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.