RESUMO
Two efficient and practical methods of synthesis of the C-10 substituent of DV-7751 (1), a novel quinolone carboxylic acid, were established. The first method utilizes an optical resolution of racemic 8-amino-6-benzyl-6-azaspiro[3.4]octane (13), while the second employs an enantioselective microbial reduction of 6-benzyl-5,8-dioxo-6-azaspiro[3.4]octane (8b). The enantiomeric excess of (S)-8-amino-6-benzyl-6-azaspiro[3.4]octane (11) with each method of synthesis is greater than 96%.
Assuntos
Anti-Infecciosos/química , Ascomicetos/metabolismo , Fluoroquinolonas , Anti-Infecciosos/síntese química , Anti-Infecciosos/metabolismo , Cromatografia Líquida de Alta Pressão , Modelos Químicos , EstereoisomerismoRESUMO
The esterase from Micrococcus sp., which hydrolyzes n-propyl-2-fluorocyclopropanecarboxylate (3) enantioselectively, was highly purified by three types of chromatography. The purified enzyme was inactivated by Hg and diisopropyl fluorophosphate (DFP). It was a monomer with a molecular weight of about 35000. The enzyme exhibits esterase activity towards many aliphatic propyl esters. The enantioselectivity for substrate (3) using purified enzyme did not differ from that of crude enzyme.
Assuntos
Esterases/isolamento & purificação , Micrococcus/enzimologia , Esterases/metabolismo , Peso Molecular , Especificidade por SubstratoRESUMO
The key intermediate of a 20(S)-camptothecin 1 synthesis was obtained in a highly enantioselective fashion using an enzyme-catalyzed resolution. A commercially available protease was found to exhibit the highest enantioselectivity with moderate activity, and (S)-ethyl 2-acetoxy-2-[6-(acetoxymethyl)-1,1-(ethylenedioxy)-5-oxo- 1,2,3,5-tetrahydroindolizin-7-yl]butanoate 7c of 98% e.e. was obtained as the remaining substrate.
Assuntos
Antineoplásicos/síntese química , Camptotecina/análogos & derivados , Endopeptidases/metabolismo , Camptotecina/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Hidrólise , Cinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estereoisomerismo , Especificidade por SubstratoRESUMO
Debenzylating enzyme from Aspergillus niger enzyme (commercial crude cellulase) catalyzes the hydrolysis of cetraxate benzyl ester hydrochloride (2), a precursor of the antiulcer agent (1). The enzyme was highly purified by three kinds of chromatographies (hydrophobic, ion exchange, gel filtration) with a recovery of 36%. The content of the debenzylating enzyme was about 0.1% in the crude cellulase, but the enzyme showed no cellulase activity. The purified enzyme was inactivated by Hg2+, and diisopropyl phosphorofluoridate (DFP). It was a monomer with a molecular weight of about 35,000, and its isoelectric point was estimated to be 5.3. It showed a debenzylating activity for the phenylpropionic acid benzyl ester moiety of various benzyl ester derivatives, and the benzyl ester of phenylalanine or that of tyrosine was also well hydrolyzed.
Assuntos
Aspergillus niger/enzimologia , Hidrolases de Éster Carboxílico/isolamento & purificação , Ácidos Cicloexanocarboxílicos/isolamento & purificação , Ácidos Cicloexanocarboxílicos/metabolismo , Ácido Tranexâmico/isolamento & purificação , Ácido Tranexâmico/metabolismo , Cromatografia Líquida de Alta Pressão , Especificidade por Substrato , Ácido Tranexâmico/análogos & derivados , Ácido Tranexâmico/análiseRESUMO
Cetraxate hydrochloride (1) (antiulcer agent) has been industrially produced by the chemical protective method of p-hydroxy propionic acid derivatives. Screening of enzymes which quantitatively hydrolyzed cetraxate benzyl ester hydrochloride (2) into 1 was undertaken to establish a novel enzymatic method of production of 1. It was found that the enzyme activity for debenzylation of 2 is contained in cellulase enzymes originated from Aspergillus sp. Lower alkyl groups or phenyl groups of p-hydroxy propionic acid derivatives are likewise selectively hydrolyzed by the cellulase enzyme. This enzymatic synthetic method is very useful for the industrial preparation of 1.
Assuntos
Antiulcerosos/síntese química , Ácidos Cicloexanocarboxílicos/síntese química , Ácido Tranexâmico/síntese química , Aspergillus , Celulase , Métodos , Ácido Tranexâmico/análogos & derivadosRESUMO
The syntheses of N1- and N2-isopropylformycin (10, 11), formycin 3',5'-cyclic and 2',3'-cyclic phosphate (3,7) and their N-methyl and N-isopropyl derivatives (13, 15, 19, 23) are described. It was observed that substitution at N1 or N2 with a bulky alkyl group or cyclic phosphorylation of the ribose moiety made formycin resistant to adenosine deaminase.