井冈胺产生菌的选育与工艺条件的研究
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摘要
井冈霉素是我国最大的一类农用抗生素，对纹枯病有好的防治作用，目前在我国大量使用，其市场价格低廉。井冈胺是井冈霉素的组成部分，是重要的医药中间体，其销售价格是井冈霉素的几十倍。因此以井冈霉素为原料生产井冈胺具有巨大的经济效益和社会效益。
本实验拟从井冈霉素出发，利用微生物培养和酶催化的基本原理和技术，研究微生物菌株的生理生化特性，实现井冈霉素的有效微生物酶降解。通过菌种的诱变和培养工艺的优化，提高微生物菌株的分解酶活力。
首先对本实验室已筛选到的菌株经过紫外诱变和亚硝基胍诱变后，得到了一株在生理特性上有较大区别的菌株，诱变后的菌株能使井冈胺的产量提高到一倍以上。
对新筛选到的菌株进行了培养工艺条件的优化，得到发酵培养基的最适初始pH值为8.0，最佳发酵温度为30℃，最适底物浓度为1％。在培养基优化过程中，研究了碳源、氮源、磷源和无机离子对发酵的影响。碳源以井冈霉素为好，最佳浓度为1％，氮源选择了1％的(NH_4)_2SO_4；选择了有促进作用的CaCl_2、KCl、MgSO_4和ZnSO_4，对其浓度进行了单因素试验和正交试验，结果表明，在最佳培养基条
浙江工业大学硕士学位论文
件下发酵液中井冈胺的含量达到了2.43mg/ml，井冈胺得率有71 .5%，
比在原培养基基础上所得的结果l.6omg/ml，产量提高了51.9%。
最后对菌种产生的酶进行了分离纯化和酶的性质研究。经过一系
列的纯化酶的纯化倍数达到了巧.37，产率为9.6%。对酶的性质经过初
步研究，结果表明:酶的最适pH值为8.0，pH值稳定范围为7一8，最适
反应温度为40℃，温度稳定范围在40℃以下，CaZ+和K+对该酶有强烈的
激活作用，而FeZ十和SDS对该酶有明显的抑制作用，以井冈霉素为底
物该酶的Km一22.smmol几，vm一59.17ogml一‘h一’。
Validamycins, effective fungicide against the sheath blight of rice plants, is the most widely used homemade farm-antibiotics. It has a low price while valienamine, an important intermediate of medicine, is much more expensive. So it is potential in economical and social benefits to produce valienamine from validamycins.
In this dissertation, we were expected to depend on the principium and skill of microorganism culture and enzyme catalyse to research the character of microorganism strain, furthermore, we were also expected to improve valienamine yield via mutation strain and optimizing the whole fermentation process.
At first, a highly valienamine-producing variation strain was screened from its original strain by treating with UV as well as NTG., which was fairly different in physiological properties from former. In producing valienamine from validamycins, the new one was double than the old.
After the optimizing fermentation process for new strain, the results showed that the optimum temperature was 30℃ ,the optimum pH was 8.0 and the substrate concentration was 1%. Furthermore, the optimum carbon and nitrogen resource were investigated, including inorganic compound which were promoting for fermentation. Validamycins was the optimum corbon resource and the optimum nitrogen resource was sulfate ammonium. Calcium chloride, potassium chloride, bitter salt and zine sulfate could improve the yield of valienamine. The last results showed that under the condition of the best culture medium, the yield of valienmine reached 2.43mg/ml, which compared with the former almost improved 51.9%.
At last, the enzyme produced by strain was purified and the character of enzyme
was researched. After a series of purification, the multiple of purified enzyme was 15.37 and the production rate was 9.6%, respectively. The analysis of enzymatic character showed that the optimum temperature was 40℃ and the optimum pH was 8.0. The enzyme was relatively stabilization in pH 7-8, and it was thermo-stability below 40℃. Most metal ion such as Ca2+and K+ had forceful activation whereas Fe2+and SDS had distinct restrain. The Michaelis constant (Km) was 22.8mmol/l and Vm was 59.17μgml~(-1)h~(-1).
