Nghiên cứu tổng hợp và khảo sát hoạt tính sinh học của alphitonin, maesopsin và một số dẫn xuất của chúng

VIN HN LM KHOA HC V CễNG NGH VIT NAM HC VIN KHOA HC V CễNG NGH - DIP TH LAN PHNG NGHIấN CU TNG HP V KHO ST HOT TNH SINH HC CA ALPHITONIN, MAESOPSIN V MT S DN XUT CA CHNG LUN N TIN S HO HC H NI 2015 VIN HN LM KHOA HC V CễNG NGH VIT NAM HC VIN KHOA HC V CễNG NGH .*** DIP TH LAN PHNG NGHIấN CU TNG HP V KHO ST HOT TNH SINH HC CA ALPHITONIN, MAESOPSIN V MT S DN XUT CA CHNG LUN N TIN S HO HC Chuyờn ngnh: Húa Hu c Mó s: 62.44.01.14 NGI HNG DN KHOA HC: TS NGUYN QUC VNG PGS TS TRNH TH THY H NI - 2015 i LI CAM OAN Tụi xin cam oan õy l cụng trỡnh nghiờn cu ca riờng tụi di s hng dn khoa hc ca TS Nguyn Quc Vng v PGS.TS Trnh Th Thy Cỏc s liu v kt qu c nờu lun ỏn l trung thc v cha tng c cụng b bt k cụng trỡnh no khỏc Tỏc gi lun ỏn NCS Dip Th Lan Phng ii LI CM N Lun ỏn ny c hon thnh ti Vin Húa sinh bin Vin Hn lõm Khoa hc v Cụng ngh Vit Nam Kinh phớ thc hin t ti thuc Qu Nafosted, Mó s ti 104.01-010.10 (34- Húa) Trong quỏ trỡnh nghiờn cu, tỏc gi ó nhn c nhiu s giỳp quý bỏu ca thy cụ, cỏc nh khoa hc cng nh ng nghip, bn bố v gia ỡnh Trc ht, tụi xin trõn trng cm n nhúm nghiờn cu ca GS Trn Vn Sung ó phỏt hin, m hng nghiờn cu cho lun ỏn ny Tụi xin by t lũng bit n sõu sc nht, s cm phc v kớnh trng nht n TS Nguyn Quc Vng v PGS TS Trnh Th Thy nhng ngi thy ó tn tõm hng dn khoa hc, ng viờn, khớch l v to mi iu kin thun li nht cho tụi sut thi gian thc hin v hon thnh lun ỏn Tụi xin chõn thnh cm n Ban lónh o, hi ng khoa hc, phũng Qun lý tng hp Vin Húa sinh bin; Ban lónh o, phũng o to v Nghiờn cu khoa hc Hc vin Khoa hc v cụng ngh; th cỏn b, ging viờn Khoa Húa hc, Phũng T chc Cỏn b v Ban Giỏm hiu Trng i hc Quy Nhn ó to iu kin thun li v giỳp tụi sut thi gian thc hin lun ỏn Tụi xin trõn trng cm n th cỏn b phũng Cụng ngh Húa dc ó nhit tỡnh giỳp , ng viờn tụi hc cng nh quỏ trỡnh thc nghim hon thin lun ỏn Cui cựng, tụi xin by t lũng bit n chõn thnh v sõu sc n ton th gia ỡnh, bn bố v nhng ngi thõn, c bit l chng v hai gỏi yờu quý ó luụn quan tõm, khớch l v ng viờn tụi sut quỏ trỡnh hc tp, nghiờn cu v hon thnh lun ỏn Tụi xin trõn trng cm n! Tỏc gi lun ỏn Dip Th Lan Phng iii MC LC Trang LI CAM OAN i LI CM N ii MC LC iii DANH MC CC CH VIT TT DNG TRONG LUN N vii DANH MC CC BNG x DANH MC CC HèNH xi M U .1 CHNG TNG QUAN .3 1.1 Cỏc hp cht flavonoid 1.1.1 Hp cht flavonoid 1.1.2 Flavonoid glycoside 1.2 Hot tớnh sinh hc ca aurone v auronol 1.2.1 Aurone húa hc tr liu ung th 1.2.1.1 Aurone nh l cht iu chnh s khỏng a thuc qua protein Pgp 1.2.1.2 S c ch