TAP c m HOA HQC
DOI: 1OI5625/0866-7144.2014-0062
T. 52(6) 723-727 THANG 12 NAM 2014
THANH PHAN HOA HpC VA HOAT TJNH GAY DOC T S BAO CCiA CAC Hgp C H A T TU" LOAl HA'I M I E N StyVissa flabelliformis
Ngo Van Quang^ Nguyin Xuan Nhiem', Pham Hai \en\ Dirong Thi Dung', Dan Thi Thiiy Hkng\
Hoang Le Tuan Anh', Chau Van Minh', Phan Van Kiem'*
' Vien Hda sinh biin, Vien Hdn lam Khoa hgc va Cdng nghi Viet Nam
^Vien Hda hgc. Vien Hdn lam Khoa hgc vd Cdng nghi Viet Nam Din Tda soan 24-6-2014; Chip nhan dang 4-12-2014 Abstract
By various chromatographic separations, four known compounds, 2,2-bis[4-(2,3-dihydroxypropoxy)- phenyl]propane (1), 2,2-bis[4-(2,3-epoxypropoxy)phenyl] propane (2), cholest-7-en-3p,5a,6p-triol (3) and 29- hydroxystigmasta-5,24(28)-dien-3P-ol (4) were isolated from the sponge Stylissa flabelliformis. Their structures were elucidated by specfroscopic methods and in comparison with the reported data. Ali isolated compounds were evaluated for cytotoxic activity on human cancer cell lines, including HepG-2, KB, LU-1, MCF-7 LNCaP, SW-480, MKN-7, and HL-60. As the results, compounds 3 and 4 exhibited moderate activities in all human cancer cell lines with the IC50 values of 10.32-26.06 pg/mL.
Keywords. Stylissa flabelliformis, dictyonellidae, cytotoxicity.
1. MO DAU
Loai hai mien Stylissa flabelliformis (hg Dictyonellidae), cd hinh dang quat mau vang dugc tim thay d cac viing nhiet ddi thudc Thai Binh Duong. Cho den nay chua cd mgt nghien ciiu nao ve thanh phan hda hgc cung nhu hoat tinh sinh hgc loai S. flabelliformis. Bai bao nay thdng bao qua frinh phan lap va xac dinh cau friic hda hgc ciia bdn hgp chit: 2,2-bls[4-(2,3-dihydroxypropoxy)phenyl]- propane (1), 2,2-bis[4-(2,3-epoxypropoxy)phenyl]- propane (2), cholest-7-en-3|3,5a,6p-friol (3) va 29- hydroxystigmasta-5,24(28)-dien-3p-ol (4) tir loai S.
Flabelliformis va kit qua gay dgc te bao cua chiing tren 8 ddng tl bao ung thu ngudi thuc nghiem.
2. THLTC NGHIEM VA PHU'ONG PHAP 2.1. Mau hai mien
Mau hai mien Stylissa flabelliformis dugc thu vao diang 5 nam 2012 tai Khanh Hda. Ten khoa hgc dugc TS. Dd Cdng Thung, Vien Tai nguyen va Mdi tnrdng biln giam djnh. M I U tieu ban (SF1206) dugc luu trir tai Vign Hda sinh biln, Vien Han lam Khoa hgc va Cdng ngh? Viet Nam.
2.2. Hda chat, thiet bi
Sdc ky lop mong (TLC): Thuc hi?n tren ban mdng trang san DC-Alufolien 60 F254 (Merck 1,05715), RP18 F254s (Merck); phat hien chit bing den tii ngoai d hai budc sdng 254 nm va 365 nm hoac dimg thudc thir la dung dich H2S0fl 10 % dugc phun diu len ban mdng, siy khd rdi ho ndng tir tir den khi hien mau.
Sdc ky cot (CC): Dugc tien hanh vdi chat hap phu la Silica gel pha thudng va pha dao. Silica gel pha thudng cd cd hat la 0,040-0,063 mm (240-430 mesh). Silica gel pha dao YMC (30-50 |im, Fuji Silysia Chemical Ltd.).
Phd cdng hudng tic hgt nhdn (NMR): Do fren may Bruker AM500 cua Vien Hda hgc, Vien Han lam Khoa hgc va Cdng nghe Viet Nam.
