1、 國立臺灣師範大學學術研究計畫補助 心血管及相關疾病新藥物分子之開發研究 ORD 94-2 (ORD 93-C) 總主持人： 許順吉 教授 (化學系) 分項計畫主持人： 姚清發 教授 (化學系) 陳焜銘 教授 (化學系) 呂國棟 副教授 (生命科學系)具生物活性分子的分離、合成及其生物活性測試離體及活體實驗丹皮與赤芍可涼血活血，丹皮偏於清心，赤芍偏於涼肝，丹皮與赤芍可涼血活血，丹皮偏於清心，赤芍偏於涼肝，合用可使血流暢而不留瘀，可治高血壓兼防治血栓形成。合用可使血流暢而不留瘀，可治高血壓兼防治血栓形成。OOHOOOHOHOHOOOOHOOOH中藥成份分離分析 芍藥粉碎後甲醇萃取兩次濃縮深棕色稠
2、狀物甲醇層正己烷層MeOH/n-Hexane partitionDiation HP-20 column chromatography (20 cm * 6.5 cm I.D.)acetone frF100% MeOH frE60% MeOH frD frC frB20% MeOH40% MeOH100% H2O frA濃縮 橙色稠狀物Sephadex LH-20 column MeOH 前段配糖體大分子Silica column chromatography (MeOH/CHCl3=1/7-1/6)TLC (MeOH/CHCl3=1/5) 收集Rf=0.32TLC (MeOH/CHCl3=1
3、/4) PF赤芍AU0.000.020.040.060.080.100.120.140.160.18nm200.00250.00300.00350.00195.7232.1273.4381.6230nmPF牡丹皮粉碎後以n-Hexane浸泡n-Hexane萃取物過濾過濾液固體減壓濃縮濃縮液靜置上層油狀液體結晶物用少量n-Hexane沖洗n-Hexane沖洗液再結晶PN丹皮AU0.0000.0100.0200.0300.0400.0500.0600.0700.0800.0900.100nm200.00250.00300.00350.00193.4230.9275.8335.2369.6AU0.0
4、00.020.040.060.080.100.120.140.160.180.200.220.240.260.280.30nm200.00250.00300.00350.00210.9274.6313.8230nmPaeonol (PN)及paeoniflorin (PF)的分子結構OOHOOOHOHOHOOOOHOOOH化學合成:具生物活性分子的製備化學合成包含四部份:一、對掌分子金屬複合物的製備二、有關氧化腈(nitrile oxide)及其反應機構的研究三、和環保概念有關的研究，主要是使用碘分子(I2)、六硝酸 二銨鈰 (Cerium Ammonia Nitrate: CAN)、及氯三甲
5、基矽烷(trimethylsilylchloride:TMSCl)等試劑為催化剤，將各種受質如硝基烯，,-不飽和醛類、酮類、酸類、或酯類和其他各種試劑反應以合成具有生物活性的化合物四、三丙烯基鋁(triallylaluminum)和羰基化合物(carbonyl compound)中的醛類或酮類反應產生醇類之探討Local Products for Advanced Organic CatalysisAsymmetric ReductionAsymmetric 3+2 Nitrile Oxide CycloadditionAsymmetric Michael AdditionAsymmetric
6、 Baylis-Hillman ReactionAsymmetric AziridinationAsymmetric CyclopropanationAsymmetric EpoxidationAsymmetric AllylationAsymmetric CyanationAsymmetric 4 + 2 Diels-Alder ReactionEnantioselectivc CatalysisNanoscience Drugs Discovery and Development MeMeNOONaMeMeNONaO(DMSO)2PtCl2H2O, rtNOONOOPtTo the (S,
7、S)-dimerized ligand was treated with (DMSO)2PtCl2 at rt in H2O. The fine yellow precipitate was obtained slurry within 1 h. The mixture was stirred for 12 h and then cooled to 0 oC for 1 h. The fine yellow precipitate was collected by filtration, washed with cold water and dried in vacuo to give the
8、 desired product. The product was dissolved in CH3CN and recrystallized from CH3CN/CH2Cl2 to get limpid crystal in 35% yield.對掌分子金屬複合物的製備MeMeNOONaMeMeNONaOCH3CN, rtNOONOOPdPd(OAc)2To the (S,S)-dimerized ligand ( 2.5g ) in CH3CN ( 80 ml ) was added Pd(OAc)2 ( 1.3g, 1.05 eq ) in rt. After 2h, the reac