ca Cyclin-Dependent Kinases (CDK) .8 1.2.1.3 Tng tỏc ca cỏc aurone vi th th adenosine .9 1.2.1.4 Aurone chng ung th thụng qua s phõn chia DNA 10 1.2.1.5 Aurone c ch hỡnh thnh mch mỏu u 11 1.2.1.6 Aurone nh nhng tỏc nhõn chng oxi húa .12 1.2.2 Aurone v auronol khỏng kớ sinh trựng 13 1.2.3 Aurone v auronol nh tỏc nhõn khỏng khun, khỏng nm, khỏng viờm 14 1.2.4 Aurone nh tỏc nhõn chng virus .16 1.2.5 Aurone iu tr bnh v da 17 1.2.6 Aurone iu tr bnh tiu ng 18 1.2.7 H dch v nh hng ca thc vt i vi h dch 18 1.3 Tng hp aurone 19 1.3.1 Gii thiu aurone .19 iv 1.3.2 C s phng phỏp tng hp aurone 20 1.3.2.1 Phn ng Houben - Hoesch .20 1.3.2.2 Phn ng theo Friedel - Crafts 21 1.3.2.3 Phn ng ngng t Claisen - Schmidt .21 1.3.3 Tng hp aurone t benzofuranone 22 1.3.3.1 Tng hp tin cht benzofuranone 22 1.3.3.2 Cỏc phng phỏp tng hp aurone t benzofuranone .25 1.3.4 Tng hp aurone t chalcone 30 1.3.4.1 Tng hp tin cht chalcone 30 1.3.4.2 Cỏc phng phỏp tng hp aurone t chalcone 32 1.4 Tng hp auronol 33 1.4.1 Phng phỏp tng hp auronol theo I.G Sweeny 33 1.4.2 Phng phỏp tng hp auronol theo Kiehlmann and Li 34 1.4.3 Phng phỏp tng hp auronol theo Reik Lửser 34 1.4.4 Phng phỏp tng hp auronol theo Srikrishna v Mathews 35 1.4.5 Phng phỏp bỏn tng hp auronol theo GS Trn Vn Sung 35 1.5 Cỏc phng phỏp tng hp glycoside 36 1.5.1 Gii thiu chung v glycoside 36 1.5.2 Mt s phng phỏp tng hp O-glucoside .37 1.5.2.1 Phn ng Michael 37 1.5.2.2 Phn ng Fischer 37 1.5.2.3 Phn ng Koenigs-Knorr 38 1.6 Hp cht cha nitrile húa dc v phng phỏp tng hp dn xut nitrile .39 CHNG I TNG, MC TIấU V PHNG PHP NGHIấN CU 41 2.1 i tng nghiờn cu 41 2.2 Mc tiờu 41 2.3 Phng phỏp nghiờn cu 41 2.3.1 Phng phỏp phõn lp cỏc hp cht 41 v 2.3.2 Phng phỏp tng hp v tinh ch sn phm 42 2.3.3 Phng phỏp xỏc nh cu trỳc húa hc 43 2.3.4 Kho sỏt hot tớnh c ch dch v hot tớnh c t bo ca cỏc cht tng hp c .43 2.3.4.1 Hot tớnh kớch thớch t bo lympo 43 2.3.4.2 Hot tớnh c t bo 44 CHNG THC NGHIM 46 3.1 Phõn lp v tng hp cỏc auronol v auronol glucoside 46 3.1.1 Phõn lp cỏc auronol glucoside t lỏ cõy Chay Bc B (A tonkinensis) v iu ch maesopsin .46 3.1.1.1 Phõn lp maesopsin 4-O--D-glucopyranoside (TAT2); alphitonin4-O--D-glucopyranoside (TAT6) .46 3.1.1.2 iu ch maesopsin 48 3.1.2 Bỏn tng hp alphitonin 49 3.1.2.1 Phõn lp astilbin t r Th phc linh (Smilax glabra Wall ex Roxb.) .50 3.1.2.2 Thy phõn astilbin iu ch taxifolin 52 3.1.2.3 Phn ng ng phõn húa taxifolin tng hp alphitonin 53 3.1.3 Tng hp ton phn cỏc auronol alphitonin v maesopsin .54 3.1.3.1 Tng hp cỏc aurone 56 3.1.3.2 Tng hp auronol t aurone 61 3.1.4 Tng hp