2.3. Phan lap cac hop chat
Mau Stylissa flabelliformis (4,2 kg) dugc lam sach de loai bd muoi natri clorua sau dd chiet vdi MeOH, sieu am 3 lan trong 15 gid thu dugc 15,0 g dich chiet sau khi loai bd dung mdi d ap suat thap.
Djch chiet nay dugc them nudc va chiet bang dung mdi chloroform (CHCI3) thu dugc can chilt CHCI3 (7,5 g) va can nudc (6,8 g). Can chilt CHCI3 (7,5 g) dugc dua len cot sac ky silica gel vdi dung mdi rua giai rt-hexan-axeton (40:1—»0:1, v/v) thu dugc 3 phan doan SFIA (2,5 g), SFIB (1,2 g) va SFlc'(2,3
TCHH, T 52(6), 2014
g), Phan doan SFIB (1,2 g) dugc phan tach bing cot silica gel pha thudng vdi he dung mdi w-hexan/etyl axetat (10/1, v/v) thu dugc 2 phan doan SFIBI (0,4 g) va SF1B2 (0,6 g). Hgp chit 4 (12,0 mg) thu dugc khi sir dung sic ky cot silica gel pha thudng vdi he dung mdi cloroform/axeton (7/1, v/v). Phan doan SFIC (2,3 g) dugc phan tach bing cot sac ky silica gel pha thudng vdi he dung mdi o-hexane/ethyl acetate (6/1, v/v) thu duoc 2 phan doan SFICI (1,3 g) va SF1C2 (0,8 g). Tilp tuc phan tach SFICI bing cot sic ky silica gel pha thudng, he dung mdi
«-hexan/axeton (5/1, v/v) thu dugc hgp chat 3 (8,0 mg). Phan doan nudc (6,8 g) dugc dua len cot sac ky silica gel pha dao vdi he dung mdi acetone/nude (2/2, v/v) thu dugc 2 phan doan SF2A (4,3 g) va SF2B (1,7 g). Phan doan SF2A (4,3 g) dugc phan tach bang cot silica gel pha thudng vdi he dung mdi riia giai chloroform/ethyl acetate (1/1, v/v) thu dugc 2 phan doan SF2A1 (2,8 g) va SF2A2 (1,2 g) Phan doan SF2A1 (2,8 g) dugc phan tach bang cot sic ky silica gel pha dao vdi he dung mdi riia giai metanol/nudc (1/1, v/v) thu dugc hgp chat 1 (17,0 mg) va2(7,0mg).
2,2-Aw[4-(2,3-
dihydroxypropoxy)phenyl]propane (1): chat hot mau trang. Cong thirc phan tir: C21H2SO6. Khdi lugng phan tii: 376. ' H - N M R (500 MHz, CDCI3) va '^C-NMR (125 MHZ, CDCI3), xem bang 1.
Phan Vdn Kiem vd cdng sif 2,2-6K[4-(2,3-epoxypropoxy)phenyllpropane (2): Chit hot mau fring. Cdng tliiic phan tir: C21H34O4.
Khdi lugng phan hi: 340,41. ' H - N M R (500 MHz, CDCI3) va ' ^ C - N M R (125 MHz, CDCI3), xem bang 1,
ChoIest-7-en-3p,5a,6p-triol (3): Chit bgt mau tring. Do quay cue: [af^ • -20,8 (c = 0,1, MeOH).
Cdng thirc phan tu: C27H46O3. Khdi lugng phan tii;
418. 'H-NMR (500 MHz, DMSO-de) va '^C-NMR (125 MHz, DMSO-de), xem bang 2.
29-Hydroxystigmasta-5,24(28)-dien-3p-ol (4):
Chit bgt mau frang. Dd quay cue: \af^ : -22 (c =0,2, CHCI3). Cdng thiic phan tu: C29H48O2. Khdi lugng phan tu: 428. ' H - N M R (500 M'HZ, CDCI3) va '^C- NMR (125 MHZ, CDCI3), xem bang 2.
