VIN HN LM KHOA HC V CễNG NGH VIT NAM HC VIN KHOA HC V CễNG NGH *** H VIT C NGHIấN CU THNH PHN HểA HC V HOT TNH SINH HC CA MT S LOI THUC CHI UVARIA L - H NA (ANNONACEAE) LUN N TIN S HểA HC H NI, NM 2015 VIN HN LM KHOA HC V CễNG NGH VIT NAM HC VIN KHOA HC V CễNG NGH *** H VIT C NGHIấN CU THNH PHN HểA HC V HOT TNH SINH HC CA MT S LOI THUC CHI UVARIA L - H NA (ANNONACEAE) LUN N TIN S HểA HC Chuyờn ngnh: Húa hc hu c Mó s: 62.44.01.14 Ngi hng dn khoa hc: PGS.TS Phan Vn Kim PGS.TS Nguyn Th Hoi H NI, NM 2015 LI CAM OAN Tụi xin cam oan: õy l cụng trỡnh nghiờn cu ca riờng tụi di s hng dn khoa hc ca PGS.TS Phan Vn Kim v PGS.TS Nguyn Th Hoi Cỏc kt qu thu c lun ỏn hon ton trung thc v cha c cụng b bt k cụng trỡnh no khỏc Tỏc gi lun ỏn H Vit c LI CM N Lun ỏn ny c hon thnh ti Vin Húa sinh bin, Vin Hn lõm Khoa hc v Cụng ngh Vit Nam Tụi xin by t lũng bit n chõn thnh v sõu sc n PGS.TS Phan Vn Kim v PGS.TS Nguyn Th Hoi l nhng ngi ó hng dn tn tỡnh, chu ỏo v to mi iu kin giỳp tụi thi gian thc hin lun ỏn Tụi xin trõn trng cm n s quan tõm giỳp ca Hc vin Khoa hc v Cụng ngh, Ban lónh o Vin Húa sinh bin, Phũng Qun lý Tng hp ó to iu kin v giỳp tụi hon thnh lun ỏn Tụi xin trõn trng cm n Ban Giỏm Hiu trng i hc Y Dc Hu i hc Hu, Ban Ch nhim Khoa Dc ó giỳp v to mi iu kin thun li cho tụi thi gian lm lun ỏn Tụi xin chõn thnh cm n th cỏn b Phũng Th nghim sinh hc, Vin Cụng ngh sinh hc, Vin Hn lõm Khoa hc v Cụng ngh Vit Nam ó giỳp tụi hon thnh cỏc nghiờn cu v hot tớnh sinh hc Tụi cng xin by t lũng bit n ti th cỏn b Phũng nghiờn cu cu trỳc, Vin Húa sinh bin, Vin Hn lõm Khoa hc v Cụng ngh Vit Nam ó giỳp tụi nhit tỡnh sut thi gian thc hin lun ỏn ny Cui cựng, tụi xin chõn thnh cm n gia ỡnh v bn bố ó c v, ng viờn tụi hon thnh lun ỏn Tụi xin trõn trng cm n ! H Ni, ngy thỏng nm 2015 Tỏc gi lun ỏn H Vit c MC LC MC LC i DANH MC CC Kí HIU V CH VIT TT iv DANH MC CC BIU BNG vii DANH MC CC HèNH ix DANH MC CC PH LC xiii M U Chng TNG QUAN TI LIU 1.1 Gii thiu s lc v h Na (Annonaceae) 1.2 Gii thiu v chi Bự d (Uvaria) 1.2.1 c im thc vt, phõn b v cụng dng 1.2.2 Cỏc nghiờn cu v thnh phn húa hc 1.2.2.1 Lp cht acetogenin 1.2.2.2 Lp cht alkaloid 1.2.2.3 Lp cht flavonoid 1.2.2.4 Lp cht a oxy húa cyclohexene 11 1.2.2.5 Lp cht terpenoid 13 1.2.2.6 Mt s hp cht khỏc 14 1.2.3 Cỏc nghiờn cu v hot tớnh sinh hc 16 1.2.3.1 Hot tớnh gõy c t bo 16 1.2.3.2 Hot tớnh khỏng khun, khỏng nm 20 1.2.3.3 Hot tớnh khỏng ký sinh trựng 21 1.2.3.4 Hot tớnh khỏng virut 23 1.2.3.5 Hot tớnh khỏng viờm 23 1.2.3.6 Hot tớnh chng ỏi thỏo ng 23 1.2.3.7 Hot tớnh liờn quan n tim mch 24 1.2.3.8 Hot tớnh bo v gan 24 1.2.3.9 Hot tớnh khỏc 25 1.2.3.10 C ch tỏc dng ca mt s hp cht c phõn lp t chi Uvaria 25 1.2.3.11 Mi quan h cu trỳc húa hc - hot tớnh sinh hc ca cỏc hp cht c phõn lp t chi Uvaria 27 1.3 Gii thiu s lc v cỏc loi Bự d tớa, Bự d lỏ ln v Bự d rõu 29 1.3.1 Loi Bự d tớa 29 1.3.2 Loi Bự d lỏ ln 30 1.3.3 Loi Bự d rõu 31 Chng I TNG V PHNG PHP NGHIấN CU 33 2.1 i tng nghiờn cu 33 2.2 Phng phỏp nghiờn cu 34 2.2.1 