Doxazolidine, a proposed active metabolite of doxorubicin that cross-links DNA.
A crystal structure establishes doxoform as a dimeric formaldehyde conjugate of the oxazolidine of doxorubicin. Doxoform is a prodrug of doxazolidine, a monomeric doxorubicin formaldehyde-oxazolidine. Both doxoform and doxazolidine inhibit the growth of cancer cells at 1-4 orders of magnitude lower concentration than doxorubicin. They also inhibit the growth of cancer cells better than doxsaliform, a prodrug for an acyclic doxorubicin-formaldehyde conjugate. Doxoform rapidly hydrolyzes to doxazolidine, which then hydrolyzes to doxorubicin with a half-life of 3 min in human serum at 37 degrees C. Both doxoform and doxazolidine are taken up by multidrug-resistant MCF-7/Adr cells 3- to 4-fold better than doxorubicin. A molecular model suggests that doxazolidine can cross-link DNA by direct reaction with a G-base in a tautomeric form with synchronous ring opening of the oxazolidine. These results point to doxoform being a prodrug for doxazolidine that is the reactive species that directly cross-links DNA.
Post
Glen C
GC
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215, USA.
Barthel
Benjamin L
BL
Burkhart
David J
DJ
Hagadorn
John R
JR
Koch
Tad H
TH
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D010080:Oxazoles; D011355:Prodrugs; C545998:doxazolidine; C120610:doxoform; D004317:Doxorubicin; D004247:DNA