The Effects of Podophyllotoxin Derivatives on Noncancerous Diseases: A Systematic Review.

Podophyllotoxin (PPT) is commonly used for genital warts due to its antimitotic properties and relatively good accessibility since it can be extracted from plants in low-economy countries. However, due to relatively high toxicity, it cannot be used in a systematic way (intravenously). Thus, there is a need to find or create an equally effective derivative of PPT that will be less toxic. Natural PPT is a suitable and promising scaffold for the synthesis of its derivatives. Many of them have been studied in clinical and preclinical models. In this systematic review, we comprehensively assess the medical applications of PPT derivatives, focusing on their advantages and limitations in non-cancerous diseases. Most of the existing research focuses on their applications in cancerous diseases, leaving non-cancerous uses underexplored. To do that, we systematically reviewed the literature using PubMed, Embase, and Cochrane databases from January 2013 to January 2025. In total, 5333 unique references were identified in the initial search, of which 44 were included in the quantitative synthesis. The assessment of the quality of eligible studies was undertaken using the PRISMA criteria. The risk of bias was assessed using a predefined checklist based on PRISMA guidelines. Each study was independently reviewed by two researchers to evaluate bias in study design, reporting, and outcomes. Our analysis highlights the broad therapeutic potential of PPT derivatives, particularly in antiviral applications, including HPV, Dengue, and SARS-CoV-2 infections. Apart from their well-known anti-genital warts activity, these compounds exhibit significant anti-inflammatory, antimitotic, analgesic, and radioprotective properties. For instance, derivatives such as cyclolignan SAU-22.107 show promise in antiviral therapies, while compounds like G-003M demonstrate radioprotective effects by mitigating radiation-induced damage. To build on this, our review highlights that PPT derivatives, apart from anti-genital warts potential, exhibit four key properties-anti-inflammatory, antimitotic, analgesic, and radioprotective-making them promising candidates not only for treating viral infections such as HPV, Dengue, and SARS-CoV-2 but also for expanding their therapeutic potential beyond cancerous diseases. In conclusion, while PPT derivatives hold great potential across various medical domains, their applications in non-cancerous diseases remain limited by the scarcity of dedicated research. Continued exploration of these compounds is essential to unlock their full therapeutic value.