Doxoform and Daunoform: anthracycline-formaldehyde conjugates toxic to resistant tumor cells.
The recent discovery that the clinically important antitumor drugs doxorubicin and daunorubicin alkylate DNA via catalytic production of formaldehyde prompted the synthesis of derivatives bearing formaldehyde. Reaction of the parent drugs with aqueous formaldehyde at pH 6 produced in 40-50% yield conjugates consisting of two molecules of the parent drug as oxazolidine derivatives bound together at their 3'-nitrogens by a methylene group. The structures were established as bis(3'-N-(3'-N,4'-O-methylenedoxorubicinyl)) methane (Doxoform) and bis(3'-N-(3'-N,4'-O-methylenedaunorubicinyl))methane (Daunoform) from spectroscopic data. Both derivatives are labile with respect to hydrolysis to the parent drugs. 3'-N,4'-O-Methylenedoxorubicin and 3'-N,4'-O-methylenedaunorubicin are intermediates in the hydrolysis. Daunoform reacts with the self-complementary deoxyoligonucleotide (GC)4 faster than the combination of daunorubicin and formaldehyde at an equivalent concentration to given drug-DNA adducts. In spite of hydrolytic instability, Doxoform is 150-fold more toxic to MCF-7 human breast cancer cells and 10000-fold more toxic to MCF-7/ADR resistant cells. Toxicity to resistant cancer cells is interpreted in terms of higher lipophilicity of the derivatives and circumvention of catalytic formaldehyde production.
Fenick
D J
DJ
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215, USA.
Taatjes
D J
DJ
Koch
T H
TH
D000478:Alkylation; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005557:Formaldehyde / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D013058:Mass Spectrometry; D008956:Models, Chemical; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D010080:Oxazoles; D005557:Formaldehyde; D004317:Doxorubicin; D004247:DNA; D003630:Daunorubicin