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© Yang SI, Institut Pasteur
Publication : Journal of medicinal chemistry

Synthesis and biological study of a new series of 4′-demethylepipodophyllotoxin derivatives

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Journal of medicinal chemistry - 27 Jan 2005

Duca M, Guianvarc'h D, Meresse P, Bertounesque E, Dauzonne D, Kraus-Berthier L, Thirot S, Léonce S, Pierré A, Pfeiffer B, Renard P, Arimondo PB, Monneret C

Link to Pubmed [PMID] – 15658872

J. Med. Chem. 2005 Jan;48(2):593-603

Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4′-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4beta-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4′-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.