Phng phỏp phõn lp, tinh ch cỏc hp cht 34 2.2.2 Phng phỏp xỏc nh cu trỳc húa hc ca cỏc hp cht 34 i 2.2.3 Phng phỏp ỏnh giỏ hot tớnh sinh hc 35 Chng THC NGHIM V KT QU 38 3.1 X lý mu v chun b cỏc cao chit 38 3.2 Phõn lp cỏc hp cht t loi Bự d tớa 38 3.3 Phõn lp cỏc hp cht t loi Bự d lỏ ln 40 3.4 Phõn lp cỏc hp cht t loi Bự d rõu 42 3.5 Tớnh cht vt lý v d kin ph ca cỏc hp cht ó phõn lp 45 3.6 Hot tớnh sinh hc ca cỏc cao chit v cht tinh khit t cỏc loi Bự d tớa, Bự d lỏ ln v Bự d rõu 48 Chng KT QU V THO LUN 49 4.1 ỏnh giỏ hot tớnh gõy c t bo in vitro ca cao chit t loi Bự d tớa, Bự d lỏ ln v Bự d rõu 49 4.2 Xỏc nh cu trỳc húa hc ca cỏc hp cht c phõn lp t loi Bự d tớa, Bự d lỏ ln v Bự d rõu 51 4.2.1 Cỏc hp cht c phõn lp t loi Bự d tớa 53 4.2.1.1 Hp cht UGLE1 (cht mi): ()-3-O-Debenzoylzeylenone 53 4.2.1.2 Hp cht UGC4: Pipoxide chlorohydrin 61 4.2.1.3 Hp cht UGC5: ()-Zeylenone 63 4.2.1.4 Hp cht UGC6: ()-Zeylenol 67 4.2.1.5 Hp cht UGC8: ()-Pipoxide 70 4.2.1.6 Hp cht UGC9: Lupeol 72 4.2.1.7 Hp cht UGW1: Sakurasosaponin 73 4.2.1.8 Hp cht UGW2: Ardisiacrispin B 77 4.2.1.9 Hp cht UGLW1: (Z)-3-Hexenyl-1-O--D-glucopyranoside 81 4.2.1.10 Hp cht UGLW3 (cht mi): Grandionoside A 83 4.2.2 Cỏc hp cht c phõn lp t loi Bự d lỏ ln 93 4.2.2.1 Hp cht UCC5 (cht mi): Cordauvarin A 93 4.2.2.2 Hp cht UCC6: Cyathoviridine 101 4.2.2.3 Hp cht UCC10: -Sitosterol palmitate 103 4.2.2.4 Hp cht UCC11: ()-Spathulenol 105 4.2.2.5 Hp cht UCC12: 5,6-Epoxyalnusane-3-ol 107 4.2.2.6 Hp cht UCE3BII: Glutin-5-en-3-ol 109 4.2.2.7 Hp cht UCE4BI: Taraxerol 110 4.2.2.8 Hp cht UCE8: Velutinam 112 4.2.2.9 Hp cht UCE9: Aristolactam A Ia 114 4.2.3 Cỏc hp cht c phõn lp t loi Bự d rõu 115 4.2.3.1 Hp cht UFC1: 5-Glutinen-3-one 115 4.2.3.2 Hp cht UFC3B1: (22E,24R)-Ergosta-4,6,8(14),22-tetraen-3one 117 4.2.3.3 Hp cht UFE3A: Oxoanolobine 119 4.2.3.4 Hp cht UFE4A: Daucosterol 121 4.2.3.5 Hp cht UFE5B (cht mi): Ufaside 122 4.2.3.6 Hp cht UFE7A: Catechin 131 ii 4.3 ỏnh giỏ hot tớnh gõy c t bo in vitro ca cỏc hp cht c phõn lp t loi Bự d tớa, Bự d lỏ ln v Bự d rõu 134 4.3.1 Hot tớnh gõy c t bo in vitro ca cỏc hp cht trờn dũng t bo ung th LU-1 134 4.3.2 Hot tớnh gõy c t bo in vitro ca cỏc hp cht UGLE1 v UGW2 trờn cỏc dũng t bo khỏc 135 KT LUN 138 KIN NGH 140 DANH MC CC CễNG TRèNH CễNG B 141 TI LIU THAM KHO 142 PH LC iii DANH MC CC Kí HIU V CH VIT TT Cỏc phng phỏp sc ký CC Column Chromatography HPLC High Performance Liquid Chromatography TLC Thin Layer Chromatography Cỏc phng phỏp ph H-NMR Proton Nuclear Magnetic Resonance Spectroscopy 13 C-NMR Carbon-13 Nuclear Magnetic Resonance Spectroscopy APCI-MS Atmospheric Pressure Chemical Ionization Mass Spectrometry CD Circular Dichroism Spectroscopy COSY Correlation Spectroscopy Sc ký ct thng Sc ký lng hiu nng cao Sc ký bn mng DEPT Ph cng hng t ht nhõn proton Ph cng hng t ht nhõn carbon 13 Ph ion húa húa hc ỏp sut khớ quyn Ph nh sc trũn Ph tng tỏc hai chiu H-1H Ph DEPT NOESY Ph ion húa phun mự in t Ph tng tỏc d ht nhõn qua nhiu liờn kt Ph