Thymidylate synthetase-catalyzed conversions of E-5-(2-bromovinyl)-2'-deoxyuridylate

E-5-(2-Bromovinyl)-2'-deoxyuridylate (BrvdUMP), the first metabolite in the processing of the antiviral agent E-5-(2-bromovinyl)-2'-deoxyuridine (BrvdUrd), is an excellent alternate substrate for dTMP synthetase. The nucleophilic catalyst of the enzyme adds to the 6-position of the heterocycle and converts the normally inert 5-bromovinyl group of BrvdUMP to a reactive allylic bromide in which both carbons of the side chain are susceptible to nucleophilic attack. These centers react with nucleophiles in the reaction mixture, 2-mercaptoethanol and water, to give three diastereomeric products which have been isolated and characterized. Possible implications of these findings as related to the mechanism and selectivity of BrvdUrd as an antiviral agent are discussed.