RESUMO
Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates and drugs has become important and state of the art in the pharmaceutical industry. There has been an increasing awareness of the enormous potential of microorganisms and enzymes (biocatalysts) for the transformation of synthetic chemicals with high chemo-, regio- and enatioselectivities providing products in high yields and purity. In this article, biocatalytic processes are described for the synthesis of key chiral intermediates for development pharmaceuticals.
Assuntos
Enzimas/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Biocatálise , Humanos , Conformação Molecular , Preparações Farmacêuticas/químicaRESUMO
Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates and drugs has become increasingly important in the pharmaceutical industry. There has been an increasing awareness of the enormous potential of microorganisms and enzymes derived there from for the transformation of synthetic chemicals with high chemo-, regio- and enatioselectivities. In this article, biocatalytic processes are described for the synthesis of chiral alcohols and unntural aminoacids for pharmaceuticals.
RESUMO
Biotransformation of the highly substituted pyridine derivative 2-amino-4-methyl-3-nitropyridine by Cunninghamella elegans ATCC 26269 yielded three products each with a molecular weight of 169 Da which were identified as 2-amino-5-hydroxy-4-methyl-3-nitropyridine, 2-amino-4-hydroxymethyl-3-nitropyridine, and 2-amino-4-methyl-3-nitropyridine-1-oxide. Biotransformation by Streptomyces antibioticus ATCC 14890 gave two different products each with a molecular weight of 169 Da; one was acid labile and converted to the other stable product under acidic conditions. The structure of the stable product was established as 2-amino-4-methyl-3-nitro-6(1H)-pyridinone, and that of the less stable product was assigned as its tautomer 2-amino-6-hydroxy-4-methyl-3-nitropyridine. Four of the five biotransformation products are new compounds. Several strains of Aspergillus also converted the same substrate to the lactam 2-amino-4-methyl-3-nitro-6(1H)-pyridinone. Microbial hydroxylation by C. elegans was found to be inhibited by sulfate ion. In order to improve the yield and productivity of the 5-hydroxylation reaction by C. elegans, critical process parameters were determined and Design of Experiments (DOE) analyses were performed. Biotransformation by C. elegans was scaled up to 15-l fermentors providing 2-amino-5-hydroxy-4-methyl-3-nitropyridine at ca. 13 % yield in multi-gram levels. A simple isolation process not requiring chromatography was developed to provide purified 2-amino-5-hydroxy-4-methyl-3-nitropyridine of excellent quality.
Assuntos
Cunninghamella/metabolismo , Piridinas/química , Piridinas/metabolismo , Streptomyces antibioticus/metabolismo , Aspergillus/isolamento & purificação , Aspergillus/metabolismo , Reatores Biológicos , Biotransformação , Cunninghamella/isolamento & purificação , Fermentação , Concentração de Íons de Hidrogênio , Hidroxilação , Peso Molecular , Óxidos/metabolismo , Piridinas/isolamento & purificação , Projetos de Pesquisa , Streptomyces antibioticus/isolamento & purificaçãoRESUMO
A total of 39 microbes were screened for the ability to selectively N-demethylate (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)aminopyrimidin-5-yl)-3,5-dihydroxy-hept-6-enoic acid (I), a potential drug for lowering blood cholesterol levels. Two Streptomyces species were found to carry out the desired N-demethylation. Bioconversion by Streptomyces griseus A.T.C.C. 13273 and product recovery were scaled up to the multi-gram level.
Assuntos
Bactérias/metabolismo , Fungos/metabolismo , Pirimidinas/metabolismo , Triazóis/metabolismo , Biotransformação , Metilação , Streptomyces/metabolismoRESUMO
Microbial hydroxylation of o-bromophenylacetic acid provided 2-bromo-5-hydroxyphenylacetic acid. This enabled a route to the key intermediate 4-bromo-2,3-dihydrobenzofuran for synthesizing a melatonin receptor agonist and sodium hydrogen exchange compounds. Pd-mediated coupling reactions of 4-bromo-2,3-dihydrobenzofuran provided easy access to the 4-substituted-2,3-dihydrobenzofurans.