phõn gii cao ion húa phun mự in t Ph tng tỏc d ht nhõn qua mt liờn kt Ph hng ngoi Hng s tng tỏc tớnh bng Hz Ph NOESY Distortionless Enhancement by Polarisation Transfer ESI-MS Electron Spray Ionization Mass Spectrometry HMBC Heteronuclear Multiple Bond Correlation HR-ESI-MS High Resolution - Electron Spray Ionization - Mass Spectrometry HSQC Heteronuclear Single Quantum Coherence IR Infrared Spectroscopy J (Hz) UV (ppm) s d t singlet doublet triplet Nuclear Overhauser Effect Spectroscopy Ultraviolet Spectroscopy (ppm = part per million) q quint dd quartet quintet double doublet iv Ph t ngoi dch chuyn húa hc tớnh bng phn triu dt double triplet br broad m multiplet Cỏc dũng t bo 3T3, TIG-3 Normal cell A2058 Human caucasian metastatic melanoma A2780 Human ovarian cancer A549 Human bronchogenic carcinoma Bel-7402 Human hepatoma BGC Human gastrocarcinoma H522 Human bronchogenic carcinoma HCT-8 Human colon carcinoma HeLa Human cervical adenocarcinoma Hep-G2 Human hepatocellular carcinoma HL-60 Human promyelocytic leukemia Hs683 Human glioblastoma HT29 Human colon carcinoma HTC116 Human colon carcinoma K562 Chronic myelogenous leukemic KB Human epidermoid carcinoma KLM-1 Human pancreatic cancer LNCaP Human prostate adenocarcinoma LU-1 Human bronchogenic carcinoma MCF-7 Human breast adenocarcinoma MDA-MB-231 Metastatic human breast cancer MIA PaCa-2 Human pancreatic cancer MKN-7 Human gastrocarcinoma NCI-H446 Human bronchogenic carcinoma P-388 Lymphocytic leukemia PANC-1 Human pancreatic cancer PSN-1 Human pancreatic cancer SK-Mel-2 Human melanoma carcinoma SK-Mel-28 Human melanoma carcinoma SK-MES-1 Human bronchogenic carcinoma SW-480 Human colon adenocarcinoma T98G Human glioblastoma U251 Human glioblastoma v T bo thng Khi u hc t ỏc tớnh ngi da trng Ung th bung trng Ung th phi Ung th gan Ung th d dy Ung th phi Ung th rut kt Ung th c t cung Ung th gan Ung th mỏu cp tớnh Ung th nóo Ung th rut kt Ung th rut kt Ung th bch cu tu Ung th biu mụ Ung th tuyn tu Ung th tin lit tuyn Ung th phi Ung th vỳ Ung th vỳ Ung th tuyn tu Ung th d dy Ung th phi Ung th mỏu lympho Ung th tuyn tu Ung th tuyn tu Ung th da Ung th da Ung th phi Ung th rut kt Ung th nóo Ung th nóo Cỏc ký hiu vit tt khỏc AGEs Advanced Glycosylation End Products CTPT FI50 Feeding Index 50% GI50 IC50 IC90 IZD LC100 LD50 MBC MEC MIC Mp OD PC PC50 Growth Inhibition 50% Inhibitory Concentration 50% Inhibitory Concentration 90% Inhibition Zone Diameter Lethal Concentration 100 Lethal Dose 50 Minimum Bactericidal Concentration Minimum Effective Concentration Minimum Inhibitory Concentration Melting point Optical Density Polyoxygenated Cyclohexene Preferential Cytotoxic 50% Cỏc sn phm ca quỏ trỡnh glycat hoỏ Cụng thc phõn t Ch s c ch 50% sc n ca cụn trựng Nng c ch s phỏt trin 50% Nng c ch 50% Nng c ch 90% ng kớnh vũng khỏng khun Nng gõy cht 100% Liu c cp tớnh Nng dit khun ti thiu Nng nh hng ti thiu Nng c ch ti thiu im chy Mt quang a oxy húa ca cyclohexene Nng c ch 50% t bo