Nucleosides of 2-Fluoroadenine

Mechanisms of anti-cancer action and pharmacology of clofarabine

“…9-β-D-arabinofuranosyladenine (araA)). Since the clinical activity of araA was found to be limited due to its rapid deamination 5 by adenosine deaminase (ADA) [5], ADA-resistant halogenated arabinosyl derivatives such as 2-fluoro-9-β-arabinofuranosyladenine (fludarabine) were then developed [6]. Thereafter, because of the insolubility of fludarabine, its 5´-monophosphate derivative (fludarabine monophosphate, FaraA, Fludara ® ), was designed for conversion into fludarabine aA by endogenous phosphatases.…”

“…The rationale behind its design was to combine the structural features of cladribine and fludarabine ( Figure 1). Like cladribine and fludarabine, clofarabine is toxic to both non-proliferating human lymphocytes and rapidly proliferating cells, while 6 being resistant to phosphorylitic cleavage and deamination-stable in acidic environments.…”

Synthesis of Novel 2'-Spirocyclopropanoid 4'-Deoxythreosyl Phosphonic Acid Nucleoside Analogues

“…The reaction mixture was refluxed for 24 h. The reaction mixture was filtered through a pad of Celite, evaporated, and purified by silica gel column chromatography using methanol and methylene chloride (12:1) to give ethyl phosphonate analogue 17 (387 mg, 81%) as a white solid: mp 176-178 ºC; (18). Transformation of 6-chloropurine to adenine derivative 18 was performed from 17 by the similar ammonolysis procedure as described for 15: yield 55%; mp 177-179 ºC; UV (MeOH) λ max 261.5 nm; (rel)-(1'S,3'S)-Diethyl {9-(3'-vinyl-2'-spiropropyl-dihydrofuran-1'-yl) 2-fluoro-6-chloropurine} phosphonate (21). Phosphonate nucleoside analogue 21 was prepared from 20b using the same cross-metathesis procedure as described for 14: yield 62%; (rel)-(1'S,3'S)-Diethyl {9-(3'-vinyl-2'-spiropropyl-dihydrofuran-1'-yl) 2-fluoro-6-aminopurine} phosphonate (22a) and (rel)-(1'S,3'S)-diethyl {9-(3'-vinyl-2'-spiropropyl-dihydrofuran-1'-yl) 2-amino-6-chloropurine} phosphonate (22b).…”

A New Paradigm for Developing Antiviral Drugs Exemplified by the Development of Supremely High Anti-HIV Active EFdA

“…Additionally, the three were also active against a non-nucleoside reverse transcriptase inhibitorresistant Y181C. Further, the three purine derivatives were highly potent against the HIVs isolated from seven heavily drug-experienced patients with acquired immune deficiency syndrome (AIDS) as efficiently as against wild-type HIV [14,15,26]. Thus, 4'EdA, 4'Ed2AA, and 4'EdG were highly potent against all the existing HIVs.…”