Mitomycin, prodrugs

G. M. Dubowchik, K. Mosure, J. O. Knype, R. A. Firestone, Cathepsin B-Sensitive Dipeptide Prodrugs. 2. Models of Anticancer Drugs Pachtaxel, Mitomycin C and Doxorubicin , Bioorg. Med. Chem. Lett. 1998, 8, 3347-3352. 

The so-called self-immolative prodrugs are other relevant and intriguing examples as candidates for ADEPT (Fig. 8.17). Here, the primary bioactivation product is not the active agent, but an intermediate that breaks down spontaneously to liberate this active agent. Various cytotoxic drugs that bear an amino group were investigated, i. e., 4-[bis(2-chloroethyl)amino]aniline, actinomycin D, doxorubicin, and mitomycin C [206]. These were trans-... 

There is complete reduction of a p- or o-quinone to the corresponding hydroquinone or catechol, respectively. In the human liver, carbonyl reductase may play a role in the reduction of some quinones. Catechols are primary substrates for catechol o-me-thyl transferase, but also undergo sulfation. However, for the antitumor quinones, mitomycin C, adriamycin, and daunomycin, two-electron reduction serves as an efficient bioactivation mechanism, elegantly affirming the concept of bioreductive alkylation for the preferential bioactivation of antitumor prodrugs with oxygen deficient tumors. 

Cytotoxic antibiotics produce their effect mainly by direct action on DNA. Anthracyclines include the important drugs doxorubicin, aclarubicin and idarubicin. Related compounds are mitozantrone and epirubicin. Some others are the Streptomyces antibiotic dactinomycin. and the metalchelating glycopeptides especially bleomycins. Mitomycin effectively is a prodrug that is converted in the body to an alkylating agent. 

The half-lives of cathepsin B cleavage of doxorubicin prodrug 41 and mitomycin C prodrug 43 were much shorter than those of paclitaxel prodrugs 40 and 42, indicating steric hindrance by the paclitaxel part of the prodrug.4... 

Zalipsky S, Saad M, Kiwan R, Ber E, Yu N, Minko T. Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor Insights of the mechanism of action. J Drug Target 2007 15 518-530. 

In an attempt to achieve higher tumour selectivity, antibody-directed enzyme prodrug therapy (ADEPT) has been applied to phosphate prodrugs of the anticancer drugs etoposide, doxorubicin, mitomycin and phenol mustard [127, 128]. The prodrugs release the parent drug at the tumour by hydrolysis catalyzed by alkaline phosphatase linked to a tumour-selective antibody. 

K. Hoste, E. Schacht and B. ftfliovd. Synthesis and biological evaluation of PEG-substituted macromolecular prodrugs of mitomycin C, /. Bioactive Compat. Polym., 17,123-138 (2002). 

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