Recent progress in the natural products research on the phenanthrene-fused indolizidine ring scaffold: Structural diversity, biological activity, and synthetic studies.

Phenanthroindolizidine alkaloids (PIA) are a class of natural nitrogen-containing secondary metabolites characterized by a unique fused five-ring skeleton. They possess multiple modification sites and exhibit a wide range of pharmacological activities. These compounds are widely distributed in various plants and some herbivorous insects, though they occur in very low content. To date, over a hundred individual compounds have been isolated from natural sources. In vitro and in vivo studies have demonstrated that PIA possesses a variety of pharmacological effects, including antitumor, anti-inflammatory, antiviral, antibacterial, and antiparasitic properties. It also exhibits agricultural bioactivities such as plant antibacterial and insecticidal effects; however, issues such as central nervous system toxicity and gastrointestinal toxicity severely limit its clinical translation. This paper systematically reviews research progress on PIA from 1935 to 2025, summarizing the natural distribution, biosynthetic pathways, and chemical synthesis routes of these compounds, and providing a comprehensive overview of their diverse biological activities, mechanisms of action, and structure-activity relationships. Additionally, in light of the toxicological characteristics of PIA, the paper explores strategies for reducing toxicity and enhancing efficacy, such as structural modifications and dosage form optimization. This review synthesizes the scattered research findings in this field and clarifies the structure-activity and structure-toxicity relationships, thereby providing a systematic theoretical framework for the molecular design, targeted synthesis, and innovative drug development of this class of alkaloids.