本实验拟从井冈霉素出发，利用微生物培养和酶催化的基本原理和技术，研究微生物菌株的生理生化特性，实现井冈霉素的有效微生物酶降解。通过菌种的诱变和培养工艺的优化，提高微生物菌株的分解酶活力。
首先对本实验室已筛选到的菌株经过紫外诱变和亚硝基胍诱变后，得到了一株在生理特性上有较大区别的菌株，诱变后的菌株能使井冈胺的产量提高到一倍以上。
对新筛选到的菌株进行了培养工艺条件的优化，得到发酵培养基的最适初始pH值为8.0，最佳发酵温度为30℃，最适底物浓度为1％。在培养基优化过程中，研究了碳源、氮源、磷源和无机离子对发酵的影响。碳源以井冈霉素为好，最佳浓度为1％，氮源选择了1％的(NH_4)_2SO_4；选择了有促进作用的CaCl_2、KCl、MgSO_4和ZnSO_4，对其浓度进行了单因素试验和正交试验，结果表明，在最佳培养基条
浙江工业大学硕士学位论文
件下发酵液中井冈胺的含量达到了2.43mg/ml，井冈胺得率有71 .5%，
比在原培养基基础上所得的结果l.6omg/ml，产量提高了51.9%。
最后对菌种产生的酶进行了分离纯化和酶的性质研究。经过一系
列的纯化酶的纯化倍数达到了巧.37，产率为9.6%。对酶的性质经过初
步研究，结果表明:酶的最适pH值为8.0，pH值稳定范围为7一8，最适
反应温度为40℃，温度稳定范围在40℃以下，CaZ+和K+对该酶有强烈的
激活作用，而FeZ十和SDS对该酶有明显的抑制作用，以井冈霉素为底
物该酶的Km一22.smmol几，vm一59.17ogml一‘h一’。
Validamycins, effective fungicide against the sheath blight of rice plants, is the most widely used homemade farm-antibiotics. It has a low price while valienamine, an important intermediate of medicine, is much more expensive. So it is potential in economical and social benefits to produce valienamine from validamycins.
In this dissertation, we were expected to depend on the principium and skill of microorganism culture and enzyme catalyse to research the character of microorganism strain, furthermore, we were also expected to improve valienamine yield via mutation strain and optimizing the whole fermentation process.
At first, a highly valienamine-producing variation strain was screened from its original strain by treating with UV as well as NTG., which was fairly different in physiological properties from former. In producing valienamine from validamycins, the new one was double than the old.
After the optimizing fermentation process for new strain, the results showed that the optimum temperature was 30℃ ,the optimum pH was 8.0 and the substrate concentration was 1%. Furthermore, the optimum carbon and nitrogen resource were investigated, including inorganic compound which were promoting for fermentation. Validamycins was the optimum corbon resource and the optimum nitrogen resource was sulfate ammonium. Calcium chloride, potassium chloride, bitter salt and zine sulfate could improve the yield of valienamine. The last results showed that under the condition of the best culture medium, the yield of valienmine reached 2.43mg/ml, which compared with the former almost improved 51.9%.
At last, the enzyme produced by strain was purified and the character of enzyme
was researched. After a series of purification, the multiple of purified enzyme was 15.37 and the production rate was 9.6%, respectively. The analysis of enzymatic character showed that the optimum temperature was 40℃ and the optimum pH was 8.0. The enzyme was relatively stabilization in pH 7-8, and it was thermo-stability below 40℃. Most metal ion such as Ca2+and K+ had forceful activation whereas Fe2+and SDS had distinct restrain. The Michaelis constant (Km) was 22.8mmol/l and Vm was 59.17μgml~(-1)h~(-1).
引文
[1] 曹军卫，马辉文，微生物工程，北京，科学出版社，2002：22-33
[2] 熊宗贵，发酵工艺原理，北京，中国医药科技出版社，1995：63-76
[3] 周加祥，刘铮，生物分离技术与过程研究进展，化工进展，2000(6)：38-40
[4] 孙彦，生化分离工程，北京，化学工业出版社，1998：3-4
[5] 毛忠贵，生物技术下游技术，北京，中国轻工业出版社，1999：3-12
[6] 李荣秀，生物医药分离纯化新技术，中国生化医药杂志，1999，20(4)：206-209
[7] 徐炎华，欧阳平凯，韦萍，我国生物分离纯化技术现状及发展方向，江苏化工，1996，24(2)：4-6
[8] 童望宇，人表皮生长因子工艺的应用基础研究，浙江大学博士论文，2001：12-13
[9] 严希康，生化分离技术，上海，华东理工大学出版社，1991：101-102