2.4. Danh gia hoat tinh diet te bao ung thu 8 ddng te bao ung thu dugc thii" nghiem bao gdm: Hep-G2 (ung thu gan), KB (ung thu bieu mo), LU-1 (ung thu phoi), MCF-7 (ung thu vu), LNCaP (ung thu tuyen tien liet), SW-480 (ung thu rugt ket), MKN-7 (ung thu da day) va HL-60 (ung thu bach cau). Phuong phap thit dugc tien hanh theo theo phuang phap SRB dugc mieu ta bdi Skehan va cs [I]; Likhiwitayawuid va cs [2] hien dang dugc ap dung tai Vien Nghien cuu ung thu Qudc gia cua My (NCI) va Trudng Dai hgc Dugc, Dai hgc Tdng hgp Illinois, Chicago, My.
LTinh I • c i u friic hda hgc ciia cac hgp chit 1-4 va cac hgp chat tham khao
3. KET QUA VA THAO LUAN NMR va DEPT ciia 1 cho bill sir xuit hien tin hieu ciia 1 don vi epoxy propanol tai 5c 44,79, 50,20 v^
^ Hgp chat 1 thu dugc dudi dang chat hot mau 68,77; 4 tin hieu cua I vdng thom the para t?! 6c frang. Tren phd H-NMR cho bill cac proton thom 143,68, 127,79, 114,03, va 156,63; mgt don vi tai 6H 7,13 (d, y = 8,5 Hz) va 6,81 (d, J= 8,5), ggi y propane tai 5c 21,04 (2C) va 41,78 (b^ng 1). Kit hgp su cd mat cua vdng thom th^para, va tin hieu ciia 6 tra cim tai lieu va so sanh so lieu phd NMR cua 1 proton ciia methyl bac 4 tai 5H 1,62 (s). Phd ''C- vdi 2,2-6«[4-(2,3-epoxypropoxy)phenyl]propane
TCHH, T. 52(6), 2014 Thdnh phan hda hgc vd hogt tinh.
Bdng I: Sd lieu phd NMR cua hgp chat 1 va 2 va ciia cac hgp chat tham khao C
1 2 3 r 2',6' 3',5' 4' 1", 3"
2"
1 Sc"
68,8 50,3 44,9 143,7 127,9 114,0 156,4 31,1 41,8
S c "
68,77 50,20 44,79 143,68 127,79 114,03 156,63 31,02 41,74
8 „ " ( y = H z ) 4,18 (dd, 3,5, 11,5) 3,95 (dd, 5,5, 11,5) 3,33 (m) 2,89 (t, 5,0)/2,73 (m)
-
7,13 (d, 8,5) 6,80 (d, 8,5)-
1,62 (s)-
2 8c"
70,5 70,0 70,5 143,7 128,3 114,6 157,5 31,2 41,9
ec'-' 63,62 70,47 69,13 143,71 127,84 113,99 156,45 31,04 41,78
i„"-(J^Hz) 3,99 (brd, 10,0) 4,03 (brd, 10,0) 3,69 (m) 3,77 (brd, 9.5) 3,99(brd, 9,5)
-
7,13 (d, 8,0) 6,82 (d, 8,0)-
1,62 (s)-
"'Do frong CDCl3,'''l00 MHz, ''500 MHz,*5ccua2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane [3], 6c cua vemoniether S [4].
cho thay su phii hgp ve gia fr| do dich chuyen hda hgc d tit ca cac vi fri [3]. Cac tuong tac HMBC giira H-1 (8H 3,95 va 4,18) vdi C-2 (5c 50,20), C-3 (5c 44,79), va C-4' (5c 156,63) ggi y sir cd mat cQa vdng epoxy t^i C-2/C-3 va lien kit vdi vdng thom qua cau oxi tai C-1 ciia nhanh propanol, Cac tuong tac HMBC tir H- 1" (5n 1,62) tdi C-I' (5c 143,68) va C-2" (5c 41,74) ggi y hai vdng benzen lien ket vdi C-2" ciia nhanh propane thd 2 (Hinh 2). Tir cac bing chiing phd neu fren, cau triic hda hgc cua 1 dugc xac djnh la 2,2- 6w[4-(2,3-epoxypropoxy)phenyl] propane.
