• NghiSn CIFU - Ky thujt
and effects on postprandial glycemlc and oxidative stress responses In Hispanic women". Ph. D., Wghia Po(/te(^nic Institute and State University, p. 1-18.
2. Al-Tamimi E. K. et al. (2010), "Clinical study.
Consumption of cross linked resistant starch (RS4XL) on glucose and insulin responses In humans", Joumal of Nutrition and Metabolism, p. 1-6.
3. Briffaut C , et al. (2004), "Method - specific certification of free sugars and starch/ glucose in two artificial food materials: BCR-644 and BCR-645", EUR Report 20987, p. 33-42.
4. Danaei G. et al. (2011), 'National, regional, and global trends in fasting plasma glucose and diatietes prevalence since 1980' systematic analysis of health examination surveys and epidemiological studies with 370 country - years and 2.7 million participants'. The Lancet, 378 (9785), p. 31-40
5. FAO (2009), "Compendium of Food Additive
Specification", FAO JECFA Monographs, p. 52-53.
6. Khondkar D., Tester R. F., Karkalas J. (2009),
"Effect of cross - linking on the resistance to enzymatic hydrolysis of waxy maize starch and low - methoxy pectin", Food Hydrocoltoids, 23, p. 387-393.
7 Megazyme (2002), Resistant starch Assay procedure, p. 4-9.
8. National Starch Food Innovation (2005), Application for the approval of RS4 - fibre modified starch (phosphated di - starch phosphate) from high amylose maize starch, 258/97, p. 33-55.
9. H6dsdgi M, et al. (2010), "In vitro digestibility of native and resistant starches: Correlation to the change of its rhelogical properties", Food Bbprocess Technotogy, p. 1-11.
10. Li G. et al (2011). "Characterization of Phosphate Monoester Resistant Starch", International Joumal af Food Praperiies, 14(5), p 978-987.
Tong hop piperin
Trirong NgQC Tuyen , Lir Thien Nhan , Tran Huu Dung 'Khoa Dirac -DHY- Duac TP. Ho Chi Minh,
^Khoa Duac -DHY- Duac Hue
D^t vin de
Piperin (bioperin) - ttidnh p h i n chfnh cua tieu den - Id gia vj thudng cd trong bu'a an m i i gia dinh. Piperin va d i n c h i t cua nd ed nhiiu edng dyng nhu ehing eo gidt, an tiian. trj roi logn sac to"^, tang cudng higu lye cua nhdm khdng sinh quindin, eureumin vd mdt s i vitamin vd dudng chit Gan ddy, nghidn euu mdi ve piperin eho thay ed tdc dgng tii ung thu vii vd dang dupe thu pha ba d ngudi'^ Chfnh d i i u ndy da khuyin khich chiing tdi nghien eiru t i n g hpp piperin vd tir ea sd ndy de t i n g hpp ede d i n c h i t piperin nhdm t o sung giup tim ra cdc d i n chit mdi ed hogt tinh.
Nguyen lieu va phircng phap Nguydn ligu
Piperonal (Merck, 99%), edc nguyen ligu, dung mdi khdc n h u aeetaldehyd, kali hydroxyd, natri hydroxyd, acid malonie, acid hydroelone, thionyl clorid, ethanol, dielorometan, n- hexan (Tnjng Quoc) dgt tidu ehuan phdng thi nghigm.
Tong h p p piperin ILF nguyen lieu piperonal
Tong hgp (E)-3-(3,4-methylendloxyphenyl) rylaldehyd (SPi) tif piperonaP^
Cho 5 g piperonal vao binh cau 2 co 500 ml.
