Targeting Cancer Hallmarks with Melatonin-based Analogues and Hybrids: From Pleiotropic Hormone to Multitarget...

Cancer remains one of the leading causes of mortality worldwide and represents a multifactorial disease characterized by the dysregulation of multiple interconnected biological processes, including uncontrolled cell proliferation, resistance to apoptosis, metabolic reprogramming, angiogenesis, chronic inflammation, immune evasion, and metastatic dissemination. Within this complex scenario, melatonin has attracted increasing interest as a pleiotropic oncostatic molecule capable of modulating several cancer hallmarks through both receptor-dependent (MT1/MT2) and receptor-independent mechanisms, including redox regulation, mitochondrial modulation, and interference with key signaling pathways such as PI3K/AKT/mTOR and HIF-1α/VEGF. In addition, melatonin has been shown to influence tumor-associated inflammatory responses, epithelial-mesenchymal transition, and microenvironmental signaling, further supporting its multitarget pharmacological profile. Despite its favorable safety profile and broad spectrum of biological activities, the direct clinical translation of melatonin as an adjuvant anticancer agent remains limited by poor oral bioavailability, short plasma half-life, rapid metabolic degradation, and relatively low potency at pharmacologically relevant concentrations. These limitations have prompted significant medicinal chemistry efforts aimed at the design and development of melatonin analogues, derivatives, and hybrid molecules with improved pharmacokinetic and pharmacodynamic properties. This review provides a comprehensive and critical overview of recent advances (2020-2026) in the field of melatonin-based anticancer agents, with particular emphasis on rational drug design strategies, Structure- Activity Relationships (SAR), and the identification of relevant molecular targets, including hormone- dependent pathways, epigenetic modulators, cell-cycle regulators, and hypoxia-related signaling cascades. Overall, the collected evidence highlights the potential of melatonin as a versatile pharmacophore for the development of multitarget anticancer agents and underscores future perspectives for its optimization in oncology-oriented drug discovery.