Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides.

Katherine L Seley-Radtke,Kartik Temburnikar

doi:10.3762/bjoc.14.65

Abstract

C-nucleosides have intrigued biologists and medicinal chemists since their discovery in 1950's. In that regard, C-nucleosides and their synthetic analogues have resulted in promising leads in drug design. Concurrently, advances in chemical syntheses have contributed to structural diversity and drug discovery efforts. Convergent and modular approaches to synthesis have garnered much attention in this regard. Among them nucleophilic substitution at C1' has seen wide applications providing flexibility in synthesis, good yields, the ability to maneuver stereochemistry as well as to incorporate structural modifications. In this review, we describe recent reports on the modular synthesis of C-nucleosides with a focus on D-ribonolactone and sugar modifications that have resulted in potent lead molecules.

Highlights

Nucleic acids form the genetic blueprint for all living organisms and are involved with a wide range of cellular functions [1,2,3,4,5,6,7,8,9]
Nucleic acids are composed of a monomeric nucleoside unit that features an aromatic nitrogenous moiety connected to a pentose sugar, which in turn is attached to a phosphate group (Figure 1) [7]
We describe reports of different applications and structural variants that have expanded the diversity of the C-nucleosides

Summary

Introduction

Nucleic acids form the genetic blueprint for all living organisms and are involved with a wide range of cellular functions [1,2,3,4,5,6,7,8,9]. Despite the greater stability of the E3 conformer, it is the faster reacting conformer (E3 or 3E) that affects the ratio of diastereomers in the final product [80] This difference in reactivity results in the differences in various α/β mixtures obtained during the synthesis of C-nucleosides using the D-ribonolactone approach. The desired stereoselectivity for 2'-deoxy analogues was obtained when BF3·OEt2 was used Another route to the synthesis of C-nucleosides was demonstrated by direct addition of aryl lithium reagents to the 2'-OMe ribonolactone (Figure 11B). Subsequent synthesis of the enol triflate (−)-46 (Figure 13B), Suzuki coupling and hydrogenation afforded the optically pure carbocyclic tubercidine analogue (−)-53 This compound has shown potent activity against breast cancer cell lines and human foreskin fibroblasts [53]

Conclusion

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