9、tion was added ether ( 100ml ) and stirred 0 oC for 1h. The resulting solution was filtered. The filtrate was concentrated to get desired product (75%) which was recrystallized from CH3CN/CH2Cl2.對掌分子金屬複合物的製備OHONHOONSSdimer ligandNOONOOPtPt SSdimerThe 1H NMR spectrumOHONHOONSSdimer ligandNOONOOPtPt S
10、SdimerThe 13C NMR spectrumOHONHOONSSdimer ligandNOONOOPdPd SSdimerThe 1H NMR spectrumOHONHOONSSdimer ligandNOONOOPdPd SSdimerThe 13C NMR spectrumOHONHOONRRdimer ligandNOONOOPdPd RRdimerThe 1H NMR spectrumOHONHOONRRdimer ligandNOONOOPdPd RRdimerThe 13C NMR spectrumOHONHOONSSdimer ligandNOONOOPtPt SSd
11、imerNOONOOPdPd SSdimerThe comparison of IR spectraOHONHOONRRdimer ligandNOONOOPdPd RRdimerThe comparison of IR spectra+1aPhENO2+PhENOHCl(1)0 oCPhNOKOPCl3E3aH+PhECNEE2a (E = COOMe)+t-BuOKEEEE4a (28%)5a (26%)6a (23%)PhNO2氧化腈(nitrile oxide)及其反應機構的研究氧化腈(nitrile oxide)及其反應機構的研究+1a-78 oCPCl32c (E = COOMe)
12、+t-BuOKPhNO2PhNHOKOEEEE+(2)+10(-)cis-11trans-11PhEENO2ONPhEEH12PhCNEE+HHHONHEEPhHHH-78 oCB氧化腈(nitrile oxide)及其反應機構的研究+ArNOKOPCl3RH+t-BuOKEArNO2RHEEArEENO2H+ArNOPCl2ORHER = H or CH2CH=CH2_EE(1) Cl-ArENOHClERCl2PO-ArENOHER_H+ArEERNOONHPhEE+_Cl3POPCl3(R = H)ArEERCNPCl3Cl-_HCl+HCl_Ar = Phpyridine(2) rea
13、rrangeR = CH2CH=CH2, or 3-(cyclohexen-1-yl)ONPhHEE碘分子(I2)催化的反應+I2 (5 mol%)Neat123ROR3ROR1SR4R3R2(3)R1R2R4SH碘分子(I2)催化的反應NO2+HNI2etherHNNO2534NHNHNO2Ar76ArAroror(4)碘分子(I2)催化的反應O+I2ON+NNN1a94aa5aaNR42a: R4 = H2b: R4 = CH3+R4R4R4R4Et2O(5)碘分子(I2)催化的反應HOOPh+I2HOOPhPhSneat, different temp1d2a3daPhSH(6)碘分子(
14、I2)催化的反應OOOOI2r.t.NHOOOCHOO1a235a(7)NH4OAc4碘分子(I2)和CAN催化的反應OOR1R1H2NH2NR2I2r.t.NNR1R1R2(8)OOR1R1H2NH2NR2CAN (5mo%)tape waterNNR1R1R2(9)TMSCl催化的反應CHONH2OTMSClCH3CN, r.t.NHONHO(10) 三丙烯基鋁 (triallylaluminum) 和羰基 (carbonyl group)化合物中的醛類或酮類及其衍生物反應之探討OR1R2OHR1(CH2=CHCH2)3Al+ dry etherR2(CH2=CHCH2)3Al+ dry
15、etherR1R2NR1HNR2R3R3(11)(12) 天然萃取物與合成化合物對平均動脈血壓之影響心血管疾病為國人十大死因，而高血壓更嚴重影響國人健康，各大藥廠無不竭盡心力研發降低降血壓之藥物。本研究主要測試本計劃其他主持人即化學系許順吉教授、陳焜銘教授及姚清發教授所提供七種化合物之心血管反應 實驗材料及方法:1. 取週齡於12至16週之雄性大白鼠(Wistar)，體重約250+330克。2.平均動脈血壓之測量 注射urethane (1.4g/kg, I.P.)，將其全身麻醉後進行股動靜脈插管。將內含heparin (100 U/ml)之polyethylene導管(PE50)插入股動脈，
16、並連接壓力轉換器與放大器，以偵測血壓與心跳之變化。 -40-40-30-30-20-20-10-100 010102020Change of MBP (mmHg)PF alone (dissolved in 20% DMSO) 00.51.02.04.08.016.0*(mg/kg)-30-30-25-25-20-20-15-15-10-10-5-50 05 5101015152020Change of MBP (mmHg)PN alone (dissolved in 10% DMSO)00.51.02.04.08.016.0(mg/kg)-40-40-30-30-20-20-10-100 0
