The evolving chemistry of cADPR analogues: from marine discovery to calcium signaling tools

Cyclic adenosine diphosphate ribose (cADPR) is a key second messenger that regulates intracellular Ca²⁺ homeostasis via ryanodine receptor (RyR)-dependent pathways. However, its limited membrane permeability and susceptibility to hydrolysis hinder its application as a molecular probe or therapeutic agent. To address these concerns, extensive efforts have focused on the total synthesis of cADPR analogues, aiming to obtain chemically stable and cell-permeable derivatives with tailored properties. Among the various cellular systems expressing a functional cADPR signaling machinery, Jurkat and neuronal cells are of particular interest, as dysregulation of intracellular calcium levels has been observed in these cellular systems in the contexts of HIV infection and neuroblastoma development, respectively. Accordingly, this review highlights the recent advances in the design and synthesis of cADPR analogues, offering new insights in structure-activity relationship (SAR) studies in Jurkat and neuronal cells, and emphasizing the importance of balancing structural stability, cellular uptake, and receptor affinity to achieve an effective Ca²⁺ mobilization. Overall, the findings discussed herein contribute to a deeper understanding of cADPR chemical biology and provide a synthetic platform for the rational design of cutting-edge Ca²⁺-modulating agents with potential diagnostic and therapeutic applications.