Mitomycins, bioactivity

Belcourt, M.F. Hodnick, W. F. Rockwell, S. Sartorelli, A. C. Bioactivation of mitomycin antibiotics by aerobic and hypoxic Chinese hamster ovary cells overexpressing DT-diaphorase. Biochem. Pharm. 1996, 51, 1669-1678. 

FIGURE 5.12 Bioactivation of mitomycin C, the first step of which involves reduction of the quinone. 

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-... 

Following a similar strategy, the synthesis of tetracyclic models of aziridinomitosenes, bioactive degradation products of mitomycins, was based on the Reformatsky reaction of thiolactam 100, as shown in equation 59. The synthetic plan and reagent design were directed to the use of an intramolecular Heck reaction of 101 to complete the target skeleton146. 

Many mitomycin analogues have been prepared by partial synthesis, and two of them have received clinical trials.Unexpected toxicity has led to their withdrawal, however. The present clinical candidates. BMY-25067 and KT 6149. contain disulfide sulxstituents on the 7-amino group. Control of the quinone reduction potential is especially. stre.ssed in analogue. studies, because reduction is the key step in bioactivation of the.se molecules. - ... 

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. 

The bioactive benzimidazolequinone 131 has been synthesized by demethylation of the dimethoxybenzimidazole 129 followed by facile oxidation of the intermediate dihydroxy compoimd 130 by ferric chloride to yield the quinone 131 in excellent yield (Scheme 23). Synthesis of the related ben-zimidazolequinones 134 was achieved by dinitration of 132 followed by the reduction of 133 and oxidation as above. The benzimidazole-6,9-dione 134 has been found to be 300 times more cytotoxic towards the human skin fibroblast cell line in the MTT assay than the clinically used bioreductive drug, mitomycin C. Attaching methyl substituents onto the quinone moiety increased reductive potential and decreased cytotoxicity and selectivity towards hypoxia [67]. 

AO and XO are cytosolic enzymes and are closely related. However, they differ in their substrate/inhibitor specificities. AO is involved in the metabolism of several clinically significant drugs such as famciclovir, zaleplon, zonisamide, and ziprasidone [69-72], XO has a narrower substrate specificity than AO and is mainly active toward purines and pyrimidines. XO plays a role in the oxidation of several chemotherapeutic agents and has been implicated in the bioactivation of mitomycin B [73]. 

Pritsos, C.A. and SartoreUi, A.C., Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics. Cancer Res., 46, 3528,1986. 

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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