17、101020203030Change of MBP (mmHg)Co-administration of PF and PN (dissolved in 20% DMSO)00.51.02.04.0*(mg/kg)-10-10-5-50 05 5101015152020252530303535Change of MBP (mmHg)00.51.02.04.08.016.032.0*Yao-1 alone (dissolved in 20% DMSO)(mg/kg)-10-10-5-50 05 5101015152020Change of MBP (mmHg)00.51.04.08.016.03
18、2.064.0Yao-2 alone (dissolved in 10% DMSO)(mg/kg)-30-30-25-25-20-20-15-15-10-10-5-50 05 5101000.51.02.04.08.016.032.0Change of MBP (mmHg)Yao-3 alone (dissolved in 20% DMSO)*(mg/kg)-25-25-20-20-15-15-10-10-5-50 05 5101000.51.02.04.08.016.0*Change of MBP (mmHg)Yao-4 alone (dissolved in 20% DMSO)(mg/kg
19、)-15-15-10-10-5-50 05 51010151500.51.05.010.020.050.0 100.0Change of MBP (mmHg)Yao-5 alone (dissolved in 30% DMSO)(mg/kg)實驗結果摘要:結果顯示有三種 藥品具有降低平均動脈血壓之效果(分別為PF、Yao-3 及 Yao-4)，一種藥品具有提昇平均動脈血壓之效果(Yao-1)，餘下三種藥品則對平均動脈血壓無明顯之影響(PN, Yao-2 及Yao-5)，但其中PN 可增強PF降低平均動脈血壓之效果。 研究成果發表1. Chu, C.-M.; Gao, S.; Sastry, M
20、. N. V.; Yao, C.-F. “Iodine-catalyzed Michael addition of mercaptans to a,b-unsaturated ketones under solvent-free conditions” Tetrahedron Lett, 2005, 46, 4971-4974. (SCI )2. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-F. ” Molecular iodine-catalyzed one-pot synthesis of 4-substituted-1,4-dihydropyri
21、dine derivatives via Hantzsch reaction” Tetrahedron Lett, 2005, 46, 5771-5774. (SCI)3. Shivaji, V. M.; Sastry, M. N. V.; Wang, C.-C.; Yao, C.-F. “Molecular iodine: A powerful catalyst for the easy and efficient synthesis of quinoxalines” Tetrahedron Lett, 2005, 46, 6345-6348. (SCI)4. Tu, Z.; Jang, Y
22、.; Lin, C.; Liu, J.-T.; Hsu, J.; Sastry, M. N. V. N.; Yao, C.-F. “The study of reaction mechanism for the transformation of nitronate into nitrile by phosphorus trichloride” Tetrahedron 2005, 61, 10541-10551. (SCI)5. Lin, C.; Hsu, J.; Sastry, M. N. V.; Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. “I2-ca
23、talyzed Michael addition of indole and pyrrole to nitroolefins” Tetrahedron 2005, 61, 11751-11757. (SCI)6. More, S. V.; Sastry, M. N. V.; Yao, C.-F. “Cerium (IV) ammonium nitrate (CAN) as a catalyst in tap water : A simple, proficient and green approach for the synthesis of quinoxalines”Green Chem.,
24、 2006, 8, 91-95. (SCI)7. Ko, S.; Lin, C.; Tu, Z.; Wang, Y.-F.; Wang, C.-C.; Yao, C.-F. “CAN and iodine-catalyzed reaction of indole or 1-methylindole with a,b-unsaturated ketone or aldehyde” Tetrahedron Lett, 2006, 47, 487-492. (SCI)8. Gao, S.; Tzeng, T.; Chu, C.-M.; Liu, J.-T.; Lin, C.; Sastry, M.
