Cardiac glycosides: structural diversity, chemical ecology, bioactivity, and artificial synthesis

Covering: up to 2025Cardiac glycosides (CGs), a class of metabolites found in nature, comprise sugar residues, unsaturated lactone rings, and steroidal cores. As renowned phytotoxins, they play vital roles in maintaining ecological balance. CGs have been widely used in the treatment of cardiovascular diseases such as heart failure and tachyarrhythmia for more than 200 years. Recent studies have revealed that CGs have numerous applications in various disease therapeutic areas, including anticancer, immunomodulatory, anti-inflammatory, antiviral, and neuroprotective effects. However, the medicinal resources of CGs are mainly reliant on natural plant and animal extracts, which not only limits their sustainable supply but also increases development costs. With the growing understanding of the pharmacological value of CGs and their increasing demand in the pharmaceutical industry, the sustainable supply of medicinal resources will become a bottleneck limiting their further development. Therefore, the artificial synthesis of target active ingredients, including chemical (semi)synthesis and biosynthesis, is becoming a hot topic among scholars worldwide. This paper presents the first systematic review of recent research advances in the structure, distribution, chemical ecology, biological activities, and artificial synthesis of CGs. Finally, we discuss the current challenges and urgent issues in this field, aiming to promote the widespread application of CGs in medicine through comprehensive pharmacological studies and exploration of synthesis techniques.