Thdm 100 ml eon va 100 ml nude cat vdo binh cau. Lam lanh h i n hap bdng nude da, sau dd eho tir tir 3,5 g natri hydroxyd 10%. K h u i y deu hon hpp phan irng va gii> nhiet do binh phdn irng tir 15-25°C. Nhd gipt tir tCr 5,3 g aeetaldehyd vd kiem tra phan irng bdng SKLM silicagel 60 Fz54. Sau khi phdn irng k i t thue, ehiet djeh phan ung vdi diethyl ether, bay hai djeh ether de thu san p h i m thd. Chgy s i c ki edt Silicagel 60 vdi dung mdi rua giai la ether d i u hoa - ethyl aeetat (12:1) de tinh che sdn pham ( S P I ) . Xac dinh hieu suat phan irng, dg tan, mp, Rf tren SKLM va cau triic phan t u eua S P I bang pho IR (FTIR 8201 PC, Shimadzu), p h i UV-VIS (UV-VIS U2010, Shimadzu), pho ^H-NMR (Bruker AV-500) vdi dung mdi DMS0-d6, vdi chat ehuan ngi tetramethylsilan (TMS)
Tong hap acid (2E,4E)-5-(1,3-benzodioxol- 5-yl}penta-2,4-dienoic (SPz) tCrSP/^'
Cho 0,5 g SPi va 0,6 g acid malonie vao binh eau 100 mi. Sau do them 1 ml pyridin vao
T4P CHI DlT^C HQC - 09/2012 (SO 437 NAM 52)
NghiSn di'u - Ky thu^t
h6n hyp r^n. KhuAy (J4u, cho vii gipt piperidin vio hin hvp. Oun h6l liru hin hp'p phin Crng 6 59°C trong 4 glir, sau d6 4 70°C trong 1 gi*, k l ^ tra phin i>ng bing SKLM. Sau khi phdin O-ng xong, r6t hfin hpp phdn i>ng vdo cdc c<5 md c6 chCra 10 ml HCI 5 M dang du'pc ldm Ijnh vi khuAy eiu. Lpc thu tua vi rCra bing dung dlch HCI 5 M. nia tDa bing nuAc Isnh. Kit tinh 1^1 sin phim trong ethanol. Lpc thu tua, dem siy tua ft dp suit glim d i thu sdn phim (SP:). Xdc djnh hl$u suit phdn i>ng, dO tan, mp. Ri trdn SKLM vd ciu true phdn tCr cOa SP; bing phi IR, phi UV-VIS, phi 'H-NMR trong dung mil DMS0-d6 vd'i chit chuin nOI tetramethylsilan (TMS) vd phi khii lu'png (MS) du'pc ghi bing mdy khii phi miciOTOF-Q.
Tdng htfp (iE,4E).S-(1,34}aniodloxol-S-yl)- 1-(plper1dln-1'-yl)penta'2,4.dlen-1-on (piperin) tifSP,
Cho 0,22 g SPi vd 0.15 ml piperidin vdo blnh ciu 250 ml. Cho 10 ml dicloromethan (DCM) vdo blnh ciu. khuiy diu vd Idm lanh blnh ciu.
Thim 0,15 g triethylamin vdo btnh ciu vd nhi gipt chdm 0,15 ml thionyl clorid vdo binh ciu.
Sau khi nhi gipt xong. ndng nhidt d i lin 50°C vd dun hii liru trong 7 gift. Khi phdn Crng kit thuc. c i quay bic hai hit dung mdi thu dupe cin, Oem n>a cin vd'i nif6c cit. Cho cin vdo
dung dlch NaOH 2,5% vd Ipc thu sin phim rin.
Siy sin phim d u i l dp suit glim d i thu dupe sin phim Unh khiit. Xdc d|nh hiiu suit phdn Crng, d i tan, mp, Ritidn SKLM vd ciu tnJc phdn tt>
cCia SPj bing phi IR, phi UV-VIS. phi 'H-NMR trpng dung mil DMS0-d6 v i i chit chuin nii tetramethylsilan (TMS) vd phi khii lifpng (MS) duvc ghi bing mdy khii phi mIcrOTOF-Q. Ding thii, d i tinh khiit cua sdn phim xdc djnh bing HPLC Shimadzu RP-C,6 (du<mg kInh cit 4.6"^
25"). Pha ding Id acetonitril: nu*c cit (40 : 60), tic d i ding 1 ml/1 phut, buVc sing phdt hlin 348 nm. Miu dii chliu Id piperin tnjng methanol dupe chiit xuit ti> hat tiiu den (Piper nignjm L Piperaceae).
Thvc nghlfm, k4t qui vd bin lu$n Qud trinh thi/e nghiim. ting hpp piperin du'pc thi/c hi$n qua ba giai dean gim ba phdn Crng khdc nhau vdi giai doan thi> nhit Id ting hpp (£)-3-(3.4-methylendioxy-phenyl) acrylaldehyd (SP,) tir piperonal, giai doan thCr hai Id ting hpp aad (2E,4e)-5-(1,3-benzodioxol- 5-yl)penta-2,4-dienoic (SP:) tir SP, vd giai doan ba Id ting hpp di/pc (2£,'4£)-5-(1,3- benzodioxol-5-yl)-1-(piperidin-1'-yl)penta-2,4- dien-1-on (piperin) tCr SP:. Qui trinh ting hpp dupe biiu diin qua sa d i bin di/ii.