Phd ' H - N M R ciia 2 cho bilt su xuit hien tin hieu ciia cac proton thom tai 5H 6,82 (2H, &,J= 8,0 Hz) va 7,13 (2H, d, J= 8,0 Hz) dac frung cho vdng thom thi para. Phd '^C-NMR va DEPT ciia 2 xuit hien tin hieu ciia I don vj glycerol tai 5c 63,62, 70,47, 69,13; 1 vdng thom thi para tai 6c 143,71, 127,84, 113,99, va 156,45; mgt don vi propane tai 5c 21,04 (2C) va 41,78.
Tra cihi tai lieu tham khao nhan thay sd lieu phd NMR ciia 2 tuang tu vdi hgp chat 2,2-6«[4-(2,3- epoxypropoxy)phenyl]propane [3] va vemoniether S [4], Do chuyen dich hda hgc 5c hoan toan triing khdp d cac vj fri ngoai tru cd su khac biet d don vj glycerol.
djch hda hgc 5c C-2 va C-3 cCia glycerol cua 2 da djch chuyin vl frudng ylu [5c 70,47 (C-2) va 69,13 (C-3)]
so vdi 5c 50,3 (C-2) va 44,9 (C-3) hrong img cua 2,2- 6is[4-(2,3-epoxypropoxy)-phenyl]propane [3]. Dieu nay da ggi y cd sir md vdng epoxy. Tir cac bang chung phd nay cho phep ket luan cau triic ciia hgp chat 2 dugc xac djnh la 2,2-bis[4-<2,3-dihydroxypropoxy)- phenyljpropane, mdt hgp chat da dugc ban tdng hgp nhung day la iin diu tien dugc phan lap tir tu nhien.
Hgp chit 3 thu dugc dudi chat bdt vd dinh hinh mau fring. Phan tich phd ' H-NMR cua 3 cho thay sir xuit hien tin hieu ciia 5 nhdm metyl trong dd cd 2
nhdm methyl bac 3 tai 5H 0,53 (3H, s, H-18), 0,89 (3H, s, H-19) va 3 nhdm metyl bac 2 tai 5H 0,85 (3H, d, y = 6,5 Hz, H-26), 0,85 (3H, d, J = 6,5 Hz, H-27), 0,94 (3H, d,J= 6,5 Hz, H-21) ggi y cho cau true khung cholesterol; 1 nhdm oxymethine tai vi tri 3,76 (IH, m, H-3) va 1 tin hieu proton ciia ndi ddi the 3 iin tai 5H 5,08 (IH, dd, J= 2,5 va 6,5 Hz, H-6). Phd '^C-NMR va DEPT cua 3 xuat hien tin hieu ciia 27 cacbon (bang 2), trong dd, cd tin hieu ciia 5 nhdm methyl tai 5c 11,78 (C-18), 17,64 (C-19), 18,63 (C- 21), 22,62 (C-26), 22,34 (C-27); tin hleu 10 cacbon methylene tai 5c 31,14 (C-1), 32,41 (C-2), 38,69 (C- 4), 23,26 (C-11), 40,16 (C-12), 21,29 (C-15), 27,40 (C-16), 35,54 (C-22), 22,62 (C-23) 38,88 (C-24); 2 nhdm oxymethine tai 5c 65,92 (C-3), 72,10 (C-6) va 1 tin hieu dac trung cho mdt lien kit ddi thi 3 iin tai 6c 119,39 (C-7); 4 cacbon bac 4 vdi tin hieu ciia mgt cacbon olefinic tai 5c 139,67 (C-9). Tir nhihig dif kien phd fren cho phep du doan cau triic ciia 3 la cholest-7-en-3j3,5o;,6^-triol. De xac dinh chinh xac ciu triic ciia 3, phd HSQC va HMBC dugc thuc hien. Phan tich cac tuong tac tren phd HSQC cho phep ta gan tin hi?u ciia proton lien ket true tiep vdi cacbon. Phan tich chi tilt cac tuong tac fren phd HMBC cho thay cd tuong tac giira proton H-19 (5H 0,89) vdi C-1 (8c 31,14)/C-5 (5c 74,42)/C-9 (5c 42,22)/C-10 (5c 36,59) va tuang tac giira H-7 (5„
