TY - JOUR
T1 - Structure-bioactivation relationship of a series of podophyllotoxin derivatives
AU - van Maanen, Johannes M S
AU - van den Akker, Eric
AU - de Vries, John
AU - Bakkenist, Tonnie R J
AU - Lankelma, Jan
AU - Retel, Jan
AU - Pinedo, Herbert M.
PY - 1988
Y1 - 1988
N2 - 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.
AB - 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.
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U2 - 10.1016/0277-5379(88)90330-6
DO - 10.1016/0277-5379(88)90330-6
M3 - Article
C2 - 3181265
AN - SCOPUS:0023753371
SN - 0277-5379
VL - 24
SP - 1415
EP - 1419
JO - European Journal of Cancer and Clinical Oncology
JF - European Journal of Cancer and Clinical Oncology
IS - 9
ER -