Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)Nghiên cứu thành phần hóa học và hoạt tính sinh học của củ rễ cây Mạch môn (Ophiopogon japonicus (L.f.) KerGawl.)
i B GIÁO D O VI N HÀN LÂM KHOA H C VÀ CÔNG NGH VI T NAM H C VI N KHOA H C VÀ CÔNG NGH Nguy NGHIÊN C U THÀNH PH N HỐ H C VÀ HO T TÍNH SINH H C C A R C CÂY M CH MÔN (OPHIOPOGON JAPONICUS (L.f.) KER-GAWL.) LU N ÁN TI N S HÓA H C Hà N i 2018 ii B GIÁO D O VI N HÀN LÂM KHOA H C VÀ CÔNG NGH VI T NAM H C VI N KHOA H C VÀ CÔNG NGH Nguy NGHIÊN C U THÀNH PH N HOÁ H C VÀ HO T TÍNH SINH H C C A R C CÂY M CH MÔN (OPHIOPOGON JAPONICUS (L.f.) KER-GAWL.) Chuyên ngành: Hóa h Mã s : 62.44.01.14 LU N ÁN TI N S HÓA H C NG D N KHOA H C: PGS TS Nguy n Ti TS Nguy Hà N i 2018 t i L uc Nguy n Ti is ng d n c a PGS TS t TS Nguy Các s li u k t qu lu n án hoàn tồn trung th c cơng b b t k cơng trình khác Hà N Tác gi lu n án Nguy ii L IC Lu c hoàn thành t i Vi n Hoá sinh bi n, Vi n Hàn lâm Khoa h c Công ngh Vi t Nam V i lòng bi c, tơi xin bày t lòng bi t TS Nguy ch b o t o m i PGS TS Nguy n Ti n i th u ki ng d n, h t lòng tơi th i gian làm lu n án Tôi xin trân tr ng c b c a Vi o Vi n Hóa sinh bi n t p th cán om u ki n thu n l i cho tơi su t q trình h c t p nghiên c u th c hi n lu n án Tôi xin chân thành c - Vi n Hóa Sinh bi Ho t ch t sinh h c bi t TS Nguy n ThS Ph m Thanh Bình c ng s c li u bi n o, TS Nguy n H u ki , có nh ng l i khun b ích nh ng góp ý quý báu vi c th c hi n hồn thi n lu n án Tơi xin bày t lòng bi b n bè nh c nh t t i tồn th quan tâm, khích l ng viên tơi su t q trình h c t p nghiên c u Xin trân tr ng c Tác gi Nguy iii M CL C Trang ph bìa L i L ic ii M cl c iii Danh m c ch vi t t t vi Danh m c b ng ix Danh m c hình x M U NG QUAN 1.1 Gi i thi u v chi Ophiopogon 1.2 Gi i thi u v M ch môn 1.2.1 Vài nét v th c v t h c 1.2.2 Cơng d ng tính v 1.2.2.1 T i Vi t Nam 1.2.2.2 Trên th gi i 1.2.3 Các nghiên c u v thành ph n hóa h c ho t tính sinh h c c a M ch mơn 1.2.3.1 Thành ph n hóa h c 1.2.3.2 Ho t tính sinh h c 18 U 2.1 2.2 2.3 2.4 26 26 ng nghiên c u 26 u nh c u trúc hóa h c h p ch t t tính sinh h c 27 29 iv 2.4.1 c t bào 2.4.2 s n sinh NO 29 31 C NGHI M VÀ 34 34 3.1 Chi t phân l p h p ch t 3.2 H ng s v t lý d ki n ph c a h p ch TH O LU N 4.1 nh c u trúc h p ch t phân l c nh c u trúc nhóm ch t benzofuran p 39 45 45 47 4.1.1.1 H p ch t OJ-1 47 4.1.1.2 H p ch t OJ-2 53 4.1.1.3 H p ch t OJ-3 58 4.1.1.4 H p ch t OJ-4 62 4.1.1.5 H p ch t OJ-5 68 4.1.2 nh c u trúc nhóm ch t homoisoflavonoid 72 4.1.2.1 H p ch t OJ-6 72 4.1.2.2 H p ch t OJ-7 77 4.1.2.3 H p ch t OJ-8 82 4.1.2.4 H p ch t OJ-9 87 4.1.3 nh c u trúc nhóm ch t flavonoid 92 4.1.3.1 H p ch t OJ-10 92 4.1.3.2 H p ch t OJ-11 97 4.1.4 nh c u trúc nhóm ch t eudesmane sesquiterpenoid 97 4.1.4.1 H p ch t OJ-12 99 4.1.4.2 H p ch t OJ-13 104 4.1.4.3 H p ch t OJ-14 107 v 4.1.5 nh c u trúc h p ch t khác 110 4.1.5.1 H p ch t OJ-15 4.2 4.2.1 Ho t tính sinh h c c a h p ch t phân l c t bào 4.2.2 Ho t tính c ch s n sinh NO K T LU N VÀ KI N NGH 110 c 116 116 119 121 123 124 vi DANH M C CH Human A549 lung adenocarcinoma epithelial