5,08) vdi C-6 (5c 72,10)/C-9 (5c 42,22)/C-14 (5c 54,06) ggi y 2 nhdm hydroxyl tai C-5 va C-6; lien kit ddi dugc xac dinh tai vj tri C-7/C-8 dua vao tuong tac glQa proton H-7 (5H 5,08) vdi C-6 (5c 72,10)/C-9 (5c 42,22)/C-14 (5c-54,06) va giira H-9 (5H 1,92) vdi C-7 (5c 119,39)/C-8 (5c 139,67)/C-10
TCHH, T. 52(6), 2014
(5c 36,59)/ C-11 (5c 22,26) (hinh 2). Tir nhttng dii- kien pho neu tr«n, kk hap so sanh voi so lieu pho cua hgp chat 3^-hydroxycholest-5-en-7-one [5] va ciia hgp chat 24-mety!en-27-metylch[oestanc-
Phan Van Kiem va cong si/
3p,5a,6p-triol [6] o nhihig phin ciu true tuong dSng CO thS khing dinh hgp chit 3 la cholest-7-en- 3^,5a,6^-friol. Bay la iin diu tien s3 lieu ph6 IH- va "C-NMR diy du cua hgp chit 3 dugc cong b6.
c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Bdng 2: S6 lieu pho
6c"
36,5 31,3 70,6 41,9 165,2 126,3 202,4 45,5 50,1 38,4 21,3 38,8 41,9 50,1 26,4 28,6 54,9 12,1 17,4 35,8 19,0 36,3 23,9 39,6 28,1 22,6 22,9
8c®
32,5 31,1 67,7 41,0 76,3 74,2 34,8 30,4 46,1 38,5 21,3 40,2 43,0 56,2 24,2 28,2 56,4 12,2 16,8 35,9 18,8 34,9 30,8 155,4 41,8 19,8 28,4 107,2 11,9
NMR cua hgp chat 3 va 4 3
8 c "
31,14 32,41 65,92 38,96 74,42 72,10 119,39 139,67 42,22 36,59 23,26 40,16 43,04 54,06 21,29 27,40 55,54 11,78 17,64 35,54 18,63 35,54 22,62 38,88 27,35 22,62 22,34
6„"-''(J=Hz) l,33(m)/l,60(d, 11,0) l,37(m)/l,47(m) 3,76 (m) 1,98 (m)
-
3,39 (m) 5,08 (dd, 2,5,4,5)
-
1,92 (m)
-
l,13(m)/l,32(m) l,86(m)/l,50(m)
-
1,78 (m) 1,42 (m) l,2S(m)/l,82(m) 1,20 (m) 0,53 (s) 0,89 (s) 1,37 (m) 0,90 (d, 6,5) 1,08 (m) l,51(m)/l,38(m) 1,17 (m) 1,52 (ra) 0,85 (d, 6,5) 0,84 (d, 6,5)
1
va cua cac hgp chat tham khao 4 8c'
37,2 31,9 71,8 42,3 140,8 121,6 31,6 36,4 50,1 36,5 21,1 39,7 42,3 56,7 24,3 28,2 55,6 11,8 19,4 36,3 18,7 34,5 26,4 150,6 31,9 21,9 22,0 120,8 59,5
Oc 37,26 31,90 71,79 42,29 140,78 121,67 31,66 36,36 50,12 36,51 21,08 39,75 42,37 56,75 24,30 28,27 55,63 11,84 19,39 34,56 18,71 36,40 26,39 150,64 31,90 21,95 22,06 120,88 59,48
8„'Vy=Hz)
3,53 (m)
5,35 (m)
-
0,68 (s) 1,26 (s) 0,98 (d, 6,5)
-
1,03 (s) 1,03 (s) 5,35 (m) 4,17 (d, 7,0)
•Do trong DMSO-d,, 'CDCl,, =125 MHz, '500 MHz, "5c ciia 3p-hydroxycholest-5-en-7-one [5],
®6c cua 24-metylen-27-metylchloestance-3P,5o,6p-triol [6], '5c cua 29-hydroxystigmasta-5,24(28)-dien-3-P-ol [7].