Piperonal Acid pipcnnic (SP2)
So* d 6 1 : i) Aeetaldehyd, NaOH 10%, 15-20 °C; 11) Acid malonie. pyridin, piperidin. 70 "C;
ill) Thionyl clorid. triethylamin, piperidin, DCM, 50 °C.
Qua ba phdn irng tuang d6i dan gidn da t6ng hgrp thdnh edng piperin tir piperonal.
0 phdn irng diu tidn, khi nhi$t d0 qud thip tir 5 - 8 "C thi higu sudt phdn irng gidm do piperonal b| tdch ra thdnh gigt diu mdu ndu dudi ddy. Nhidt dO 0 - 5°C thi aeetaldehyd bj triing hp'p thdnh dgng trimer. Cdn d di^u ki$n nhi^t dd eao SCC tht d l sinh ra nhiiu tgp. Khi diing KOH Idm eho dd nhdl dung djch cao, khudy mdt thdi gian thi djch trd ndn dde qudnh Idm cdn trd phdn irng Do dd didu ki^n tdi uu cho phan irng Id nhi$t dd tir 15 - 25°C, trong mdi trudng pH kidm id dung djch natri hydroxyd 10%,
Sau khi phan irng kdt thiic, chidt djeh phdn irng vdi diethyl ether, bay hai d|ch ether dup'c
ehdt Idng ddc sdnh. Ch^y sdc kl cQt Silicagel 60 vdi dung mdi n>a gidi Id ether ddu hod - ethyl aeetat (12:1) thu dup'c sdn phdm SP1. Sdn phdm SPI (CioHeOa; M=176,17) Id cdc tinh thd hinh kim, mdu vdng nhgt, kdm tan trong nudc ignh, tan trong nude ndng. Tan t6t trong edn, methanol, cloroform, dicloromethan, ethyl aeetat, Mp = 76,3 "C; Rf = 0,58 (trong pha dOng 100% clorofonn). Hidu suat phdn ung: 30%. UV-
VIS (MeOH, nm): 338,0; 297,0; 247,5; 220,0. IR(KBr, cm-^): 3033,0 (C-Hbenzen); 1670,2 (C=0);
1483,2 (-0-C-0-). 'H-NMR (500 MHz, DMSO) 5 (ppm): 9,60 (IH; d; J=7,5 Hz; H,); 7.63 (IH; d;
J= 15,5 Hz; Hs); 7.43 (IH; d; > 1,5 Hz; Hz);
7,23 (IH; dd; J= 1,5 Hz; 8,0 Hz; He); 7,01 (IH; d;
56 TAP CHI DUQC HQC-09/2012 (S6 437 NAM 52)
» Nghien cQ'U - Ky thugt
> 8,0 Hz: Hs); 6,76 ( I H ; dd; > 8,0 Hz; 16,5 Hz;
H2);6,11(2H;s;HcH2).
6 phdn Crng hai, d i h i i u s u i t cao thi piperidin vd pyridin phdi t i l thiSu, thM gian t i i u u phdn Ci'ng Id 5 gifr, v i i hi#u s u i t khd cap (93,6%). Trpng khi tSng t h i i gian phdn Crng lai k h i n g Idm tdng hidu suit thu h i i . K i t tinh lai sdn p h i m trong ethanol.
Lpc thu tua. dem s i y tOa i ' dp s u i t gidm. Sdn phim SP2 (acid piperinic) (CizHioO.; M=218.20) Id edc tinh t h i hinh kim. tan 50 p h i n trong c i n , tan 275 p h i n trong c i n n i n g , tan (t trong diethyl ether vd h i u nhu khdng tan trong nu'dc (phCi hpp v i i Merck 1 l " ' , ndm 1989). m p = 217,3 °C; R,=
0,75 (ether d i u hod - AcOEt = 2;1 + 1 gipt AcOH). UV-VIS (MeOH. nm): 342,0; 308,0:
253,0; 243,0. IR (KBr. cm"'): 2918,1 (OH„a):
2945: 2830 (CH,); 1712.7 (C=0): 1649.0: 1600.8 (-C=C-C=C-). ESl-MS m/i:. 241,0 (M+Na)*. ' H - NMR (500 MHz. DMSO) 6 (ppm): 12.18 ( I H ; br;
HCOOH): 7.32-7.27 ( I N ; ddd. > 3.5 Hz: 7.5 Hz;
15.0 Hz; Hs): 7.23 ( I H ; d; J= 1,5 Hz; H,): 7,00 (IH: dd: J= 1,5 Hz; 8,0 Hz; H „ ) ; 6,97-6,96 (2H;
m: H,o; Hs): 6,92 ( I H , d, > 8.0 Hz; H,); 6,05 (2H;
s: Hii): 5.92 (1H; d; J= 15.50 Hz; Hj).