cell line BEL-7402 Human hepatoma cell line CC Column Chromatography 13 Carbon-13 C NMR CH2Cl2 Nuclear DMEM Magnetic Resonance Spectroscopy cacbon 13 dichloromethan Diclometan Distortionless DEPT VI T T T Enhancement by Polarisation Transfer Medium DMEM DMSO Dimethylsulfoside Dimethylsulfoside EC100 Effective concentration 100% EC50 Effective concentration 50% ED50 Effective dose 50% Epidermal EGFR ESI-MS 1 H- H COSY Hela mô Electronspray Ionization Mas ù Spectrum Magnetic Resonance Spectroscopy 1 Factor T Receptor Proton H NMR Growth H-1H Chemical Correlation Spectroscopy Hela human cervix cell line proton Shift vii Hep-3B Hep-G2 Human hepatoma cell line Human hepatocellular carcinoma cell line Heteronuclear HMBC HSQC Bond Connectivity High HR-TOF-MS Multiple Resolution Time of-Flight Mass Spectrometer Heteronuclear Single Quantum Coherence IC50 Inhibitory concentration 50% IR Infrared Spectroscopy IUPAC KB International Union of Human epidemoid carcinoma cell line Lipopolysaccharide LU Lung carcinoma cell lines MeOH Methanol Mp MTT Lipopolysacaride Human breast adenocarcinoma cell line Minimal MIC Pure and Applied Chemistry LPS MCF-7 gian bay ú inhibitory concentration Melting Point [3-(4,5-dimethylthiazol-2- [3-(4,5-dimetylthiazol-2-yl)2,5- yl)2,5-diphenyltetrazolium diphenyltetrazoli bromua] viii bromide] NSCLC Non-small cell lung cancer U i t bào không nh SK-MEL-2 Human melanoma cell line TKI Tyrosine kinase inhibitor yrosine kinase TLC Thin layer chromatography ng TMS Tetrametyl Silan s Tetrametyl Silan 120 OJ-2 50 = 29,1 µ ( c bi m ) 2,3- t h p ch t có tác d ng kháng viêm c ch ng minh th hi n r ng h p ch t có khung 2,3nh th nghi m in vivo dihydrobenzofuran-2-one có kh Các h p ch t có khung 5-chloro-6-cyclohexyl-2,3-dihydrobenzofuran-2-one có ý c ch m nh i ch t tham kh o diclofenac t t c thí nghi m [100] tomentosa c phân l p t h t Prunus p ch c th nghi c k t qu dòng t bào BV-2 [101] T k t qu nghiên c c ch m nh s s n sinh NO r ng, nhóm ch t dihydrobenzofuran t r c M ch môn m t ngu n kháng viêm t t nhiên r t ti c nghiên c u sâu công nghi p s n xu tìm ngu n kháng viêm m i c ph m Hai h p ch t thu c nhóm homoisoflavonoid homoisopogon A (OJ-6) homoisopogon B (OJ-7 22,5 19,3 M n hi n tác d ng c ch s n sinh NO v i giá tr IC50 ng Các h p ch th nghi m l n nh t 30 M u không th hi n tác d ng 121 K T LU N VÀ KI N NGH V nghiên c u thành ph n hóa h c T r c M ch môn (O japonicus), 15 h p ch t ã g m 09 h p ch t m i, 02 h p ch t l h p ch c phân l p bao c phân l p t thiên nhiên 04 t Các h p ch t thu c nhóm ch t benzofuran (05 ch t), homoisoflavonoid (04 ch t), flavonoid (02 ch t), eudesmane sesquiterpenoid (03 ch t) steroidal glycoside (01 ch t) C u trúc hóa h c c a nh : Nhóm ch t benzofuran: (2R)-(4-methoxybenzyl)-5,7-dimethyl-6-hydroxyl2,3-dihydrobenzofuran (OJ-1, ch t m i), 2-(2-hydroxyl-4-methoxy-benzyl)-5methyl-6-methoxyl-2,3-dihydrobenzofuran (OJ-2, ch t m i), 2-(4-hydroxy- benzyl)-5,6-dihydroxylbenzofuran (OJ-3, ch t m i), 2-(4-methoxy-benzyl)-6,7dimethoxyl-2,3-dihydrobenzofuran (OJ-4, ch t m i l u phân l