Structure-bioactivation relationship of a series of podophyllotoxin derivatives

Johannes M S van Maanen, Eric van den Akker, John de Vries, Tonnie R J Bakkenist, Jan Lankelma, Jan Retel, Herbert M. Pinedo

Research output: Contribution to journalArticle

Abstract

With the aim of elucidating the structural requirements for O-demethylation of the antitumor agent VP-16-213 by cytochrome P-450, the binding of a series of podophyllotoxin derivatives to rat liver microsomal cytochrome P-450 was studied. The examined podophyllotoxin derivatives were: VP-16-213, VM-26, podophyllotoxin, 4′-demethylepipodophyllotoxin (the aglycone of VP-16-213 and VM-26) and 3,5-dimethoxy-4-hydroxytoluene (a model compound for the E-ring of VP-16-213). The binding to phenobarbital (Pb)-induced microsomes was more extensive than that to 3-methylcholanthrene (3-MC)-induced microsomes. Experiments on the binding to cytochrome P-450 in Pb-induced microsomes led to the following findings: (a) the presence of the polycyclic skeleton is necessary for binding; (b) the presence of the sugar moiety gives a further extension of binding, and changes in the sugar moiety affect binding; (c) binding increases on elevation of hydrophobicity; (d) the E-ring itself does not bind. For binding to cytochrome P-450 in 3-MC-induced microsomes conclusions (a) and (d) appeared to hold true. For the O-demethylation of the podophyllotoxin derivatives containing the dimethoxyphenol ring by Pb- and 3-MC-induced microsomes, the following order was observed: VM-26 > VP-16-213 > aglycone ≫ E-ring. A similar sequence was observed for the cytotoxicity against Chinese hamster ovary cells.

Original languageEnglish (US)
Pages (from-to)1415-1419
Number of pages5
JournalEuropean Journal of Cancer and Clinical Oncology
Volume24
Issue number9
DOIs
StatePublished - 1988
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    van Maanen, J. M. S., van den Akker, E., de Vries, J., Bakkenist, T. R. J., Lankelma, J., Retel, J., & Pinedo, H. M. (1988). Structure-bioactivation relationship of a series of podophyllotoxin derivatives. European Journal of Cancer and Clinical Oncology, 24(9), 1415-1419. https://doi.org/10.1016/0277-5379(88)90330-6