Biocatalysis in Drug Discovery and Development

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1 PROGRESS IN CHEMISTRY Vol. 19 No. 12 Dec., ( ),,, : Q503 ; O : A : X(2007) Biocatalysis in Drug Discovery and Development Chen Yijun 3 Wu Xuri (Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing , China) Abstract Due to the advantages including mild conditions, high catalytic efficiency, high stereoselectivity and regioselectivity and less byproducts, biocatalysis has been widely utilized and applied in drug discovery and development. Moreover, biocatalysts can be structurally changed and optimized through new technologies such as directed evolution, which could be better suited for biocatalytic processes. In this review, recent progress in the field of application of biocatalysis in drug discovery and development is briefly introduced and discussed. Key words biocatalysis ; biocatalyst ; metabolites ; chiral drugs ; drug discovery and development [2 ] 70,, ( 44 %) [1 ], (30 %), [3, ],,,, ph 1 [4 ],,,, ,, : e2mail :yjchen - com. cn,

2 , 211,,,,Michels [6 ] : (1) ; (2), ; (3) ; (4), [5 ],, 2, 96, 16 25, (bergenin 1), 3 (1) : [6 ] 1 bergenin Fig. 1 Process of generating bergenin derivatives by combinatorial biocatalysis [6 ]

3 ( ) ( ) ( [7 ] ) ( ) ( ),,,de la Ggutte [8 ], 2 Loratadine hydroxyzine, Fig. 2 Biotransformation and active metabolites of loratadine and hydroxyzine 212 [10 ], P450 P450,,,,, (14), ( S)262 (11), 62 [9 ] : (1) (10) ; (2) ; (3) 11 13, Streptomyces ; (4) ; (5) antibioticus (14) ( S )262 ; (6) (11) [16 ] (3) : ( desloratadine 7) (loratadine 6) ( 2), 10 [10 ],, (cetirizine 9) (hydroxyzine 8) (2), H1 [11 ],, [16 ] [12 15 ] 3 62Hydroxybuspirone buspirone Fig. 3 Biotransformation of 62hydroxybuspirone and 213 buspirone [16 ], [10 ]

4 ,, 311,,, [19 ] 4 Fig. 4 Reactions catalyzed by hydrolytic enzymes [19 ], ( S)2 (23) (5), ( R)2 (22) ( R, R)2, Patel [19 ] PS230 32, 222 (24), S2 44 % (25) R2( + )2 (26) (5), 25, 37 %, ee 97 % [3 ],,, [17 ] Goswami [18 ] Aspergillus niger Rhodotorula glutinis 12{ 2, 3 2 dihydrobenzo[ b ]furan24 2yl}21, 22oxirane (15) ( S)2 (16) ( R)2 (17), ee 95 %, 45 % (4), ( S)2 ( S)232acetylthio222methyl propanoic acid (19) Patel [19 ] 32acetylthio222methyl propanoic acid (18), 19, 24 %, ee 95 %(4) [19 ] , Fig. 5 Esterification reactions in biocatalysis [19 ],, 312, 2,,,, Campos [20 ] Pseudomonas cepacia, (21) R2 (22),

5 ,, 9815 % NADH, ( S)262 (32) Ceranopril 62, (30) D L2 (29) Hanson [21 ] Providencia alcalifaciens N2 2 2L2 (31) ( S)262 (32), (6), ee [22 (27) 28, %, R ] L2 2L2 NADH ( 29) ( 6), 95 %, ee [21,22 ] 6 [21,22 ] Fig. 6 Reactions catalyzed by oxidoreductases 31212, ( S )2tertiary leucine ( 37) Thermoactinomyces intermedius, (8), %, ee 9915 % NADH Patel [23 ] Sphingomonas paucimobilis L (LAT) allysine ethylene acetal (39) 35 (7), LAT E. coli 3, 8 2, ( S )2allysine ethylene acetal [25, ( GOX) ] Hanson [26 ], 65 % 67 % (8) NADH H +, CO 2 H + HIV21, [24 ] ( S )2 Thermoactinomyces intermedius 38,,

6 [23 ] 7 Fig. 7 Reactions catalyzed by aminotransferases [23 ] [24,26 ] 8 [24,26 ] Fig. 8 Reductive aminations in biocatalysis [30,31 ], 4 [32 ],,,,,,, ph, ( R)2 Terao [33 ], 74 (68277), 188, 411, 412, [27 ] Declerck [28 ] (), Pichia stipitis ( PsXDH) Annaluru [29 ] PsXDH,, 1018, 2018,,,,

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8 [22] Hanson R, Schwinden M D, Banerjee A, et al. Bioorg. Med. Chem., 1999, 7(10) : [23] Patel R N, Banerjee A, Nanduri V, et al. Enzyme Microb. Technol., 2000, 27(6) : [24] Patel R N. Enzyme Microb. Technol., 2002, 31(6) : [25] Patel R N. Biomol. Eng., 2001, 17(6) : [26] Hanson R, Howell J, LaPorte T, et al. Enzyme Microb. Technol., 2000, 26(5Π6) : [27] Bornscheuer U T, Pohl M. Curr. Opin. Chem. Biol., 2001, 5 (2) : [28] Declerck N, Machius M, Wiegand G, et al. J. Mol. Biol., 2000, 301 (4) : [29] Annaluru N, Watanabe S, Pack S P, et al. J. Biotechnol., 2007, 129 : [30] Sriprapundh D, Vieille C, Zeikus J G. Protein Eng., 2000, 13 (4) : [31] Kumar S, Tsai C J, Nussinov R. Protein Eng., 2000, 13 (3) : [32] Pack S P, Yoo YJ. J. Biotechnol., 2004, 111 (3) : [33] Terao Y, Ijima Y, Miyamoto K, et al. J. Mol. Catalysis B : Enzymatic, 2007, 45(1Π2) : [34] Arnold F H. Chem. Eng. Sci., 1996, 51(23) : [35] Cadwell R C, Joyce G F. PCR Methods Appl., 1994, 3 (6) : [36] Stephens D E, Rumbold K, Permaul K, et al. J. Biotechnol., 2007, 127 (3) : [37] Stemmer W P C. Nature, 1994, 370 (6488) : [38] Fortin P D, Macpherson I, Neau D B, et al. J. Biol. Chem., 2005, 280 (51) : [39] Rosic N N, Huang W, Johnston W A, et al. Gene, 2007, 395 (1Π2) : 40 48

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