25、N. V.; Yao, C.-F. “Iodine Catalyzed Conjugate Addition of Mercaptans to ,-Unsaturated Carboxylic Acids under Solventfree condition” Tetrahedron Lett, 2006, 47, 1889-1892. (SCI)9. More, S. V.; Sastry, M. N. V.; Yao, C.-F. “TMSCl Catalyzed Aza-Diels-Alder Reaction: A Simple and Efficient Synthesis of
26、Pyrano- and Furanoquinoline” Synlett. 2006, xxxx-xxxx. (SCI)10. Shen, K.-H.; Yao, C.-F. “A Novel and Efficient Method for the Allylation of Carbonyl Compounds and Imines using Triallylaluminum” J. Org. Chem. 2006, 71, xxxx-xxxx. (SCI)11. Kulkarni, N. A. and Chen, K* “Excellent diastereoselective all
27、ylation of camphor derived glyoxylic oxime ethers mediated by a Lewis acid” Tetrahedron Lett. 2006, 47, 611-613. (SCI)12. Kulkarni, N. A.; Wang, S. G.; Lee, L. C.; Tsai, H. R.; Venkatesham, U. and Chen, K.* “Highly diastereoselective allylation and reduction of chiral camphor-derived a-ketoamides” T
28、etrahedron: Aymmetry 2006, 17, 336-346. (SCI) 13. Chen, J. H.; Venkatesham, U.; Lee, L. C. and Chen, K.* “Diastereoselective Allylation of -Ketoamides Bearing amphor N-Tosylpyrazolidinone Auxiliary: Efficient Synthesis of Highly Optically Active Two Stereoisomers” Tetrahedron 2006, 62, 887-893. (SCI
29、)14. Lu, K. T.; Chiou, R. Y. Y.; Chen, L. G.; Chen, M. H.; Tseng, W. T.; Hsieh, H. T. and Yang, Y. L. “Neuroprotective effects of resveratrol on cerebral ischemia-induced neuro loss mediated by free radical scavenging and cerebral blood flow elevation” J. Agricultural and Food Chem. 2006, xxxx-xxxx.
30、 (SCI 2.327) (SCI)15. Yang, Y. L.; Su, Y. W.; Ng, M. C.; Chao, P. K.; Tung, L. C. and Lu, K. T. “Extract of Gingo biloba Egb761 facilitates extinction of conditioned fear measured by fearpotentiated startle” Neuropsychopharmacology 2006, xxxx-xxxx. (SCI 4.941) 未來研究方向 依據動物實驗結果: 藉由探討藥品對一氧化氮(nitric oxi
31、de)的生 成，或其對血管內皮素(endothelin)的作用，以釐清其作用機轉 注射不同比例天然物分子 修飾現有分子結構 合成結構新穎分子 開發新合成方法 相關的毒理測試和作用機轉的探討 感謝聆聽 敬請指教U5qM)iEZavR2nI&fAW7sN+kF!cxS4pK*hCX9uP0mH$ezU5rM)iEZawR2nJ&fBW7sO+kF!cxT4pK(hCY9uP1mH$ezU6rM)jEZbwR2oJ&fBW7tO+kG!cyT4pL(hCY9uQ1mH%ezU6rM-jEZbwR3oJ&gBW7tO+lG!cyT4qL(hDY9uQ1mI%ezV6rN-jE#bwR3oJ*gBW8t
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40、6rM-jEZbwR2oJ&gBW7tO+lG!cyT4pL(hDY9uQ1mH%ezV6rM-jE#bwR3oJ&gBW8tO+lG!dyT4qL(hDY9vQ1mI%eAV6rN-jE#bwS3oJ*gBX8tO0lG!dyT5qL(iDYavQ1nI%eAV6sN-jF#bxS3oK*gBX8tP0lG$dyU5qL)iDYavQ2nI%fAV7sN-kF#bxS3pK*gCX8tP0lH$dyU5qM)iDZavQ2nI&fAV7sN+kF#cxS3pK*hCX8uP0mH$dzU5qM)iEZavR2nJ&fAW7sN+kF!cxS4sN+kF!cxS4pK(hCX9uP0mH$ez
