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|Title:||Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers|
|Abstract:||A process for the resolution of a racemic mixture of nucleoside enantiomers that includes the step of exposing the racemic mixture to an enzyme that preferentially catalyzes a reaction in one of the enantiomers. The nucleoside enantiomer (-)-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane is an effective antiviral agent against HIV, HBV, and other viruses replicating in a similar manner.|
|Inventor(s):||Liotta; Dennis C. (Stone Mountain, GA), Schinazi; Raymond F. (Decatur, GA), Choi; Woo-Baeg (North Brunswick, NJ)|
|Assignee:||Emory University (Atlanta, GA)|
|Filing Date:||Mar 05, 2004|
|Claims:||1. A method for the resolution of a racemic mixture of nucleoside enantiomers, comprising: reacting a C5'-hydroxyl group of a mixture of nucleoside racemates with an acyl compound to produce a racemic mixture of C5'-esters and exposing the racemic mixture of C5'-esters to an enzyme that preferentially catalyzes a reaction in one of the enantiomers, wherein the enzyme is selected from the group consisting of an esterase, a lipase. substillisin, .alpha.-chymotrypsin, and cytidine-deoxycytidine deaminase. |
2. The method of claims 1, wherein the esterase is pig liver esterase.
3. The method of claims 1, wherein the lipase is selected from the group consisting of porcine pancreatic lipase and Amano PS-800 lipase.
4. The method of claim 1, wherein the enantiomers are acylated before resolution with a compound selected from the group consisting of alkyl carboxylic acids and substituted alkyl carboxylic acids.
5. The method of claim 4, wherein the alkyl carboxylic acid is selected from the group consisting of acetic acid, propionic acid, butyric acid, pentanoic acid.
6. The method of claim 1, wherein the nucleoside enantiomers are passed through a column that includes the enzyme stabilized on a support.
7. The method of claim 1, wherein the enantiomers are mixed with the enzyme in a solution.
8. The method of claim 1, further comprising carrying out the enzymatic reaction in the presence of a non-ionic surfactant.
9. The method of claim 8, wherein the non-ionic surfactant is Triton X-100.
10. The method of claim 1, further comprising the step of exposing the product of resolution to a second enzyme that enhances the resolution.
11. The method of claim 1, further comprising recrystallizing the product of resolution.
12. The method of claim 1, further comprising treating the product of resolution with a chiral acid.
13. The method of claim 12, wherein the chiral acid is selected from the group consisting of malic acid, mandelic acid, dibenzoyl tartaric acid, 3bromocamphor-8-sulfonic acid, 10-camphorsulfonic acid, and di-p-toluoyltartaric acid.
14. The method of claim 1, wherein the racemic mixture is selected from the group consisting of the 5'-O-ester and the unesterified (.+-.)-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane.
15. The method of claim 4, wherein the substituted alkyl carboxylic acid is selected from the group consisting of 2-chloropropionic acid, 2-chlorobutyric acid, and 2-chloropentanoic acid.
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