Revisiting heliomycin: Chemistry, biological activity, and perspectives for drug development

Microbial secondary metabolites continue to be used as scaffolds for the development of medications for treatment of infectious and oncological diseases. Among them, aromatic polyketides occupy a prominent place due to their structural originality and broad biological activities. Heliomycin (also known as resistomycin), an antibiotic with pentacyclic benzo[cd]pyrenequinone core, produced by Streptomyces species, represents a structurally unique member of this class. Although historically heliomycin applied as a topical antibacterial or antiviral agent, it has attracted renewed interest owing to its versatile biological profile, including, antibacterial, antifungal, and particularly anticancer activities. This review provides a comprehensive and systematic analysis of heliomycin and its analogues, covering microbial production, biosynthetic pathways, structural elucidation, total synthesis and chemical modifications. Special attention is focused on semisynthetic derivatives of heliomycin aimed for improved solubility, stability, and pharmacological properties. The biological section summarizes current knowledge on molecular targets and mechanisms of action, including interactions with DNA, topoisomerases, epigenetic regulators (HDACs, SIRT1), tumor-associated enzymes (tNOX), oxidative stress pathways, and key signaling cascades. In vivo antitumor studies and emerging structure-activity relationships are also critically discussed. Taken together the available evidence positions heliomycin not as a single-target antibiotic, but as a pleiotropic bioactive scaffold with significant potential for further drug development.