Assuntos
Aspergillus/metabolismo , Benzofuranos/metabolismo , Fenilacetatos/metabolismo , Biotransformação , Hidroxilação , Estrutura MolecularRESUMO
Chirality is a key factor in the safety and efficacy of many drug products and, thus, the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. There has been an increasing awareness of the enormous potential of microorganisms and enzymes derived therefrom for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivities. In this article, some selected enzymatic processes are described for the synthesis of chiral intermediates for pharmaceuticals.
RESUMO
BMS-353645, also known as sordarin, was of interest based on its activity against pathogenic fungi. The objective of these studies was to provide high quality starting substrate for chemical modification aimed at further improving biological activity, with particular interest in the inhibition of Aspergillus. In the work presented here, Design of Experiments, or DOE, was successfully combined with traditional approaches to significantly improve sordarin yields in fermentation flasks. Overall, yields were increased 25-fold from <100 microg/g to as high as 2,609 microg/g in flasks through the use of various medium and conduction changes supplemented with DOE. The improved process was then successfully scaled to pilot plant tanks with the best batch producing 2,389 microg/g sordarin at the 250-l scale.
Assuntos
Fermentação , Indenos/metabolismo , Sordariales/metabolismo , Projetos de PesquisaRESUMO
Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand for the bulk preparation of drug substances and agricultural products. There has been an increasing awareness of the enormous potential of the use of microorganisms and microorganism-derived enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivities. In this article, biocatalytic processes are described for the synthesis of chiral intermediates for drugs.
Assuntos
Desenho de Fármacos , Preparações Farmacêuticas/síntese química , Catálise , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Estereoisomerismo , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendênciasRESUMO
Second-generation paclitaxel analogues that require replacement of the C-4 acetate by other substituents are in development. An enzyme able to specifically remove the C-4 acetate from paclitaxel could simplify preparation of the analogues. Several strains were isolated from soil samples that contain enzyme activities able to 4-deacetylate 10-DAB (10-deacetylbaccatin III). Selection was made using plates containing 10-DAB as the sole carbon source and screening colonies for deacetylation of 10-DAB. Two strains initially isolated were identified as Rhodococcus sp. and deposited with the A.T.C.C. (Manassas, VA, U.S.A.) as strains 202191 and 202192. Whole cells were able to convert 10-DAB into 4,10-DDAB (4-deacetyl-10-deacetylbaccatin III) in 90% yield. The enzyme activity in these strains was not effective with paclitaxel and 10-deacetylpaclitaxel, although 4,10-DDAB was produced from baccatin III. The activity in these strains was associated with an insoluble fraction of cell extracts. Several additional isolates were obtained that were identified as variants of Stenotrophomonas maltophilia, and a soluble C-4 deacetylase was purified approx. 218-fold from one of them. The activity of this enzyme was limited to 10-DAB, and the enzyme was not effective with paclitaxel or baccatin III.
Assuntos
Rhodococcus/enzimologia , Microbiologia do Solo , Taxoides/metabolismo , Acetilação , Alcaloides/metabolismo , Alcaloides/farmacologia , Aminoidrolases/isolamento & purificação , Antineoplásicos Fitogênicos/metabolismo , Proteínas de Bactérias/isolamento & purificação , Paclitaxel/metabolismo , Rhodococcus/isolamento & purificação , Stenotrophomonas maltophilia/enzimologia , Stenotrophomonas maltophilia/isolamento & purificação , Taxoides/farmacologiaRESUMO
6-alpha-Hydroxy-7-deoxy-10-deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-deacetylbaccatin-III with a maximum yield of 44%.
Assuntos
Reatores Biológicos/microbiologia , Nocardia/classificação , Nocardia/metabolismo , Taxoides/isolamento & purificação , Taxoides/metabolismo , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Biotransformação , Hidrólise , Nocardia/crescimento & desenvolvimento , Projetos Piloto , Especificidade da EspécieRESUMO
A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.
Assuntos
Diterpenos/síntese química , Biotransformação , Cetonas/química , Oxirredução , Compostos Policíclicos/química , PleuromutilinasRESUMO
Chirality is a key factor in the efficacy of many drugs; thus, the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand from the pharmaceutical and agrochemical industries for the preparation of bulk drug substances and agricultural products. There has been an increasing awareness of the enormous potential of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivity. In this article, biocatalytic processes for the synthesis of chiral pharmaceutical intermediates are described.