1,3-Dioxolane derived nucleos(t)ides: synthetic strategies, current position, and future promise in antiviral and anticancer drug discovery

Abstract To date, altered nucleos(t)ides offer significant potential in antiviral and anticancer drug discovery. In the past several decades, numerous modified nucleos(t)ides have received Food and Drug Administration (FDA) approval for the treatment of viral infections and several cancers. Modifying the base or sugar of a nucleos(t)ide confers specificity and selectivity for viral RNA/DNA polymerases and highly dividing cancer cells. Ribose- and carbocyclic-based nucleosides are well established in medicinal chemistry, yielding many preclinical leads and clinical candidates with therapeutic potential. The insertion of a 1,3-dioxolane ring in place of the ribose sugar represents a unique strategy in nucleoside design to target viral DNA polymerases and rapidly proliferating cancer cells. To date, only a few 1,3-dioxolane-derived nucleos(t)ides (DDNs) have been progressed for clinical development. The chemical space of DDNs remains insufficiently explored. Substantial efforts are still required to develop novel molecules within this class, which may open new avenues for the discovery of potent antiviral and anticancer agents. This review is focused on the synthesis and development of selective DDNs and their potential in preclinical/clinical development.