auronol glucoside alphitonin-4-O--D-glucopyranoside (125)65 3.1.5 Tng hp cỏc dn xut nitrile ca auronol maesopsin, alphitonin v maesopsin-4-O--D-glucopyranoside 67 3.1.5.1 Tng hp cỏc auronol mang mt nhúm th nitrile (cht 126 v 127) .68 3.1.5.2 Tng hp cỏc auronol mang hai nhúm th nitrile (cht 128 v 129) .69 3.1.5.3 Tng hp auronol glucoside mang nhúm th nitrile (cht 130) 71 vi 3.2 Kho sỏt hot tớnh sinh hc ca cỏc cht tng hp c .71 3.2.1 Hot tớnh kớch thớch lympho bo .71 3.2.2 Hot tớnh c t bo 73 CHNG KT QU V THO LUN 75 4.1 Phõn lp v tng hp cỏc auronol v auronol glucoside 75 4.1.1 Hai hp cht auronol glucoside maesopsin-4-O--D-glucopyranoside (116) v alphitonin-4-O--D-glucopyranoside (125) 75 4.1.1.1 iu ch auronol maesopsin (98) 83 4.1.2 Bỏn tng hp auronol alphitonin (82) .86 4.1.2.1 Kt qu kho sỏt hm lng astilbin r th phc linh 86 4.1.2.2 Quy trỡnh phõn lp astilbin t r Th phc linh .87 4.1.2.3 iu ch taxifolin t astilbin 89 4.1.2.4 Phn ng ng phõn húa taxifolin tng hp alphitonin 91 4.1.3 Nghiờn cu phng phỏp tng hp ton phn ca cỏc auronol 97 4.1.3.1 Nghiờn cu phng phỏp tng hp cỏc aurone .97 4.1.3.2 Nghiờn cu tng hp cỏc auronol t aurone 112 4.1.4 Tng hp auronol glucoside alphitonin-4-O--D-glucopyranoside .126 4.1.5 Tng hp mt s dn xut nitrile ca auronol 82 v 98 131 4.1.6 Tng hp dn xut nitrile ca auronol glucoside 116 .144 4.2 Hot tớnh sinh hc ca cỏc hp cht tng hp c 148 4.2.1 Hot tớnh kớch thớch t bo lympho 150 4.2.2 Hot tớnh c t bo 151 KT LUN V KIN NGH .154 CC CễNG TRèNH CễNG B LIấN QUAN N LUN N 156 TI LIU THAM KHO .157 vii DANH MC CC CH VIT TT DNG TRONG LUN N Vit tt Vit y ABCG2 ATP binding cassette sub-family G member Ac Nhúm acetyl AIDS Acquired immunodeficiency syndrome Ag-TAT2 Maesopsin Ag-TAT6 Alphitonin ATP Adenosin triphosphat Bn Nhúm benzyl n-Bu Nhúm n-butyl t-Bu Nhúm tert-butyl CC Column chromatography (Sc ký ct) CDK Cyclin-dependent kinases CL Cutaneous leishmaniasis COSY Correlated Spectroscopy m-CPBA m-Chloroperbenzoic acid DCM Diclometan DEPT Distortionless Enhancement by Polarisation Transfer (ph DEPT) DME Dimethoxyethane DMF N,N-Dimethylformamit DNA Deoxyribonucleic acid DPPH 1,1-diphenyl-2-picryl-hydrazyl EC50 Effective concentration 50% (nng cú hiu qu 50%) ESI-MS Electrospray Ionization Mass Spectrometry (Ph lng phun mự in t ) Et Nhúm ethyl FDA Food and Drug Administration (Cc qun lý thc phm v dc phm Hoa K) viii HCV Hepatitis C virus (virus viờm gan C) Hep G2 Human hepatocellular carcinoma cell line (dũng t bo ung th gan) HIV Human immunodeficiency virus HMBC Heteronuclear Multiple Bond Correlation HPLC