41、U5rM)jEZawR2nJ&fBW7sO+kF!cxT4pK(hCY9uP1mH$ezU6rM)jEZbwR2oJ&fBW7tO+kG!cyT4pL(hCY9uQ1mH%ezV6rM-jEZbwR3oJ&gBW8tO+lG!cyT4qL(hDY9vQ1mI%ezV6rN-jE#bwS3oJ*gBW8tO0lG!dyT5qL(iDY9vQ1nI%eAV6rN-jF#bwS3oK*gBX8tO0lG$dyT5qL)iDYavQ1nI%fAV6sN-kF#bxS3oK*gCX8tP0lH$dyU5qL)iDZavQ2nI&fAV7sN-kF#cxS3pK*hCX8uP0lH$dzU5qM)iH$d
42、zU5qM)iDZavR2nI&fAW7sN+kF#cxS4pK*hCX9uP0mH$dzU5rM)iEZawR2nJ&fAW7sO+kF!cxT4pK(hCX9uP1mH$ezU6rM)jEZawR2oJ&fBW7tO+kG!cxT4pL(hCY9uQ1mH%ezU6rM-jEZbwR3oJ&gBW7tO+lG!cyT4pL(hDY9uQ1mI%ezV6rM-jE#bwR3oJ*gBW8tO+lG!dyT4qL(iDY9vQ1mI%eAV6rN-jF#bwS3oJ*gBX8tO0lG$dyT5qL(iDYavQ1nI%fAV6sN-jF#bxS3oK*gCX8tP0lG$dBX8tP0lG$
43、dyU5qL)iDYavQ2nI%fAV7sN-kF#bxS3pK*gCX8uP0lH$dyU5qM)iDZavR2nI&fAV7sN+kF#cxS4pK*hCX8uP0mH$dzU5rM)iEZavR2nJ&fAW7sO+kF!cxS4pK(hCX9uP1mH$ezU5rM)jEZawR2nJ&fBW7sO+kG!cxT4pK(hCY9uP1mH%ezU6rM)jEZbwR2oJ&gBW7tO+kG!cyT4pL(hDY9uQ1mH%ezV6rM-jE#bwR3oJ&gBW8tO+lG!dyT4qL(hDY9vQ1mI%eAV6rN-jE#bwS3oJ*gBW8tO0lG!dyT5qL(iD
44、Y9vQ1nI%eAV6sN-jF#bwS3oK*gBX8tP0lG$dyT5qL)iDYavQ2nI%fAV6sN-kF#bxS3pK*gCX8tP0lH$dyU5qM)iDZavQ2nI&fAV7sN+kF#cxS3pK*hCX8uP0mH$dzU5qM)iEZavR2nI&fAW7sN+kF!cxS4pK*hCX9uP0mH$ezU5rM)iEZawR2nJ&fBW7sO+kF!cxT4pK(hCY9uP1mH$ezU6rM)mH$ezU6rM)jEZbwR2oJ&fBW7tO+kG!cyT4pL(hCY9uQ1mH%ezU6rM-jEZbwR3oJ&gBW7tO+lG!cyT4qL(h
45、DY9uQ1mI%ezV6rN-jE#bwR3oJ*gBW8tO0lG!dyT4qL(iDY9vQ1nI%eAV6rN-jF#bwS3oK*gBX8tO0lG$dyT5qL)iDYavQ1nI%fAV6sN-kF#bxS3oK*gCX8tP0lG$dyU5qL)iDZavQ2nI%fAV7sN-kF#cxS3pN-kF#cxS3pK*gCX8uP0lH$dzU5qM)iDZavR2nI&fAW7sN+kF#cxS4pK*hCX9uP0mH$dzU5rM)iEZawR2nJ&fAW7sO+kF!cxS4pK(hCX9uP1mH$ezU5rM)jEZawR2oJ&fBW7sO+kG!cxT4pL(
46、hCY9uP1mH%ezU6rM-jEZbwR2oJ&gBW7tO+lG!cyT4pL(hDY9uQ1mI%ezV6rM-jE#bwR3oJ*gBW8tO+lG!dyT4qL(iDY9vQ1mI%eAV6rN-jE#bwS3oJ*gBX8tO0lG!dyT5qL(iDYavQ1nI%eAV6sN-jF#bxS3oK*gBX8tP0lG$dyU5qL)iDYavQ2nI%fAV7sN-kF#bxS3pK*gCX8uP0lH$dyU5qM)iDZavR2nI&fAV7sN+kF#cxS3pK*hCX8uP0pK*hCX8uP0mH$dzU5qM)iEZavR2nJ&fAW7sN+kF!cxS4pK
47、(hCX9uP0mH$ezU5rM)jEZawR2nJ&fBW7sO+kG!cxT4pK(hCY9uP1mH%ezU6rM)jEZbwR2oJ&gBW7tO+kG!cyT4pL(hCY9uQ1mH%ezV6rM-jEZbwR3oJ&gBW8tO+lG!cyT4qL(hDY9vQ1mI%ezV6rN-jE#bwS3oJ*gBW8tO0lG!dyT5qL(iDY9vQ1nI%eAV6sN-jF#bwS3oK-jF#bwS3oK*gBX8tO0lG$dyT5qL)iDYavQ1nI%fAV6sN-kF#bxS3oK*gCX8tP0lH$dyU5qL)iDZavQ2nI&fAV7sN-kF#cxS3pK*hC
