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 °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.