Spirocyclic Nucleosides in Medicinal Chemistry: An Overview

Abstract

This review describes some spiro- and pseudospironucleoside derivatives as well as their biological and pharmacological applications.

Advances in the Synthesis of Spirocyclic Nucleosides

“…The C -1′-spirocyclic nucleosides are a family of conformationally restricted nucleosides in which the spirocyclic moiety is at the anomeric position. 45 This alters the flexibility of the sugar moiety by fixing the nucleotide base in a particular orientation around the N -glycosidic bond. With the discovery of (+)-hydantocidin and a number of its analogues, anomeric spirocyclic nucleosides have attracted significant attention due to the notion that significant pharmacological leads can be identified among modified nucleoside derivatives.…”

Synthesis of Spironucleosides: Past and Future Perspectives

“…Spironucleosides are a family of conformationally restricted nucleosides in which the anomeric carbon belongs simultaneously to a pyranoid or furanoid sugar ring and to an aza-heterocyclic moiety [ 17 ]. This fixes the nucleotide base in a specific orientation around the N -glycosidic bond, thus altering the flexibility of the sugar moiety.…”

Spirocyclic Thiohydantoin Antagonists of F877L and Wild-Type Androgen Receptor for Castration-Resistant Prostate Cancer

“…The concept of conformation restriction by the cyclization of an acyclic group via a bioisosteric spirocyclic ring has emerged as an effective approach in drug discovery in the past decade. 22 Initially, we explored the structure−activity relationship (SAR) for compounds in classes 6 and 7, but unfortunately, either significant a loss of potency ( 6) or a surprising enhanced intrinsic agonism ( 7) rendered these compounds difficult to progress (data not shown). Thus we focused on scaffold 8 while simultaneously taking advantage of the insight gained from the development of 5 (JNJ-63576253).…”

“… ,, To test this hypothesis (Figure , Supplementary Section S-12), we designed rigidified scaffolds 6 , 7 , and 8 with a spirocyclic central core to add rotational restriction in thiohydantoin series (Figure ). The concept of conformation restriction by the cyclization of an acyclic group via a bioisosteric spirocyclic ring has emerged as an effective approach in drug discovery in the past decade . Initially, we explored the structure–activity relationship (SAR) for compounds in classes 6 and 7 , but unfortunately, either significant a loss of potency ( 6 ) or a surprising enhanced intrinsic agonism ( 7 ) rendered these compounds difficult to progress (data not shown).…”