0* phan Crng ba. tong hpp piperin tCr acid piperinic bang phan ung acyl hod vdi tdc nhdn thionyl clorid thi can phai n h i gipt chdm.
Triethylamin ddng vai t r i c h i t xiic tdc b i t glQ"
HCI sinh ra trdnh thuy phdn sdn p h i m piperin.
Hidu s u i t chl d mCre trung blnh ndn c i n t h i i t k i md hinh d i t i l u u qud qui trinh t i n g hpp. T i t cd cdc dung m i i dung trong phdn Crng ndy d i u khan n i n c i n chung c i t lai triethylamin, dielorometan.
Sdn p h i m piperin ( C U H I B N O J ; M=285,3) Id ode tinh t h i hinh kim trong c i n , mdu vdng nhat g i n nhu khdng mdu. Tan t i t trong c i n , clorofomi.
H i u nhu khdng tan trong nudc. Tan m i t p h i n trong ether (phCl hpp Merck 11'''). Hidu s u i t phdn Crng Id 55,61%. Mp = 129,1 °C: R,= 0,42 (toluen - AcOEt = 7 : 3 ) . UV-VIS (MeOH. nm):
342.5; 310.6; 255,5; 244,0. IR (KBr, cm"'): 3000,1 (C-Hi^nn); 2932,9; 2854,5 (CH;): 1635,5 {CO„.,a); 1620,1 (-C=C-C=0). ESI4MS mir.
286.1 (M+H)*. ' H - N M R (500 MHz. CDCb) 6 (ppm): 7,43-7,38 ( I H ; m; Hj); 6,98 ( I H ; d; > 1 , 5 Hz; H,); 6,89 (1H; dd; > 1,5 Hz: 8,0 Hz: H.);
6,79-6,70 (3H, m; Hs, H,o, H „ ) ; 6,44 ( I H ; d; J=
14,5 Hz; Hi); 5,98 (2H: s; H,;); 3,68 (4H; br; Hy, HB): 1.69-1,57 (6H; m; H j , H,,, Hs).
0 0 tinh khiit cua piperin t i n g hpp dupe k i i m tra bang HPLC RP-Ca vdi pha dpng Id acetonitril : nude cat (40 : 60), toe dd ddng 1 ml/1 phCit, bude sdng phdt hidn 348 nm vd dupe minh hoa trong hinh dudi.
1
1
•.!.l: i J
b
Hinh 1: Sic ky do mau dSi chieu piperin duvc chiet xuat tir di^gc lieu (a) (Piper nigrum L. Piperaceae) va piperin tong hgp (b) trong methanol T ^ CHi DirOC HQC - 09/2012 (SO 437 NAM 52)
I Nghidn ciyu - Ky thu$t
Kdt qud cho thdy thd-i gian luu (tn) cda piperin tdng hg^p Id 5,902 phiit vd t u a n g Crng vdl tncua mfiu ddi chd'ng (5,874 phOt). Qua kdt qud dd cho thdy hai peak trdn hai sdc ky 66 mdu tht>
vd mdu ddi chidu Id ciing mdt chdt ndn cdng khdng djnh thdm sdn phdm tdng hqrp Id piperin.
Kit Iu9n
Bdng cdc nguydn Hdu rd Udn, nhdm nghidn c u u dd tdng hp'p thdnh cdng piperin cd dd tinh khidt cao, d u ^ c kidm tra qua nhidt dd ndng chdy, SKLM, phd IR, phd UV-VIS, phd MS. phd
^H-NMR, HPLC so vdi mdu chidt tir dug-c lidu.
