Anthracycline Drugs: An Update on Chemistry, Structure-Activity Relationship, Mechanism of Action, Cardiotoxicity,...

This review aims to examine the literature on FDA-approved anthracyclines, focusing on their physicochemical and pharmacokinetic properties, and to analyze relevant studies for insights into chemistry, structure-activity relationships (SAR), mechanisms of action, and cardiotoxicity, to guide safer clinical use and future drug development.

A systematic literature search was conducted across PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar up to June 2025. Eligible articles included experimental, clinical, and review data on anthracyclines.

Anthracyclines act primarily through DNA intercalation, topoisomerase II poisoning, generation of reactive oxygen species, and histone eviction. Key SAR determinants include the aglycone core (C-13, C- 14, and C-4 substituents) and the daunosamine sugar; metabolic conversion to C-13 secondary alcohols and disturbed iron handling are major drivers of chronic cardiotoxicity. Clinically, safe administration relies on cumulative dose limits and cardiac monitoring, while liposomal formulations are validated strategies to reduce toxicity without compromising antitumor efficacy.

Integrating SAR, physicochemical, and pharmacokinetic insights provides a framework for rationally modifying scaffolds and optimizing delivery systems to expand the therapeutic window. Advances in understanding cardiotoxicity mechanisms support the development of cardioprotective agents, chemical modifications, and clinically validated strategies such as liposomal formulations, while emerging green nanomaterials, combined with nanocarrier-based co-encapsulation strategies, represent a promising, sustainable, and biocompatible approach. This review emphasizes clinically relevant dosing regimens, pharmacokinetic parameters, and cardiotoxicity thresholds, enabling consistent comparisons of FDA-approved anthracyclines.

This review clarifies key determinants of anthracycline efficacy and toxicity and recommends actionable strategies, including SAR-guided analogues and validated delivery systems, to advance safer therapies.