[10] 陈石根，周润琦，酶学，上海，复旦大学出版社，2001：95-129
[11] 徐炎华，欧阳平凯，韦萍，我国生物分离纯化技术现状及发展方向，江苏化工，1996，24(3)：4-6
[12] 姚红娟，王晓琳，膜分离技术在低分子量产品分离纯化中的应用，化工进展，2003，2：146-153
[13] 夏小燕，生物大分子分离纯化技术的重大突破，生物工程进展，1994，14(5)：40-46
[14] 郑裕国，虞炳钧，陈小龙，方煜，离子交换法提取井冈霉素的研究，农药，1996，35(11)：9-10
[15] 上海农药研究所农抗组，井冈霉素，上海，上海人民出版社，1977
[16] Degwert, U., Hulst, R.V., Pape, H., Richard, E.H., John, M., Beale, E, Keller, J.;Lee, J.R,Floss, H.G., Studies on the biosynthesis of the α-blucosidase inhibitor acarbose: valienamine, A m-C_7N unit not derived from the shikimate pathway. J.Antibiot. 1987,11 (6):855-861
[17] Humphries, M.J., Matsumoto, K., White, S.L., Olden, K., Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors, Cancer Res. 1986,46(10):5212-5222
[18] Nishimura, Y., Satoh, T., Satoh, H., Konda, S., Takeuchi, T., Azetaka, M., Fukuyasu, H., Hizuka, Y., Synthesis and antimetastatic activity of L-iduronic acid-type 1-N-iminosugars, J. Med. Chem. 1997,40(16)2626-2633
[19] Hmphries, M.J., Matsumoto, K., White, S.L., Olden, K., Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by
oligosaccharide processing inhibitors, Cancer Res. 1986,46:5215-5222
[20] Fleet, G.W.J, Karpas, A., Dwek, R.A., Fellows, L.E., Tyms, A.S., Petursson, S., Namgoong, S.K., Ramsden, N.G., Smith, P.W., Son, J.C., Witty, D.R., Jacob, G.s., Rademacher, T.W., Inhibition of HIV replication by amino-sugar derivatives, FEBS lett. 1988,23(1-2)128-132
[21] David, C., Montefioi, W., Edward Yobinson, J.R., William, M.M, Role of protein N-Glycosylation in pathogenesis of human immunodeficiency virus type 1, proc. Natl. Acad. Sci. USA. 1988,85:9248-9252
[22] Iwsa T., Studies on validamycins, new antibiotics. Ⅳ. Isolation and characterization of validamycins A and B, J. Antibiotics, 1971,24(2): 119-123
[23] Iwasa T, Higashide E, Yamamoto H, Shibata M., Studies on validamycins, new antibiotics. Ⅱ. Production and biological properities of validamycins A and B. J. Antibiotics, 1971,24(2):107-113
[24] Kameda, Y., Horri, S., The unsaturated cyclitol part of the new antibiotics, the validamycins, J.C.S., Chem.Comm. 1972:746-747
[25] Kameda, Y., Asano, Yamaguchi, T., Matsui. K., Validoxylamines as trehalase inhibitors, J. Antibiot. 1987,40:563-565
[26] Horii, S.,Iwasa, T., Kameda, Y., Studies on validamycins, new antibiotics. V. degradation studies, J.Antibiot. 1970,24:423-426
[27] Imai, K., Banno, I., Identification of a bacterium which is able to decompose validamycin, Abstract papers, Ass. Meet.; Soc. Ferment. Technol. 1979:24
[28] Kameda, Y., N. Asano. Teranishi M., Matsui K., New cyclitols, degradation of validamycin A by Flavobaterium saccharophilum, J. Antibiot. 1980,33(12): 1573-1574
[29] Kameda, Y., Asano, N., Yoshikawa, M., Matsui, K. Horii, S., Fukase, H., N-substituted valienamines, alpha-glucosidase inhibitors, J. Antibiot. 1982, 35(11): 1624-1626
[30] Kameda, Y., Asano, N., Yoshikawa, M., Takeuchi, M., Yamaguchi, T., Matsui, K., Valiolamine, a new alpha-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus, J. Antibiot. 1984,37(11): 1301-1307
[31] Kameda, Y., Asano, N., Yoshikawa, M., Matsui, K., Valienamine as an alpha-glucosidase inhibitor, J. Antibiot. 1980, 33(12): 1575-1576
[32] Horri, S., Iwasa, T., Mizata, E., Kameda, Y., Studies on validamycins, new antibiotics. Ⅵ.
