Chemoenzymatic Synthesis of Purine Modified 3′-deoxy-D-ribonucleosides and Evaluation of Their Antiproliferative Activity
Chemoenzymatic synthesis of a series of purine modified 3′ deoxyribonucleosides was studied from purine derivatives as acceptors and an excess of 3′-deoxyuridine as the donor, prepared by the chemical deamination of 3′-deoxycytidine, using recombinant uridine and purine nucleoside phosphorylases as biocatalysts in enzymatic reactions. Eight purine nucleosides were prepared in 24%-84% yields after column chromatography. Among the tested purine derivatives, 2,6-dichloropurine was found to be the best substrate in the enzymatic transglycosylation reaction catalyzed by the E. coli purine phosphorylase (PNP) via intermediate 1-phosphate-3-deoxy-D-ribofuranose, and dihalogenated purine 3'-deoxyriboside was prepared in 84% yield. The anticancer nucleoside, cordycepin, was synthesized by the enzymatic transglycosylation reaction of adenine in 70% yield from 3´-deoxyuridine. Two enzymatic approaches to 2-fluorocordycepin were tested from 2-fluoroadenine or 2-fluoroadenosine and 3´-deoxyuridine as the donor of 3-deoxy-D-ribofuranose in the transglycosylation of the 2-fluoropurine using the recombinant PNP. 3′-Deoxyribofuranosides of 2,6-chloro- and 6-chloro-purine were utilized as starting compounds for preparing novel purine modified nucleosides by the nucleophilic substitution reactions of the chlorine atom with cyclic amines or acylation reaction. A series of modified purine 3′-deoxyribonucleosides were evaluated for their in vitro antiproliferative activity on leukemia cell lines HL-60 and K-562.