p t thiên nhiên) 2-(4-methoxy-benzyl)-6,7-methylenedioxy-2,3-dihydrobenzofuran (OJ-5, ch t m i l u phân l p t thiên nhiên) Nhóm ch t homoisoflavonoid: homoisopogon A (OJ-6, ch t m i), homoisopogon B (OJ-7, ch t m i), homoisopogon C (OJ-8, ch t m i) homoisopogon D (OJ-9, ch t m i) Nhóm ch t flavonoid: 8-C-methyl-3',5,5',7-tetrahydroxy- -dimethoxy flavone (OJ-10, ch t m i) myricetin 3,4'-dimethyl ether (3',5,5',7-tetrahydroxy3,4'-dimethoxyflavone) (OJ-11) Nhóm ch t eudesmane sesquiterpenoid: ,4 ,6 -trihydroxy-5,10-bis-epieudesmane-6-O- -D-glucopyranoside (OJ-12), ,6 -dihydroxy-5,10-bis-epi- eudesm -4(15)-ene-6-O- -D-glucopyranoside (OJ-13) ,6 -dihydroxy-5,10-bisepi-eudesm-3-ene-6-O- -D-glucopyranoside (OJ-14) Nhóm ch t steroidal glycoside: (25R)-ruscogenin 1-O-(4-O-sulfo)- -Dfucopyranoside (OJ-15, ch t m i) Các h p ch t có khung 2-benzylbenzofuran r t hi m g 2-benzyl-2,3-dihydrobenzofuran h n xu t c phân l p t thiên nhiên Lu n 122 c c u trúc hoá h c c a 05 h p ch t thu c nhóm ch t Cùng v i h p ch t m i thu c nhóm ch t nh ng m i n i b t c a lu m li u hoá h c h p ch t thiên nhiên V nghiên c u ho t tính sinh h c c t bào in vitro c a h p ch t phân l p o sát ho c dòng t i kháng thu c (A549), bi u mô (KB) c t ph i (LU-1), ung (SK-Mel-2) K t qu cho th y h p ch t homoisopogon A (OJ-6) có ho t tính r t m nh dòng t bào th nghi m (LU-1, KB SK-Mel-2) v i giá tr IC50 t 0,51 n 0,66 µM, so sánh v i ch i ch ng ellipticine H p ch t (2R)-(4-methoxybenzyl)-5,7-dimethyl-6-hydroxyl-2,3dihydro benzofuran (OJ-1) có tác d ng m nh v i giá tr IC50 t 8,86 i v i dòng t i kháng thu c (A549), homoisopogon A (OJ-6) th hi n tác d ng m nh so v th hi n tác d ng gây ch t t n n 14,0 µM i ch camptothecin H p ch t A549 gây ch t th nghi m 25 50 M t tính kháng viêm d a ng c ch s s n sinh NO c a 15 h p ch t nhóm OJ-1 µ 50 OJ-2 29,1 µM H = 11,4 50 = homoisoflavonoid homoisopogon A (OJ-6) homoisopogon B (OJ-7 hi n tác d ng c ch s n sinh NO v i giá tr IC50 22,5 19,3 M u v M ch môn (O japonicus), Ki n ngh h p ch t phân l p th hi n ho r t nhi u ti c viêm ct t tính kháng viêm c bi t h p ch t homoisopogon A (OJ-6) c ho t tính sinh h c theo tác d ng gây ch t t c nghiên 123 DANH M C CƠNG TRÌNH CƠNG B C A TÁC GI N LU N ÁN Nguyen Dinh Chung, Nguyen Phuong Thao, Ha Manh Tuan, Nguyen Van Thanh, Nguyen Hai Dang, Nguyen Tien Dat New steroidal glycoside and flavonoid constituents from Ophiopogon japonicus Nat Prod Commun., 2017, 12(6), 905 906 Nguyen 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LÂM KHOA H C VÀ CÔNG NGH VI T NAM H C VI N KHOA H C VÀ CÔNG NGH Nguy NGHIÊN C U THÀNH PH N HỐ H C VÀ HO T TÍNH SINH H C C A R C CÂY M CH MÔN (OPHIOPOGON JAPONICUS (L.f.) KER-GAWL.)... M ch môn 1.2.1 Vài nét v th c v t h c 1.2.2 Cơng d ng tính v 1.2.2.1 T i Vi t Nam 1.2.2.2 Trên th gi i 1.2.3 Các nghiên c u v thành ph n hóa h c ho t tính sinh h c c a M ch môn 1.2.3.1 Thành. .. làm lu n án Tôi xin trân tr ng c b c a Vi o Vi n Hóa sinh bi n t p th cán om u ki n thu n l i cho tơi su t q trình h c t p nghiên c u th c hi n lu n án Tôi xin chân thành c - Vi n Hóa Sinh bi