Validamine, hydroxyvalidamine and validatol, new cyclitols, J. Antibiot. 1971,24:59-63
[33] Kameda Y, Asano N, Yoshikawa M, Takeuchi M, Yamaguchi T, Matsui K, Horri S, Fukase H., Validamine, a new alpha-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus, J Antibiot. 1984 Nov,37(11): 1301-1307
[34] Takeuchi, M., Kamata, K., Yoshida, M., Matsui, K., Inhibitory effect of pseudo-aminosugars on oligosaccharide glucosidases Ⅰ and Ⅱ and on lysosomal alpha-glucosidase from rat liver, J.Biochem. 1990,108(1):42-46
[35] Takeuchi, M., Kamata, K., Yoshida, M., Masui, K., Inhibitory effect of validamine, valienamine and valiolamine on activities of carbohydrases in rat small intestinal brush border membranes, Chem. Pharm. Bull. 1990,38(7):1970-1972
[36] gawa, S., Toyokuni, T., Suami, T., Synthesis of penta-N, O-acetyl-DL-valienamine and its related branched-chain unsaturated aminocylitols and cyclitols, Chem. Lett. 1980, 713-716
[37] Ogawa, S., Ara, M., Kondoh, T. Saitoh, M., Masuda, R., Toyokuni, T., Suami, T., Pseudo-sugars: Ⅵ. Synthesis of six isomers of 5-hydroxymethyl-1,2,3,4-cyclohexanetetrol(pseudo-hexopyranose) and their derivatives, Bull. Chem. Soc. Jpn. 1980,53,1121-1136
[38] Horri, S., Kameda, Y., Fukase, H., Pseudo-aminosugars, their production and use, EUR Patent 0063456al, 1982,10,27
[39] Kameda, Y., Horii, S., Yamano, T., Mcrobial transformation of validamycins, J. antibiot. 1975,28(4):298-306
[40] Asano, N., Takeuchi, M., Ninomiya, K., Kameda, Y., Matsui, K., Microbial degradation of validamycin A by Flavobacterium saccharophilum. Enzymatic cleavage of C-N linkage in validoxylamine A, J. Antibiot. 1984,37(8):859-867
[41] Horii, S., Iwasa, T., Kameda, Y., Studies on validamycins, new antibiotics. V. Degradation studies, J.Antibiot. 1971,24(1):57-58
[42] Fukase, H., Development of voglibose, an antidiabetic agent, Yuki Gosei Kagaku Kyokaishi, 1997,55:920-925
[43] Rassu, G., Auzzas, L., Pinna, L., Zanardi, F., Battistini, L., Casiraghi, G., Variable Strategy toward Carbasugars and Relatives as Illustrated by Diastereoselective Synthesis of 1-Deoxy-1-amino-pseudo-b-D-gulopyranose(Alias 1,2,4-tri-epi-Validamine), Org. Lett.
1999,1:1213-1215
[44] Fukase, H., Horii, S., Synthesis of a branched-chain inosose derivative, a versatile synthon of N-subsituted valiolamine derivatives from D-glucose, J. Org. Chem. 1992,57(13):3642-3650
[45] Kamiya, K., Wada, Y., Horii, S., Nishikawa, M., Studies on validamycins, New antibiotics. Ⅶ: The X-ray anlysis of validamine hydrobromide, J. Antibiot. 1971,24(5):317-318
[46] Ogawa, S., Toyokuni, T., Omata, M. Chida, N. Suami, T., Pseudosugars: Ⅴ. Synthesis of DL-validatol and DL-deoxyvalidatol, and their epimers, Bull. Chem. Soc. Jpn. 1980,53:455-457
[47] Ogawa, S., Iwasawa, Y., Toyokuni, T., Suami; T., Synthesis of a common structural unit of antibiotic oligostatins., Chem. Lett. 1982:1729-1732
[48] Toyokuni, T., Ogawa, S., Suami, T., Synthetic studies on the validamycins: Ⅳ. Synthesis of DL-valienamine and related branched-chain unsaturated aminocyctitols, Bull Chem. Soc. Jpn. 1983,56:1161-1170
[49] Paulsen, H., Heiker, F.R., Synthesis of chiral valienamine, Angew, Chem. Int, Ed. Engl. 1980,19(11):904-905
[50] Paulsen, H.; Herker, F.R., Synthesis von enantiomerenreinem valienamine aus quebrachitol, Liebigs Ann. Chem, 1981:2180-2203
[51] Nicotra, F., Panza, L., Ronchetti, F,., Russo, G., Stereocontrolled synthesis of (+)-valienamine, Gazz. Chim. Ital. 1989,119:577-579
[52] Yoshikawa, M., Cha, B.C., Okachi, Y., Takinami, Y., Yokoaw, Y., Kitagawq, I., Synthesis of validamine, epi-validamine, and valienamine, three optically active pseudo-amino-sugars, form D-glucose, Chem. Pharm. Bull. 1988,36:4236-4239
[53] Fukase, H., Horii. S. Synthesis of valiolamine and its N-substituted derivatived AO-128, validoxylamine G, and validamycin G via branched-chain inosose derivatives, J. Org. Chem. 1992,57-3658
[54] Kapferer, p., Sarabia, F., Vasella, A., Carasaccharides via ring-closing alkene metathesis. A synthesis of (+)-valienamine and (+)-validamine, J. Antibiot. 2000,53(4):430-435
[55] Tatsuta, K., Mukai, H., Takahashi, M., Novel synthesis of natural pseudo-aminosugars, (+-valienamine and (+)-validamine, J. Antibiot. 2000,53(4):430-435
[56] Ogawa, S., Shibata, Y., Nose, T., Suami, T., Synthetic studies on the validamycins. Ⅻ. Synthesis of optically active valienamine and validatol, Bull. Chem. Soc. Jpn.
