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

Abstract

SummaryA unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3’-fluorinated analogues were constructed from a common 3’-deoxy-3’-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3’-fluororibose purine nucleosides 1–15 and eight 3’-fluororibose 2-chloro/2-aminopurine nucleosides 16–23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3’-fluorine analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3’-fluorine purine nucleoside analogues display potent tumor cell growth inhibition activity at sub- or low micromolar concentration.

Synthesis of phosphonate derivatives of 2′-deoxy-2′-fluorotetradialdose d-nucleosides and tetradialdose d-nucleosides

“…To avoid elimination reactions and the formation of side products during the fluorination step, it was reported that the reaction had to be performed on a precursor bearing unprotected trans diol. 10 , 11 Therefore, l -xylose glycoside 9 was treated with DAST to afford the fluorinated product in 54% yield. In agreement with the literature, 6 , 7 we observed the regioselective formation of 3-fluoro- l -ribofuranoside 10 .…”

Modular, Step-Efficient Palladium-Catalyzed Cross-Coupling Strategy To Access C6-Heteroaryl 2-Aminopurine Ribonucleosides

“…To circumvent this problem, current strategies that have been developed for the preparation of 6-heteroaryl guanosines require the use of the expensive 6-iodo-2-aminoguanosine ( 2 ) substrate, ,, prepared from 1 via Finkelstein reaction . Cross-coupling strategies such as Stille, − Negishi, − and other bespoke variants , of these have been explored using both 1 and 2 . However, the toxicity associated with organotin reagents and the presence of a number of Lewis basic sites and electrophilic O-protecting groups have limited their broader utility.…”

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

“…The guanidine system is present in structural components of biomolecules, namely in the amino acid arginine or in the nucleobase guanine. It is also embodied in the nitrogenous aromatic moiety of various bioactive compounds, such as in the 2aminopurine motif, which is contained in the antibiotic natural nucleosides amipurimycin and miharamycins [22,23], and in various synthetic nucleosides exhibiting anticancer [24] and antiviral properties [25], or in the 2-aminopyrimidine moiety, which is present in the anticancer drug imatinib [26]. On the other hand, the amidine (or imidamide) system (NH2-C=NR) contained in the guanidine group is present in the cytosine and adeninebased motifs, which are found in various nucleoside analogues used as chemotherapeutic agents [27,28].…”