Pho H-NMR ciia 4 cho bi6t sir co mat cua hai proton olefin tai 5„ 5,35 (2H, ra), 1 proton oxymethine tai 5H 3,53 (ra), 2 proton oxymetylen tai
6„ 4,17, 4 nhom metyl bac ba tai 6„ 0,68 (3H, s), 1,03 (6H, s) va 1,26 (3H, s) va I nhom metyl bac hai tai 5„ 0,98 (d, J= 6,5 Hz). Pho "C-NMR va DEPT
T C H H , T. 52(6), 2 0 1 4
Phd ' H - N M R c u a 4 cho bilt sir cd mat cua hai proton olefin tgi 6H 5,35 (2H, m ) , 1 proton o x y m e t h i n e tai 5H 3,53 ( m ) , 2 proton oxymetylen tai 5H 4,17, 4 n h d m metyl bgc ba tgi 6H 0,68 ( 3 H , s), 1,03 ( 6 H , s) va 1,26 ( 3 H , s) va 1 n h d m metyl b a c hai tgi 6H 0,98 (d,J= 6,5 Hz). Phd '^C-NMR va D E P T cho biet s u cd m a t cua 2 9 cacbon vdi lien k i t ddi the ba i i n gan vdi n h d m oxymetylen C-24/C-28 rat dac trung cho mdt m a c h nhanh ciia h g p chat 2 9 - h);droxystigmasta-5,24(28)-dien-3-p-ol ( b a n g 2) [7].
So li?u phd N M R ciia 4 h o a n toan triing k h d p vdi sd li?u phd cua 2 9 - h y d r o x y s t i g m a s t a - 5 , 2 4 ( 2 8 ) - d i e n - 3 - p-ol, mdt h g p chat da biet tir loai rong nau Turbinaria ornata [7].
C a bdn h g p chat da d u g c danh gia boat tinh gay dgc te bao fren 8 d d n g te bao u n g t h u n g u d i , H e p G - 2, KB, L U - 1 , M C F - 7 L N C a P , S W - 4 8 0 , M K N - 7 va HL-60. T h e o dd, cac h g p chat 3 va 4 da the hien hoat tinh gay ddc te bao d miic d o trung binh tren t i t
Thdnh phdn hda hgc vd hogt tinh...
ca cac d d n g t l bao ung t h u thir n g h i e m vdi gia trj IC50 trong k h o a n g 1 0 , 3 2 - 2 6 , 0 6 p g / m L (bang 3 ) . T r o n g khi dd, h g p chat 1 va 2 k h d n g t h i hien boat tinh gay dgc tren tat ca cac d d n g te bao ung t h u IC50
> 1 0 0 p g / m L ( b a n g 3 ) .
Hmh 2: C a c t u o n g tac H M B C chi'nh ciia 1 va 3
Hffp chat 1 2 3 4 ElUptlcme
Bang 3: Ket qua danh gia ho^t tinh gay dgc te bao ciia cac hgp chat 1-4
HepG-2
>100
>100 12,02 25,51 1,06
KB
>100
>100 11,51 21,43 0,99
LU-1
>100
>100 13,99 25,66 0,87
I C M MCF-7
>100
>100 12,19 25,76 0,92
(lig/mL) LNCaP
>100
>100 13,29 24,73 0,70
SW-480
>100
>100 12,97 26,06 0,84
MKN-7
>100
>100 12,62 24,75 0,95
HL-60
>100
>100 10,32 21,39 0,62 Loi c a m o n . Cdng trinh ducrc hodn thdnh vol su tdi
trg kinh phi cua Bd Khoa hgc vd Cdng nghi
(02/2011/HD-NCCBUDf •*•
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Zhang, W. S. Chen, S. L. Moms-Natschke, A. S. Lin.
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Lien hi: P h a n V a n K i e m
V i e n H d a sinh bien, V i e n Han lam K h o a hgc va C d n g n g h e Viet N a m S d 18, H o a n g Q u d c Vi?t, C i u G i i y , Ha N d i
E-mail: p h a n k i e m ( g v a s t . a c . v n D i e n tfiogi: 0 9 8 3 5 5 5 0 3 1 .