1985,58:3387-3388
[57] Steven, V.L., Daniel, K.B., Darra, J.D. Alison, C.F., Stuart, J.I. Henning, W.;, P riepke, M., Dominic, J.R., 1,2-Diacetals: a new opportunity for organic synthesis, Chem. Rev. 2001,101(1):53-80
[58] Shing, T.K.M., Wan, L.H., Facile syntheses of valiolamine and its diastereomers from (-)-quinic acid. Nucleophitic substitution reactions of 5-(hydroxymethyl) cylohexane-1,2,3,4,5-pentol, J. Org. Chem. 1996,61:8468-8479
[59] Shing, T.K.M., Tam, E.K.W., Enantiospecific synthesis of (+)-crotepoxide, (+)-β-senepoxide, 9(+)-pipoxide acetate, (-)-iso-crotepoxide, (-)-seneposide, and (-)-tingtanoxide form (-)-quinic acid, J. Org. Chem., 1996,61:8468-8479
[60] Shing, T.K.M., Li, T.Y., Kok, S.H-L., Enantiospecific syntheses of valienamine and 2-epivalienamine, J. Org. Chem. 1999,64:1941-1946
[61] Kok, S.H.-L., Lee, C.C., Shing, T.K.M., A new synthesis of valienamine, J. Org, Chem. 2001,66:7184-7190
[62] Shing, T.K.M., Wan, L.H., Enantiospeccific syntheses of valiolamine and its (1R),(2R),(1R,2R) diastereomers from (-)-quinic acid, Angew. Chem.Int. Ed. Engl. 1995,34(15): 1643-1645
[63] Shing, T.K.M., Tang, Y., Enantiospecific synthesis of 2-crotonyloxy-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone(COTC) from quinic acid. J. Chem. Soc. Chem. Commun. 1990:312
[64] Shing, T.K.M., Tang, Y., (-)-Quinic acid in organic synthesis, 1. facile synthesis of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydrocyclohex-2-enone,Tetrahedron. 1990,46(18):6575-6584
[65] Shing, T.K.M., Tang, Y., A new approach ot pseudo-sugars form (-)-quinic acid: Facile syntheses of pseudo-β-D-manopyranose and pseudo-β-D-fructopyranose, J. Chem. Soc., Chem. Commun., 1990:748-749
[66] Shing,T.K.M., Tang, Y., (-)-Qunic acid organic synthesis. 2. facile synthesis pseudo-β-D-fructopyranose, Tetrahedron. 1991,47(26):4571-4578
[67] Shing, T.K.M., Vincent, W.-F.T., (-)-Quinic acid organic synthesis. Part 4:syntheses of cyclophelliitol and its (1R,6S)-(2S)-(1R,2S,6S)-diastereoisomers, J. Chem. Soc. Perkin. Trans. l. 1994:2017-2025
[68] Shing, T.K.M., Cui, Y., Tang, Y., (-)-Quinic acid in organic synthesis, 3. Stereocontrolled syntheses of pseudo-α-D-manopyranose, Tetrahedron. 1992,48(12):2349-2358
[69] Usui,T., Murate, T., Enzymatic synthesis of p-nitrophenyl α-maltopentaoside in an aqueousmethanol solvent system by moltotetraose-forming: A substrate for human amylase in serum. J.Biochem, 1988,103:969-972
[70] Kameda, Y., Asano, N.Hashimoto, T., Microbial glycosidation of validamycins., J.Antibiot., 1978,31:936-938
[71] Kameda, Y., Asano, N. Waxxe, T., Microbial glycosidation of validamycins.H.The preparation of α-and β-D-glucoside analogs of valida-mycins.J.Antibiotics 1980,33:764-766
[72] Cogoli, A.;G.Semenza: A probable oxocarbon ium ion in the reaction mechanism of small intestinal sucrase and isomaltase. J.Biol. Chem. 1975,250:7802-7809
[2] 熊宗贵，发酵工艺原理，北京，中国医药科技出版社，1995：63-76
[3] 周加祥，刘铮，生物分离技术与过程研究进展，化工进展，2000(6)：38-40
[4] 孙彦，生化分离工程，北京，化学工业出版社，1998：3-4
[5] 毛忠贵，生物技术下游技术，北京，中国轻工业出版社，1999：3-12
[6] 李荣秀，生物医药分离纯化新技术，中国生化医药杂志，1999，20(4)：206-209
[7] 徐炎华，欧阳平凯，韦萍，我国生物分离纯化技术现状及发展方向，江苏化工，1996，24(2)：4-6
[8] 童望宇，人表皮生长因子工艺的应用基础研究，浙江大学博士论文，2001：12-13
[9] 严希康，生化分离技术，上海，华东理工大学出版社，1991：101-102
