The chemical and biological properties of natural resorcylic acid lactones.

Covering: 1953 to Feb 2025Resorcylic acid lactones (RALs) represent a significant category of polyketides characterized by a β-resorcylate unit embedded in a macrolactone ring. Since the discovery of radicicol in 1953, over 300 natural RALs have been identified, showcasing remarkable structural diversity and a wide range of pharmacological activities, including antitumor, antimalarial, antifungal, and immunomodulatory effects. RALs target multiple molecular pathways, such as heat shock protein 90 (HSP90), WNT-5A, pyruvate dehydrogenase kinase 2 (PDK2), mitogen-activated protein kinase (MAPK), and peroxiredoxin 1 (PRDX1). Despite their promising pharmacological profiles, the clinical development of RALs has progressed at a sluggish pace. This review comprehensively catalogs all natural RALs reported to date, explores their bioactivity mechanisms, and critically assesses preclinical and clinical progress. By addressing gaps in mechanistic understanding and translational research, this work highlights the challenges in drug-like properties and clinical applicability, offering valuable insights for future RAL research.