Quy trinh ndy cd thd d u p e tham khdo trong nghidn ciru irng dvng dd tidp tgc tdng hg-p cdc ddn chdt piperin diing Idm nguydn lidu trong cdng nghidp dug-c phdm
S u m m a r y
f^perine was synthesized by a three-step patiiway: i) reaction of acetakiehyd with piperonal;
ii) reactkyi of piperonyl acrd^n with matonic acid and Hi) amidation of the resulting eari^oxylic intermediates (piperinic acid) with piperidine.
Stmctures of the synthesized compounds were
confirmed by Mp. MS. IR. UV-VIS. ^H-NMR, HPLC with high fidelity. This procedure proved praetic^ly api^kiabfe in the symhe^s of piperine derivatives tor use In the pharmaceutical industry.
T d i l i $ u t h a m k h d o 1. Susan Budavari, Maryadele J. O'Neit, Ann Smith, Patricia E. Heckelman. (1989). The Memk index. Merck & CO., USA
2. Amala soumyaneAh, Radhakrtshman Venkatasamy.
"UV irradiation Affects Melanocyte Sbm Jalory Activity and Protein tjindtng 01 piperine", (2006), Phytociiemistry and Phytobiotogy, 82.1541-1548.
3. Luis Esplnoza Catalan, Alejandro Madrid Villegas, Lautaro Taborga Liber. 2010.*Synthe8is of nine safrole denvalives and their antiproliferative activity towards human cancer CBIIB', J. Chit. Ctwrn.
Soc, 55, 219- 222.
4. Saul Patai, J. Edtitz-Pfefrermann and Z. Rozner.
1954, T h e Kinetics of the Knoevenaget-Doebner Reaction". J. Am. Chem. Soc, 76. 3446- 3451.
5 Lat LH, Fu QH. Uu Y, Jiang K. Guo QM, Chen QY, Yan B. Wang QQ and Shen JG. (2012). "Piperine suppresses tumor growth and metastasis in vitro and in vivo in a 4T1 munne breast cancer model". Acta PhannacoL Sin., 33(4). 523-530.
Nghien cifu dieu che thuoc trj gut allopurinol
D ^ t v a n d e
Gilt id mdt trong nhijng bdnh ly dup'c bidt ddn Idu ddi nhdt cua lodi n g u d i , tir thdi Hipocrat vdo thd ky thii- V trudc edng nguydn. Tuy nhidn.
mai ddn ndm 1683, Sydenham mdi m d td ddy dii dien bien ldm sdng eua con giit cdp, vd ddn euoi the ky XiX, Schelle, Bargman vd Woliaston mdi tim thdy vai trd eiia acid uric trong nguydn nhdn gdy bgnh, do dd b|nh giit edn dup'c gpi Id viem khdp do acid und^'.
Mpt tnDng nhirng thudc dieu trj girt ehinh hidn nay Id allopurinol. Nd vii'a ed tdc dyng Idm gidm sdn xudt vua lam tang ddo thai add uric ndn gidm ca acid unc huyet va uric ni^u "^'^l Vi vdy allopurinol dup'c sir dung rat pho bien trdn thj tara'ng.
Aliopurinoi da dup'c dua vao duoc didn nhieu nudc trong dd cd Dup'c Oien Vidt Nam IV, BP 2009 '"• ^.
58
Trtromg Phutrng, Ph^m Thj Anh Bko Dgi hpe Y-Du^rc TP. Ho Chi Minh Tuy nhidn, nguydn lidu cho vide bdo ehd cdc sdn phdm cd hogt chdt allopurinol cua nudc ta hidn nay hodn todn nhdp tir n u d c ngodi. Qua tim hidu chiing tdi nhdn thdy allopurinol hodn todn cd thd didu chd d Vidt Nam tir nhung nguydn lidu rd tidn dd kidm ' " ' . Do dd, vdi myc tidu ehu ddng t^o ngudn nguydn lidu allopurinol cd chdt lup'ng dn djnh chiing tdi tidn hdnh nghidn ciPu didu chd allopurinol. Bdi ndy Id nhung kdt qud thu dug^c trong nghidn c u u xdy d y n g qui trinh tdng hp'p allopurinol.
D o i t i l i n g , n g u y e n l i ^ u v a p h m y n g p h a p n g h i e n c i > u
Ooi t u ^ n g v d n g u y e n l i ^ u Doi twgng
Nghien c u u quy trinh tong hq^p ailopurinot'tir cde nguydn lidu don gian theo 3 b u d c :