mụi trng nuụi cy khụng dinh dng SI Selectivity Index chn lc, c tớnh bng t s IC50/MIC n-BuOH n-Butanol Ac Acetoxyl CHCl3 Chloroform Bz Benzoyl DMSO Dimethylsulfoxide OMe Methoxy EtOAc Ethyl acetate Ph Phenyl MeOH Methanol Et Ethyl SRB Sulforhodamine B Me Methyl TMS Tetramethylsilane THF Tetrahydrofuran WST-8 2-(2-Methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5- THP Tetrahydropyran (2,4-disulfophenyl)-2H-tetrazolium Ghi chỳ: Tờn cỏc hp cht, lp cht, nhúm th, chc húa hc c vit theo nguyờn bn Ting Anh m bo tớnh thng nht v chớnh xỏc vi [13] Alali, F Q., Liu, X X., and McLaughlin, J L (1999), Annonaceous acetogenins: Recent progress, J Nat Prod., 62, 504540 [14] Alfonso, D., Johnson, H A., Colman-Saizarbitoria, T., Presley, C P., McCabe, G P., and McLaughlin, J L (1996), SARs of annonaceous acetogenins in rat liver mitochondria, Nat 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Zhang, Y., Chen, R Y., and Yu, D Q (2008), Calamistrins H and I, two linear annonaceous acetogenins from the roots of Uvaria calamistrata Hance, Heterocycles, 75 (4), 933937 [194] Zhou, G X., Zhou, L E., Chen, R Y., and Yu, D Q (1999), Calamistrins A and B, two new cytotoxic monotetrahydrofuran annonaceous acetogenins from Uvaria calamistrata, J Nat Prod., 62, 261264 157 [...]... grandiflora, Uvaria cordata và Uvaria fauveliana ít được nghiên cứu về thành phần hóa học và hoạt tính sinh học ở trong nước cũng như trên thế giới Từ những l do trên, chúng tôi đề xuất đề tài: Nghiên cứu thành phần hóa học và hoạt tính sinh học của một số loài thuộc chi Uvaria L - họ Na (Annonaceae) Đề tài được thực hiện với hai mục tiêu: 1 Nghiên cứu để l m rõ thành phần hóa học chính của các loài U... chloroform và phân đoạn ethyl acetate của loài Bù dẻ l l n 42 Hình 3.4 Sơ đồ phân l p các chất từ phân đoạn chloroform và phân đoạn ethyl acetate của loài Bù dẻ râu 44 Hình 4.1 Cấu trúc hóa học của các hợp chất phân l p từ phần trên mặt đất của loài Bù dẻ tía 52 Hình 4.2 Cấu trúc hóa học của các hợp chất phân l p từ l cây Bù dẻ l l n 52 Hình 4.3 Cấu trúc hóa học của. .. 1992, một ketone có khung sesquiterpene 3 vòng, patchoulenone (250), được phân l p từ dịch chi t n-hexane của rễ loài U narum [49] Năm 1995, hai triterpenoid, glutinol (251) và taraxerol (252), được thông báo từ thành phần hoá học của loài U cordata [92], và một polyprenol l betulapren-11-ol (253) từ loài U narum [134] Năm 1997, Achenbach và cộng sự đã xác định được một carotenoid, lutein (254), từ loài. .. elliotiana l 3,6-bis(γ,γ-dimethylallyl)indole (56) [10] Năm 1984, một alkaloid mới khác l syncarpurea (57) từ loài U afzelii được công bố bởi Hufford và cộng sự [61] Cũng trong năm này, Waterman và Mohammad công bố 4 alkaloid mới, uvarindole AD (5861), từ loài U angolensis thu hái ở Tanzania [102, 172] 8 Năm 1987, Anisuzzaman tiếp tục nghiên cứu loài này và thu được thêm một alkaloid mới nữa l ... 