Structure-bioactivation relationship of a series of podophyllotoxin derivatives.
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 greater than VP-16-213 greater than aglycone much greater than E-ring. A similar sequence was observed for the cytotoxicity against Chinese hamster ovary cells.
Van Maanen
J M
JM
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
van den Akker
E
E
de Vries
J
J
Bakkenist
T R
TR
Lankelma
J
J
Retèl
J
J
Pinedo
H M
HM
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005047:Etoposide / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013713:Teniposide / Q000378:metabolism
D008748:Methylcholanthrene; D005047:Etoposide; D003577:Cytochrome P-450 Enzyme System; D013713:Teniposide; D011034:Podophyllotoxin; D010634:Phenobarbital