Nucleoside Analog Natural Products: Over a Decade of Advances in Isolation, Biological Activity, and Synthesis

Abstract

Nucleoside analogs represent one of the largest classes of anticancer and antiviral therapies, many of which have been directly or indirectly developed as a result of nucleoside natural product discovery. Over the past decade, renewed interest in this class has led to the discovery of diverse nucleoside analog natural products from microbial, marine, and fungal sources, often featuring unprecedented modifications to the nucleobase, and/or the ribose sugar 2′, 3′, 4′, and 5′ positions. This review provides a comprehensive update of novel nucleoside natural products reported between January 2015 and January 2026, encompassing their isolation, structural elucidation, biological activities, and synthetic and biosynthetic studies. Expansions to key families such as muraymycins, pseudouridimycin, tunicamycins, and puromycin analogs are discussed alongside structural revisions and unique metabolites that expand the chemical space of nucleosides. By consolidating recent advances and highlighting emerging structural and biological trends, this review aims to provide a resource for researchers in natural product chemistry, chemical biology, and medicinal chemistry, and to inspire new nucleoside drug discovery programs.