High Performance Liquid Chromatography HSQC Heteronuclear Single Quantum Coherence IC50 Imhibitory Concentration 50% (nng c ch 50%) IR Infrared spectroscopy (ph hng ngoi) K562 Chronic myelogenous leukemic cell line (dũng t bo ung th mỏu cp) KB Human epidemoid carcinoma cell line (dũng t bo ung th biu mụ) LDA Lithium diisopropylamide LPS Lipopolysaccharide LU Lung carcinoma cell lines (dũng t bo ung th phi) MCF-7 Human breast adenocarcinoma cell line (dũng t bo 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[...]... hoạt tính sinh học của alphitonin, maesopsin và một số dẫn xuất của chúng Các nhiệm vụ của luận án: - Phân lập 2 hợp chất alphitonin-4-O-β-D-glucoside (TAT6) và maesopsin- 4O-β-D-glucoside (TAT2) từ lá cây Chay Bắc bộ (Artocapus tonkinensis A Chev.) - Nghiên cứu tổng hợp các auronol là alphitonin và maesopsin và một số dẫn xuất nitrile của chúng - Nghiên cứu phản ứng glucoside hóa tổng hợp alphitonin-4-O-β-Dglucoside... protein và H2O nên nó cũng có khả năng thấm qua màng tế bào; trong một số trường hợp, nhóm nitrile cũng có tác dụng thay thế phần đường trong các phân tử glucoside [7, 8, 9, 10] Nhằm tìm kiếm các hợp chất có hoạt tính đối với hệ miễn dịch, từ phát hiện mở đường của 2 auronol glucoside và tính chất của các hợp chất mang nhóm nitrile chúng tôi chọn đề tài: Nghiên cứu tổng hợp và khảo sát hoạt tính sinh học. .. học của aurone và auronol Các hợp chất aurone và auronol thuộc nhóm flavonoid, trong đó auronol là chất hiếm gặp trong tự nhiên và ít được nghiên cứu Tuy nhiên cũng tìm thấy được hoạt tính sinh học đa dạng của chúng như chống ung thư, chống virus, chống viêm, chống oxy hóa, trị bệnh tiểu đường, các bệnh về da, kháng nấm, kháng khuẩn Sau đây, chúng ta xem xét một số hoạt tính sinh học của chúng: 1.2.1... Hình 1.22 Sơ đồ tổng hợp các hợp chất 18, 19, 20 là sản phẩm O-alkyl hóa 5b 23 Hình 1.23 Sơ đồ tổng hợp hợp chất 23 theo Hamid Nadri 23 Hình 1.24 Sơ đồ tổng hợp hợp chất 28 theo Walter M.B 24 Hình 1.25 Sơ đồ tổng hợp hợp chất 31 và 34 24 Hình 1.26 Các con đường tổng hợp aurone qua ngưng tụ giữa benzofuranone và benzaldehyde .25 xii Hình 1.27 Sơ đồ tổng hợp một số hydroxyaurone... đồ tổng hợp aureusidin theo Anastasia Detsi 32 Hình 1.41 Sơ đồ tổng hợp aurone từ chalcone sử dụng TTN/ MeOH .32 Hình 1.42 Sơ đồ tổng hợp aurone theo Gopal Bose .33 Hình 1.43 Sơ đồ tổng hợp auronol của I G Sweeny 34 Hình 1.44 Sơ đồ tổng hợp auronol của Kiehlmann and Li 34 Hình 1.45 Sơ đồ tổng hợp auronol của Reik Löser 35 Hình 1.46 Sơ đồ tổng hợp auronol theo Srikrishna và. .. - Khảo sát hoạt