- Production of recombinant human aldehyde oxidase in Escherichia coli and optimization of its application for the preparative synthesis of oxidized drug metabolites
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Recombinant human aldehyde oxidase (AO) was expressed in Escherichia coli. Different cell disruption methods and conditions of cell culture in shake flasks and bioreactors and of biotransformation on an analytical scale were tested to optimize the synthesis of oxidized AO drug metabolites. The volumetric productivity was increased 24-fold by optimizing the cell culture conditions. The highest yield was achieved in a 25 L stirred tank bioreactor under non-oxygen-limited conditions and high lactose feed rate. Suspensions of highly concentrated and well-aerated whole cells at neutral pH and relatively low temperatures led to the best conversion. The solvent for the substrate and the buffering agent for the biotransformation had an important effect. In a biotransformation with AO, 210 mg of famciclovir was converted to diacetyl penciclovir a yield of 82 %. The optimized protocol represents a viable method for the preparative synthesis of oxidized AO metabolites of drugs. Drug metabolites: Recombinant human aldehyde oxidase is expressed in Escherichia coli. The highest volumetric productivity is achieved in a 25 L stirred tank bioreactor under non-oxygen-limited conditions and high lactose feed rate. In a biotransformation with concentrated whole cells at pH 7.4 and 30 °C, 210 mg of famciclovir is converted to diacetyl penciclovir in a yield of 82 %. The optimized protocol enables the preparative synthesis of oxidized aldehyde oxidase metabolites of drugs.
- Rodrigues, Diogo,Kittelmann, Matthias,Eggimann, Fabian,Bachler, Thorsten,Abad, Sandra,Camattari, Andrea,Glieder, Anton,Winkler, Margit,Luetz, Stephan
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p. 1028 - 1042
(2014/05/06)
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- PROCESS FOR PREPARING FAMCICLOVIR
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The invention provides a process for making famciclovir, comprising reacting 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6-chloropurine (Cl-FMC) with a palladium on charcoal catalyst in water and ammonium formate. The invention also provides methods of treating viral diseases by administering the famciclovir prepared according to the above process.
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Page/Page column 6-8
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF FAMCICLOVIR
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The invention provides processes for making famciclovir with low levels of undesirable by-products. The present invention discloses a process comprises reacting a compound of formula I (acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo [4,5-b]pyridin-3-yl)-butyl ester) in the presence of a palladium on charcoal catalyst in a C1-C6 alkyl acetate and ammonium formate. The present invention further discloses a process comprises reacting a compound of formula I (acetic acid 2-- acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butyl ester) in the presence of a palladium on charcoal catalyst in a mixture of a C1-C6 alkyl acetate, a C1-C4 alcohol and ammonium formate.
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- Synthesis and evaluation of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-Amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir
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A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (1-8) and 2-amino-9-(3-alkoxycarbonyl- oxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6- deoxypenciclovir
- Kim, Dae-Kee,Lee, Namkyu,Ryu, Do Hyun,Kim, Young-Woo,Kim, Jae-Sun,Chang, Kieyoung,Im, Guang-Jin,Choi, Won-Son,Cho, Yong-Baik,Kim, Key H.,Colledge, Danni,Locarnini, Stephen
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p. 1715 - 1725
(2007/10/03)
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- Prodrugs of the Selective Antiherpesvirus Agent 9-guanine (BRL 39123) with Improved Gastrointestinal Absorption Properties
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Potential oral prodrugs of the antiherpesvirus acyclonucleoside 9-guanine (1, BRL 39123) have been synthesized and evaluated for bioavailability of 1 in the blood of mice.Reduction of 9--2-amino-6-chloropurine (13) using ammonium formate and 10percent palladium on carbon afforded the 2-aminopurine 14, which was hydrolyzed to the monoacetate 15 and to 2-amino-9-purine (5).The 2-aminopurine 5 was subsequently converted to additional monoester (17, 21-23) and diester (16, 24) derivatives and to its di-O-isopropylidene derivative 18.Both 5 and its esters (14-17, 21, 22) and also 18 were well absorbed after oral administration and converted efficiently to 1, the diacetyl (14) and dipropionyl (16) esters providing concentrations of 1 in the blood that were more than 15-fold higher than those observed after dosing either 1 or its esters (25-27).Some 6-alkoxy-9-purines (8-10), the preparation of which has been reported previously, also showed improved absorption properties, but their conversion to 1 was less efficient than for the 2-aminopurine derivatives.On the basis of these results and subsequent experiments involving determination of rates of convertion to 1 in the presence of rat and human tissue preparations, 9--2-aminopurine (14, BRL 42810) was identified as the preferred prodrug of 1.Oral bioavailability studies in healthy human subjects confirmed 14 as an effective prodrug, and this compound is now being evaluated in clinical trials.
- Harnden, Michael R.,Jarvest, Richard L.,Boyd, Malcolm R.,Sutton, David,Hodge, R. Anthony Vere
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p. 1738 - 1743
(2007/10/02)
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