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oai:gredos.usal.es:10366/1669712025-09-10T00:02:15Zcom_10366_149436com_10366_3947com_10366_3946com_10366_3823col_10366_151253

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile Miranda-Vera, Carolina Hernández, Ángela Patricia García-García, Pilar Díez, David García, Pablo Anselmo Castro, María Ángeles podophyllotoxin; natural products; chemomodulation; hybrids; cytotoxicity Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties. 2025-09-09T08:10:31Z 2025-09-09T08:10:31Z 2023 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/10366/166971 10.3390/pharmaceutics15122728 1999-4923 eng https://www.mdpi.com/1999-4923/15/12/2728 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess MDPI https://gredos.usal.es/bitstream/10366/166971/5/pharmaceutics-15-02728.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by-nc-nd/4.0/ Gredos. Repositorio Documental de la Universidad de Salamanca http://hdl.handle.net/10366/166971