tính kích thích tế bào lympho và hoạt tính độc tế bào của các sản phẩm tổng hợp được 3 CHƯƠNG 1 TỔNG QUAN 1.1 Các hợp chất flavonoid 1.1.1 Hợp chất flavonoid Flavonoid (hoặc bioflavonoid) (bắt nguồn từ Latin flavus nghĩa là màu vàng, màu của flavonoid trong tự nhiên) là nhóm hợp chất phenolic đa vòng, được tìm thấy rộng rãi trong thực vật, chúng là loại chất chuyển hóa trung gian của. .. hưởng của nhiệt độ 93 Bảng 4.5 Ảnh hưởng của dung môi 93 Bảng 4.6 Ảnh hưởng của thời gian 93 Bảng 4.7 Khảo sát độ ổn định của phản ứng 94 Bảng 4.8 Khảo sát các xúc tác dùng cho phản ứng glucosylation alphitonin 127 Bảng 4.9 Nghiên cứu các điều kiện ảnh hưởng đến hiệu suất phản ứng tổng hợp dẫn xuất nitrile một nhóm thế của hai auronol 82 và 98 133 Bảng 4.10 Nghiên. .. 29 Hình 1.34 Sơ đồ tổng hợp các dẫn xuất aurone theo Hai Chen .30 Hình 1.35 Sơ đồ tổng hợp các dẫn xuất aurone theo Suresh Kumar .30 Hình 1.36 Cơ chế tổng hợp chalcone theo phương pháp thông thường 30 Hình 1.37 Dạng anion delocalized của hợp phần benzaldehyde .31 Hình 1.38 Sơ đồ tổng hợp dẫn xuất chalcone thế 4-hydroxy theo M.R.Jayapal .31 Hình 1.39 Sơ đồ tổng hợp chalcone 71 theo Xiaoming... và 98 133 Bảng 4.10 Nghiên cứu các điều kiện ảnh hưởng đến hiệu suất phản ứng tổng hợp dẫn xuất nitrile hai nhóm thế của hai auronol 82 và 98 139 Bảng 4.11 Danh sách ký hiệu, tên và cấu tạo hóa học của các mẫu thử 149 Bảng 4.12 Hoạt tính kích thích tế bào lympho của các mẫu thử 151 Bảng 4.13 Hoạt tính độc tế bào của các mẫu thử trên tế bào thường NIH/3T3 và 4 dòng tế bào ung thư MCF7,... đồ tổng hợp 6,7-dihydroxyaurone theo S Venkateswarlu 26 Hình 1.29 Sơ đồ tổng hợp dẫn xuất dimethoxyaurone theo C Beney 27 Hình 1.30 Sơ đồ tổng hợp dẫn xuất trimethoxyaurone theo Nicholas J Lawrence 28 Hình 1.31 Sơ đồ tổng hợp aureusidin theo David Bolek 28 Hình 1.32 Sơ đồ tổng hợp aureusidin theo Zhao X 29 Hình 1.33 Sơ đồ tổng hợp aureusidin theo Jun Nishida 29 Hình 1.34 Sơ đồ tổng ... HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ …… ….***………… DIỆP THỊ LAN PHƯƠNG NGHIÊN CỨU TỔNG HỢP VÀ KHẢO SÁT HOẠT TÍNH SINH HỌC CỦA ALPHITONIN, MAESOPSIN VÀ MỘT SỐ DẪN XUẤT CỦA CHÚNG... chọn đề tài: Nghiên cứu tổng hợp khảo sát hoạt tính sinh học alphitonin, maesopsin số dẫn xuất chúng Các nhiệm vụ luận án: - Phân lập hợp chất alphitonin-4-O-β-D-glucoside (TAT6) maesopsin- 4O-β-D-glucoside... tonkinensis A Chev.) - Nghiên cứu tổng hợp auronol alphitonin maesopsin số dẫn xuất nitrile chúng - Nghiên cứu phản ứng glucoside hóa tổng hợp alphitonin-4-O-β-Dglucoside - Khảo sát hoạt tính kích thích