[10] 陈石根，周润琦，酶学，上海，复旦大学出版社，2001：95-129
[11] 徐炎华，欧阳平凯，韦萍，我国生物分离纯化技术现状及发展方向，江苏化工，1996，24(3)：4-6
[12] 姚红娟，王晓琳，膜分离技术在低分子量产品分离纯化中的应用，化工进展，2003，2：146-153
[13] 夏小燕，生物大分子分离纯化技术的重大突破，生物工程进展，1994，14(5)：40-46
[14] 郑裕国，虞炳钧，陈小龙，方煜，离子交换法提取井冈霉素的研究，农药，1996，35(11)：9-10
[15] 上海农药研究所农抗组，井冈霉素，上海，上海人民出版社，1977
[16] Degwert, U., Hulst, R.V., Pape, H., Richard, E.H., John, M., Beale, E, Keller, J.;Lee, J.R,Floss, H.G., Studies on the biosynthesis of the α-blucosidase inhibitor acarbose: valienamine, A m-C_7N unit not derived from the shikimate pathway. J.Antibiot. 1987,11 (6):855-861
[17] Humphries, M.J., Matsumoto, K., White, S.L., Olden, K., Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors, Cancer Res. 1986,46(10):5212-5222
[18] Nishimura, Y., Satoh, T., Satoh, H., Konda, S., Takeuchi, T., Azetaka, M., Fukuyasu, H., Hizuka, Y., Synthesis and antimetastatic activity of L-iduronic acid-type 1-N-iminosugars, J. Med. Chem. 1997,40(16)2626-2633
[19] Hmphries, M.J., Matsumoto, K., White, S.L., Olden, K., Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by
oligosaccharide processing inhibitors, Cancer Res. 1986,46:5215-5222
[20] Fleet, G.W.J, Karpas, A., Dwek, R.A., Fellows, L.E., Tyms, A.S., Petursson, S., Namgoong, S.K., Ramsden, N.G., Smith, P.W., Son, J.C., Witty, D.R., Jacob, G.s., Rademacher, T.W., Inhibition of HIV replication by amino-sugar derivatives, FEBS lett. 1988,23(1-2)128-132
[21] David, C., Montefioi, W., Edward Yobinson, J.R., William, M.M, Role of protein N-Glycosylation in pathogenesis of human immunodeficiency virus type 1, proc. Natl. Acad. Sci. USA. 1988,85:9248-9252
[22] Iwsa T., Studies on validamycins, new antibiotics. Ⅳ. Isolation and characterization of validamycins A and B, J. Antibiotics, 1971,24(2): 119-123
[23] Iwasa T, Higashide E, Yamamoto H, Shibata M., Studies on validamycins, new antibiotics. Ⅱ. Production and biological properities of validamycins A and B. J. Antibiotics, 1971,24(2):107-113
[24] Kameda, Y., Horri, S., The unsaturated cyclitol part of the new antibiotics, the validamycins, J.C.S., Chem.Comm. 1972:746-747
[25] Kameda, Y., Asano, Yamaguchi, T., Matsui. K., Validoxylamines as trehalase inhibitors, J. Antibiot. 1987,40:563-565
[26] Horii, S.,Iwasa, T., Kameda, Y., Studies on validamycins, new antibiotics. V. degradation studies, J.Antibiot. 1970,24:423-426
[27] Imai, K., Banno, I., Identification of a bacterium which is able to decompose validamycin, Abstract papers, Ass. Meet.; Soc. Ferment. Technol. 1979:24
[28] Kameda, Y., N. Asano. Teranishi M., Matsui K., New cyclitols, degradation of validamycin A by Flavobaterium saccharophilum, J. Antibiot. 1980,33(12): 1573-1574
[29] Kameda, Y., Asano, N., Yoshikawa, M., Matsui, K. Horii, S., Fukase, H., N-substituted valienamines, alpha-glucosidase inhibitors, J. Antibiot. 1982, 35(11): 1624-1626
[30] Kameda, Y., Asano, N., Yoshikawa, M., Takeuchi, M., Yamaguchi, T., Matsui, K., Valiolamine, a new alpha-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus, J. Antibiot. 1984,37(11): 1301-1307
[31] Kameda, Y., Asano, N., Yoshikawa, M., Matsui, K., Valienamine as an alpha-glucosidase inhibitor, J. Antibiot. 1980, 33(12): 1575-1576
[32] Horri, S., Iwasa, T., Mizata, E., Kameda, Y., Studies on validamycins, new antibiotics. Ⅵ.
