Vol. 7, Issue 2, Part C (2025)

2′ Deoxyadenosine (dAdo) resides at the critical junction of de novo and salvage deoxyribonucleotide synthesis while salvage phosphorylation of dAdo replenishes the dATP-pool, the de novo pathway via ribonucleotide reductase (RNR) generates dNTPs from ribonucleotides. Disruption of this balance as typified in adenosine deaminase (ADA) deficiency causes intracellular dAdo and dATP accumulation, potent RNR inhibition, dNTP‐pool disruption and replication stress. Concurrently, synthetic modification of the dAdo scaffold has driven the development of analogues that exploit nucleoside transporters, resist deaminative inactivation and selectively accumulate in target cells to modulate DNA repair, immune signalling and mitochondrial DNA maintenance. This review presents a unified account of dAdo’s structural and molecular properties, its role in dNTP homeostasis and cellular dynamics, the pathological consequences of salvage/de novo dysregulation, and the latest synthetic and medicinal chemistry strategies built on the dAdo framework.