Synthesis and biological evaluation of new selective cytotoxic cyclolignans derived from podophyllotoxin.

Abstract

Podophyllotoxin and some of its derivatives are cyclolignans currently used for removing warts and in the clinical treatment of malign neoplasms. As such, they have been an objective of the scientific community for decades, in the search for more potent and more selective anticancer agents. Our interest in the chemoinduction of drug selectivity led us to the design and preparation of new podophyllotoxin derivatives by reaction of podophyllic aldehyde with aliphatic, aromatic, and heteroaromatic amines. Several of the resulting imines displayed a significant selectivity against human colon carcinoma cells, even higher than that of the starting aldehyde. Additional biological studies indicate that these derivatives induce microtubule depolymerization, arrest cells at the G2/M phase of cell cycle, and are able to induce a delayed apoptosis after 48 h of treatment, characterized by caspase-3 activation.

• Authors: María Angeles Castro, Jose María Miguel del Corral, Marina Gordaliza, Pablo A García, María Antonia Gómez-Zurita, María Dolores García-Grávalos, Janis de la Iglesia-Vicente, Consuelo Gajate, Feiyun An, Faustino Mollinedo, Arturo San Feliciano
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 5 Pg. 1214-22 (Feb 26 2004) ISSN: 0022-2623 [Print] United States
• PMID: 14971901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imines
• Podophyllotoxin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Imines (chemical synthesis, pharmacology)
• Mice
• Podophyllotoxin (analogs & derivatives, chemical synthesis, pharmacology)
• Structure-Activity Relationship