 37,05 3,10 12 6<br /> 3 Q6 -1,92 0,1039 157,80 178,43 2.99 14 6<br /> 4 05 -1,69 0,1039 157,80 178,423 5,36 16 11<br /> 5 01 -1,56 0,0897 199,85 184,25 6,91 22 17<br /> 6 R2 -2,44 0,1648 83,45 52,64 2,84 12 5<br /> 7 HT -2,09 0,1506 96,22 72,85 2,37 10 3<br /> 8 HT1 -2,05 0,1262 132,42 107,48 4,69 21 11<br /> 9 HT12 -2,18 0,1537 96,22 72,85 3,89 11 3<br /> 10 HT14 -2,29 0,1484 96,22 72,85 3,47 11 3<br /> 11 HT6 -1,32 0,1240 114,43 110,91 2,85 14 6<br /> <br /> <br /> <br /> <br /> 30 TAP CHi DirOC HOC - 12/2010 (SO 416 NAM 50)<br /> • Nghien CLFU - Ky t h u a t<br /> Bang 3: Phwang trinh QSAR sa bd sw dung duy nhit mdt thdng sd md ta phan tCr<br /> 2<br /> RMSE<br /> He SO Thong so He so PT n r i^ RMSE ,, T , „ ,<br /> ^ (LOO) (LOO)<br /> -10,06397' 0 RPC- -0,64802 (1) 11 0,79 0,62 0,20 0,51 0,23<br /> 0,00608 * TPSA -2,72607 (2) 11 0,68 0,45 0,24 0,33 0,27<br /> 0,00469 * PE0E_VSA_P0L -2,50310 (3) 11 0,71 0,51 0,23 0,36 0,27<br /> Log(i/ic50) -<br /> -9,16792* Q_RPC- -0,82662 (4) 10 0,93 0,87 0,09 0,78 0,12<br /> 0,00645 * TPSA -2,85300 (5) 10 0,94 0,88 0,09 0,82 0,11<br /> 0,00460* PE0E_VSA_P0L -2,55960 (6) 10 0,92 0,84 0,11 0,72 0,14<br /> Bang 4: He s6 twang quan cheo giCra cac thdng sd md ta ph an tw va ddc tinh ti bao<br /> Log(1/ICso) Q_RPC- TPSA PEOE_VSA_POL<br /> Log(1/IC5o) 1<br /> 0_RPC- 0,79 1<br /> TPSA 0,68 -0,97 1<br /> PE0E_VSA_P0L 0,71 -0,98 0,96 1<br /> <br /> PTl.Y = -10.06x-0.648<br /> PTZ: y = 0.005x-2.736<br /> n = l l , r ' = 0.618<br /> n=ll,r^ = 0.454<br /> <br /> <br /> -1.6<br /> <br /> <br /> -1.8<br /> <br /> <br /> <br /> <br /> .5--2.2<br /> O<br /> -2.4<br /> PT4:y = -9.167x-0.826<br /> n=10,r^ = 0.871 PT5:y = 0.006x-2.853<br /> •2.6 n=10,r^ = 0.879<br /> 0.12 0.14<br /> 60 80 100 120 140 160 180 200 220<br /> Q_RPC- TPSA<br /> (A) (B)<br /> PT3:y = 0.004x-2.503<br /> n = l l , r ' = 0.506<br /> <br /> PTS: y = 0.004x-2.559<br /> -1-6 n=10, r^ = 0.840<br /> <br /> <br /> <br /> <br /> 100 150<br /> PEOE_VSA_POL<br /> (C)<br /> Hinh 1: Mdi twang quan giira hoat tinh sinh hoc va thdng s6 twang quan dien tich am tirng phin Q<br /> Q_PRC- (A), dien tich td pd bi mat phan cwc phan tw TPSA (B), tdng dien tich bi mat van der Waals phan<br /> cwc PEOE PEOE_VSA_POL(C). Dwang thing tuyin tinh xay dwng tir 11 din chit dwac ve bing dwang<br /> net dirt (- - -j. DCr lieu cua chit 11 (chim tron •) nim ngoai miin tuyin tinh cua ca sa diy lieu dwac loai bd<br /> va dwang thing tuyin tinh mai (dwang den dam mmm) dwac xay dwng cho tirng thdng sd khao sat.<br /> <br /> TAP CHl DUOC HOC - 12/2010 (SO 416 NAM 50) 31<br />  Nghien CLFU - Ky thuat<br /> Mdi quan he dinh lifcrng giira cau true va md ta phan tu' thu dugc vdi he sd tuong quan r<br /> tac dung - Phu'ang trinh QSAR kit hgp = 0,81, r^ = 0,66 va chi t i i t trinh bay d phuang<br /> Dya tren k i t qua cua phuang trinh QSAR sa trinh 7. Sau khi loai bd 1 dO' lieu n i m ngoai miin<br /> bg va phan tich 'QSAR-ngiu nhien', thdng sd gia tri tuyin tinh (chit 11), phuang trinh QSAR<br /> tuang quan dien tieh am tung phin Q Q_PRC- (8) xay dyng ed he sd tuang quan r^ = 0,93. sai<br /> 6ugc chgn d i xay dyng phuang trinh QSAR k i t sd binh phuang trung binh RMSE = 0,07. He sd<br /> hgp. Phan tieh binh phuang tdi thiiu tirng phin hdi qui danh gia cheo (LOO) cua phuang trinh<br /> (Partial Least Squares PLS) duge t i i n hanh tren (8) la q^= 0,74 vdi RMSE = 0,15. Dd thj d hinh 2<br /> Q_PRC- k i t hgp vdi eae thdng sd md ta phan biiu d i i n mdi tuang quan giua gia tri dgc tinh t i<br /> tir khae. Phan tieh PLS duge danh gia lai b i n g bao thye nghiem va tinh toan tu phuang trinh<br /> phan tich LOO. K i t qua eho thiy k i t hgp giO'a QSAR 8.<br /> Q_PRC- va 3 thdng sd md ta khae la he sd phan Phwong trinh (7): Log(1/IC5o) = -10,49557 *<br /> bd d i u nude iogP(o/w), dudng kinh phan tir (Q_RPC-) + 0,05231 * opr_nrot - 0,10256 *<br /> diameter, sd lugng cac lien k i t cd kha nang logP(o/w) - 0,02994 * diameter - 0,13838<br /> quay opr_nrot cho k i t qua r^ tdt n h i t He sd n=11; f=0,81; A^=0,66; RMSE =0,19; q^ (LOO) =<br /> tuang quan cheo giO'a eae thdng sd md ta phan 0,40; RMSE (LOO) = 0,32<br /> tu dung trong phuang trinh k i t hgp eung nhu Phwong trinh (8): Log(1/ICso) = -8,26893 *<br /> ddc tinh t i bao duge trinh bay d bang 5 vdi gia (Q_RPC-) + 0,03091 * opr_nrot + 0,02878 *<br /> tri r < 0,95. Gia tri tinh toan cua cae thdng sd md logP(o/w) - 0,03575 * diameter - 0,76362<br /> ta duge trinh bay d bang 2. Phuang trinh QSAR n=10; ^0,96; /^=0,93; RMSE =0.07; g^ (LOO) =<br /> (7) duge thiit lap cho 11 d i n c h i t vdi 4 tham sd 0,74; RMSE (LOO) = 0,15<br /> Bang 5: He sd twang quan cheo giira thdng sd md ta phan tw dung trong phwang trinh kit hgp va<br /> ddc tinh ti bao<br /> Log(1/ICsc) Q_RPC- Diameter Opr_nrot logP(o/w)<br /> L