1.2.2.2 L p chất alkaloid Alkaloid trong chi Uvaria thường tồn tại ở một số khung cơ bản như indole, quinoline, isoquinoline, aristolactam với hơn 40 hợp chất đã được phân l p và xác định cấu trúc Năm 1977, Panichpol và cộng sự công bố một hợp chất có khung bisbenzylisoquinolines mới l chondrofoline (55) từ loài U ovata [133] Năm 1979, Achenbach và Raffelsberger đã phân l p được một indole alkaloid từ loài. .. bởi Hollands và cộng sự [51] Tính đến nay, có hơn 30 loài thuộc chi Uvaria được nghiên cứu về thành phần hóa học ở các mức độ khác nhau với hơn 300 hợp chất đã được phân l p Các l p chất chính của chi này l acetogenin, alkaloid, flavonoid, dẫn xuất đa oxy hóa của cyclohexene Ngoài ra, các hợp chất terpenoid, steroid, pyrene cũng được tìm thấy trong chi này 6 1.2.2.1 L p chất acetogenin Acetogenin l ... grandiflora, U cordata và U fauveliana 2 Thử nghiệm hoạt tính sinh học của các phân đoạn và của hợp chất tách ra từ các loài trên để tìm kiếm các hoạt chất phục vụ cuộc sống 2 Chương 1 TỔNG QUAN TÀI LIỆU 1.1 Giới thiệu sơ l ợc về họ Na (Annonaceae) Trong số các họ thực vật bậc cao, họ Na thu hút sự quan tâm của nhiều nhà khoa học trên thế giới vì tiềm năng to l n của chúng trong nhiều l nh vực đời sống... biết l 2-hydroxy-3,4,6-trimethoxydihydrochalcone (160) và 5,7,8- trimethoxyflavone (161) [99] 1.2.2.4 L p chất đa oxy hóa cyclohexene L p chất đa oxy hóa cyclohexene (polyoxygenated cyclohexene - PC) l l p chất mới, thường gặp ở chi Piper (Piperaceae), chi Uvaria (Annonaceae) hay chi Croton (Euphorbiaceae) [135] Một số ít được tìm thấy ở chi Kaempferia (Zingiberaceae) [132] và chi Ellipeiopsis (Annonaceae). .. khoảng 120 chi và hơn 2000 loài, họ Na l họ thực vật l n được biết đến như nguồn cây ăn quả quan trọng Dầu từ hạt của một số loài thuộc họ này được sử dụng để sản xuất dầu ăn, xà phòng, gỗ được dùng để sản xuất rượu và hoa được sử dụng để chế các loại mỹ phẩm, nước hoa Nhiều loài thuộc họ Na còn được sử dụng trong y học cổ truyền để chữa các bệnh khác nhau [81] Trong hệ thực vật Việt Nam, họ Na l một trong... học của chi Uvaria ở trong nước còn rất ít và hầu như chỉ tập trung vào phần tinh dầu Năm 2010, Đỗ Ngọc Đài và cộng sự công bố thành phần hóa học của tinh dầu l chuối con chồng (U grandiflora) thu hái ở Hà Tĩnh Theo đó, thành phần chính của tinh dầu gồm bicyclogermacren (35,7%), -caryophyllen (13,9%) và (Z)--ocimen (10,7%) [4] Gần đây nhất, tinh dầu l và cành của loài U rufa và U cordata đã được nghiên ... L M KHOA HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ …………***………… HỒ VIỆT ĐỨC NGHIÊN CỨU THÀNH PHẦN HÓA HỌC VÀ HOẠT TÍNH SINH HỌC CỦA MỘT SỐ LOÀI THUỘC CHI UVARIA L - HỌ NA (ANNONACEAE). .. nữa, loài Uvaria grandiflora, Uvaria cordata Uvaria fauveliana nghiên cứu thành phần hóa học hoạt tính sinh học nước giới Từ l trên, đề xuất đề tài: Nghiên cứu thành phần hóa học hoạt tính sinh. .. sinh học số loài thuộc chi Uvaria L - họ Na (Annonaceae) Đề tài thực với hai mục tiêu: Nghiên cứu để l m rõ thành phần hóa học loài U grandiflora, U cordata U fauveliana Thử nghiệm hoạt tính sinh