Validamine, hydroxyvalidamine and validatol, new cyclitols, J. Antibiot. 1971,24:59-63
[33] Kameda Y, Asano N, Yoshikawa M, Takeuchi M, Yamaguchi T, Matsui K, Horri S, Fukase H., Validamine, a new alpha-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus, J Antibiot. 1984 Nov,37(11): 1301-1307
[34] Takeuchi, M., Kamata, K., Yoshida, M., Matsui, K., Inhibitory effect of pseudo-aminosugars on oligosaccharide glucosidases Ⅰ and Ⅱ and on lysosomal alpha-glucosidase from rat liver, J.Biochem. 1990,108(1):42-46
[35] Takeuchi, M., Kamata, K., Yoshida, M., Masui, K., Inhibitory effect of validamine, valienamine and valiolamine on activities of carbohydrases in rat small intestinal brush border membranes, Chem. Pharm. Bull. 1990,38(7):1970-1972
[36] gawa, S., Toyokuni, T., Suami, T., Synthesis of penta-N, O-acetyl-DL-valienamine and its related branched-chain unsaturated aminocylitols and cyclitols, Chem. Lett. 1980, 713-716
[37] Ogawa, S., Ara, M., Kondoh, T. Saitoh, M., Masuda, R., Toyokuni, T., Suami, T., Pseudo-sugars: Ⅵ. Synthesis of six isomers of 5-hydroxymethyl-1,2,3,4-cyclohexanetetrol(pseudo-hexopyranose) and their derivatives, Bull. Chem. Soc. Jpn. 1980,53,1121-1136
[38] Horri, S., Kameda, Y., Fukase, H., Pseudo-aminosugars, their production and use, EUR Patent 0063456al, 1982,10,27
[39] Kameda, Y., Horii, S., Yamano, T., Mcrobial transformation of validamycins, J. antibiot. 1975,28(4):298-306
[40] Asano, N., Takeuchi, M., Ninomiya, K., Kameda, Y., Matsui, K., Microbial degradation of validamycin A by Flavobacterium saccharophilum. Enzymatic cleavage of C-N linkage in validoxylamine A, J. Antibiot. 1984,37(8):859-867
[41] Horii, S., Iwasa, T., Kameda, Y., Studies on validamycins, new antibiotics. V. Degradation studies, J.Antibiot. 1971,24(1):57-58
[42] Fukase, H., Development of voglibose, an antidiabetic agent, Yuki Gosei Kagaku Kyokaishi, 1997,55:920-925
[43] Rassu, G., Auzzas, L., Pinna, L., Zanardi, F., Battistini, L., Casiraghi, G., Variable Strategy toward Carbasugars and Relatives as Illustrated by Diastereoselective Synthesis of 1-Deoxy-1-amino-pseudo-b-D-gulopyranose(Alias 1,2,4-tri-epi-Validamine), Org. Lett.
1999,1:1213-1215
[44] Fukase, H., Horii, S., Synthesis of a branched-chain inosose derivative, a versatile synthon of N-subsituted valiolamine derivatives from D-glucose, J. Org. Chem. 1992,57(13):3642-3650
[45] Kamiya, K., Wada, Y., Horii, S., Nishikawa, M., Studies on validamycins, New antibiotics. Ⅶ: The X-ray anlysis of validamine hydrobromide, J. Antibiot. 1971,24(5):317-318
[46] Ogawa, S., Toyokuni, T., Omata, M. Chida, N. Suami, T., Pseudosugars: Ⅴ. Synthesis of DL-validatol and DL-deoxyvalidatol, and their epimers, Bull. Chem. Soc. Jpn. 1980,53:455-457
[47] Ogawa, S., Iwasawa, Y., Toyokuni, T., Suami; T., Synthesis of a common structural unit of antibiotic oligostatins., Chem. Lett. 1982:1729-1732
[48] Toyokuni, T., Ogawa, S., Suami, T., Synthetic studies on the validamycins: Ⅳ. Synthesis of DL-valienamine and related branched-chain unsaturated aminocyctitols, Bull Chem. Soc. Jpn. 1983,56:1161-1170
[49] Paulsen, H., Heiker, F.R., Synthesis of chiral valienamine, Angew, Chem. Int, Ed. Engl. 1980,19(11):904-905
[50] Paulsen, H.; Herker, F.R., Synthesis von enantiomerenreinem valienamine aus quebrachitol, Liebigs Ann. Chem, 1981:2180-2203
[51] Nicotra, F., Panza, L., Ronchetti, F,., Russo, G., Stereocontrolled synthesis of (+)-valienamine, Gazz. Chim. Ital. 1989,119:577-579
[52] Yoshikawa, M., Cha, B.C., Okachi, Y., Takinami, Y., Yokoaw, Y., Kitagawq, I., Synthesis of validamine, epi-validamine, and valienamine, three optically active pseudo-amino-sugars, form D-glucose, Chem. Pharm. Bull. 1988,36:4236-4239
[53] Fukase, H., Horii. S. Synthesis of valiolamine and its N-substituted derivatived AO-128, validoxylamine G, and validamycin G via branched-chain inosose derivatives, J. Org. Chem. 1992,57-3658
[54] Kapferer, p., Sarabia, F., Vasella, A., Carasaccharides via ring-closing alkene metathesis. A synthesis of (+)-valienamine and (+)-validamine, J. Antibiot. 2000,53(4):430-435
[55] Tatsuta, K., Mukai, H., Takahashi, M., Novel synthesis of natural pseudo-aminosugars, (+-valienamine and (+)-validamine, J. Antibiot. 2000,53(4):430-435
[56] Ogawa, S., Shibata, Y., Nose, T., Suami, T., Synthetic studies on the validamycins. Ⅻ. Synthesis of optically active valienamine and validatol, Bull. Chem. Soc. Jpn.
