Prodrugs self-immolative

Keywords Biosensor Cancer Dendrimer Prodrug Self-immolative... 

FIGURE 5.1 Graphical structure of a tripartite prodrug with self-immolative linker. (See the color version of this figure in Color Plates section.)... 

FIGURE 5.33 Molecular structure of second-generation, self-immolative, dendritic CPT prodrug with a trigger designed for activation by PGA. 

Shamis, M. Lode, H. N. Shabat, D. Bioactivation of self-immolative dendritic prodrugs by catalytic antibody 38C2. J. Am. Chem. Soc. 2004, 126, 1726-1731. 

Gopin, A. Ebner, S. Attali, B. Shabat, D. Enzymatic activation of second-generation dendritic prodrugs conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry. Bioconj. Chem. 2006, 17, 1432-1440. 

FIGURE 5.1 Graphical structure of a tripartite prodrug with self-immolative linker. 

FIGURE 5.14 Chemical structures of AB3 self-immolative dendritic prodrugs with melpha-lan tail units and a trigger that is activated by PGA. 

Fig. 8.17. Mechanism of bioactivation of self-immolative carbamate prodrugs of cytotoxic amines. A bacterial nitroreductase coupled to a tumor-directed antibody reduces the prodrug to a hydroxylamine (Reaction a), which breaks down spontaneously to liberate the antitumor...

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-... 

A. B. Mauger, P. J. Burke, H. H. Somani, F. Friedlos, R. J. Knox, Self-Immolative Prodrugs Candidates for Antibody-Directed Enzyme Prodrug Therapy in Conjunction with a Nitroreductase Enzyme , J. Med. Chem. 1994, 37, 3452-3458. 

In order to solve this problem, we concieved a series of triparte prodrugs in which the enzyme substrate was attached to the anthracycline through a self-immolative spacer. In these prodrugs, the spacer was linked to the amino group of the anthracycline sugar unit, which is also critical for the biological activity. 

Next, in order to determine whether a self-immolative connector was essential or not when the enzyme specifier was linked at NH2-3 on the daunosamine unit of an anthracycline, we decided to prepare the prodrug 48. Enzymatic cleavage of 48, if it occured, would give rise to a carbamic acid, unstable at physiological pH, which would immediately release free doxorubicin [63]. 

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