Ribose as the preferential target for the oxidized form of elliptinium acetate in ribonucleos(t)ides. Biological activities of the resulting adducts.
The covalent binding of the oxidized form of elliptinium acetate, an antitumor drug, to various ribonucleos(t)ides is described. In the absence of a strong nucleophile on the bases, e.g., a sulfhydryl group, the main target of this quinone imine derivative is the sugar moiety. With unmodified regular bases, the first electrophilic addition always occurs on the 2'-oxygen of ribose (more slowly for pyrimidine than for purine); in a second step, cyclization of the reoxidized product leads to a spiro derivative: only one stereoisomer is detected with purine nucleoside; the other stereoisomer appears as a minor product (10-20%) with nucleotides and pyrimidine nucleosides. With modified bases, no change is observed except for bases exhibiting an additional strong nucleophilic center: oxidized elliptinium alkylates thioguanine and thioguanosine on the sulfur atom and in this last case not on the ribose moiety. All spiro derivatives are less cytotoxic than the parent compound even if the base is an antimetabolite (azauridine); however, thio-elliptinium adducts maintain high cytotoxicity.
D000470:Alkaloids / Q000378:metabolism*; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004611:Ellipticines / Q000378:metabolism*; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D012263:Ribonucleosides / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism*; D012266:Ribose / Q000378:metabolism*
D000470:Alkaloids; D000970:Antineoplastic Agents; D004611:Ellipticines; D012263:Ribonucleosides; D012265:Ribonucleotides; C027767:elliptinium; D012266:Ribose