1985,58:3387-3388
[57] Steven, V.L., Daniel, K.B., Darra, J.D. Alison, C.F., Stuart, J.I. Henning, W.;, P riepke, M., Dominic, J.R., 1,2-Diacetals: a new opportunity for organic synthesis, Chem. Rev. 2001,101(1):53-80
[58] Shing, T.K.M., Wan, L.H., Facile syntheses of valiolamine and its diastereomers from (-)-quinic acid. Nucleophitic substitution reactions of 5-(hydroxymethyl) cylohexane-1,2,3,4,5-pentol, J. Org. Chem. 1996,61:8468-8479
[59] Shing, T.K.M., Tam, E.K.W., Enantiospecific synthesis of (+)-crotepoxide, (+)-β-senepoxide, 9(+)-pipoxide acetate, (-)-iso-crotepoxide, (-)-seneposide, and (-)-tingtanoxide form (-)-quinic acid, J. Org. Chem., 1996,61:8468-8479
[60] Shing, T.K.M., Li, T.Y., Kok, S.H-L., Enantiospecific syntheses of valienamine and 2-epivalienamine, J. Org. Chem. 1999,64:1941-1946
[61] Kok, S.H.-L., Lee, C.C., Shing, T.K.M., A new synthesis of valienamine, J. Org, Chem. 2001,66:7184-7190
[62] Shing, T.K.M., Wan, L.H., Enantiospeccific syntheses of valiolamine and its (1R),(2R),(1R,2R) diastereomers from (-)-quinic acid, Angew. Chem.Int. Ed. Engl. 1995,34(15): 1643-1645
[63] Shing, T.K.M., Tang, Y., Enantiospecific synthesis of 2-crotonyloxy-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone(COTC) from quinic acid. J. Chem. Soc. Chem. Commun. 1990:312
[64] Shing, T.K.M., Tang, Y., (-)-Quinic acid in organic synthesis, 1. facile synthesis of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydrocyclohex-2-enone,Tetrahedron. 1990,46(18):6575-6584
[65] Shing, T.K.M., Tang, Y., A new approach ot pseudo-sugars form (-)-quinic acid: Facile syntheses of pseudo-β-D-manopyranose and pseudo-β-D-fructopyranose, J. Chem. Soc., Chem. Commun., 1990:748-749
[66] Shing,T.K.M., Tang, Y., (-)-Qunic acid organic synthesis. 2. facile synthesis pseudo-β-D-fructopyranose, Tetrahedron. 1991,47(26):4571-4578
[67] Shing, T.K.M., Vincent, W.-F.T., (-)-Quinic acid organic synthesis. Part 4:syntheses of cyclophelliitol and its (1R,6S)-(2S)-(1R,2S,6S)-diastereoisomers, J. Chem. Soc. Perkin. Trans. l. 1994:2017-2025
[68] Shing, T.K.M., Cui, Y., Tang, Y., (-)-Quinic acid in organic synthesis, 3. Stereocontrolled syntheses of pseudo-α-D-manopyranose, Tetrahedron. 1992,48(12):2349-2358
[69] Usui,T., Murate, T., Enzymatic synthesis of p-nitrophenyl α-maltopentaoside in an aqueousmethanol solvent system by moltotetraose-forming: A substrate for human amylase in serum. J.Biochem, 1988,103:969-972
[70] Kameda, Y., Asano, N.Hashimoto, T., Microbial glycosidation of validamycins., J.Antibiot., 1978,31:936-938
[71] Kameda, Y., Asano, N. Waxxe, T., Microbial glycosidation of validamycins.H.The preparation of α-and β-D-glucoside analogs of valida-mycins.J.Antibiotics 1980,33:764-766
[72] Cogoli, A.;G.Semenza: A probable oxocarbon ium ion in the reaction mechanism of small intestinal sucrase and isomaltase. J.Biol. Chem. 1975,250:7802-7809
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