Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

• Hang Ren,
• Haoyun An,
• Paul J. Hatala,
• William C. Stevens Jr,
• Jingchao Tao and
• Baicheng He

Beilstein J. Org. Chem. 2015, 11, 2509–2520, doi:10.3762/bjoc.11.272

• , nelarabine, cladribine, and clofarabine are an important subset of nucleoside drugs [7][8][9][10]. Purine ribonucleosides substituted at position 6 have exhibited potent antimetabolite activity [11][12][13] and aryl or heterocyclic substituents have imparted cytostatic activities against various tumor cell

• reactions on the 6-chloropurine nucleosides. Intermediate compounds 31–40 were deprotected with a saturated solution of ammonia in methanol to furnish the desired products 6–15 in 70–92% yields (Table 1). 3’-Fluoro-2-chloropurine nucleosides – cladribine and clofarabine mimics Anticancer drugs cladribine

• and clofarabine [55][56][57] are purine nucleoside derivatives having a chlorine atom at position 2 of the purine moiety. With this in mind, we designed and synthesized 2-chloropurine nucleosides 16–20 (Figure 2 and Scheme 4) with 3’-fluorine and 6-C-aromatic or heterocyclic modifications to explore a

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

• Ilja V. Fateev,
• Konstantin V. Antonov,
• Irina D. Konstantinova,
• Tatyana I. Muravyova,
• Frank Seela,
• Roman S. Esipov,
• Anatoly I. Miroshnikov and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2014, 10, 1657–1669, doi:10.3762/bjoc.10.173

• synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, 2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D

• -arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine

• enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the