Anthracycline prodrug

Bakina, E., and Farquhar, D. Intensely cytotoxic anthracycline prodrugs Galactosides. Anticancer Drug Des. 14 507-515, 1999. 

HariKrishna, D. Raghu Ram Rao, A. and Krishna, D.R. (2003) Selective activation of anthracycline prodrugs for use in conjunction with ADEPT. Drug News el Perspectives, 16, 309-318. 

In an other series of experiments (70), prodrug 73 was compared with epirubicin-4 -0(3-D-gIucuronide (100), proposed as anthracycline prodrug by Haisma et al. (71). 

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

There have been also attempts to prepare targeted drugs based on anthracyclines employing the recognition of some specific sugars by receptors on the tumor cells. Thus, a /3-glucoside derivative of adriamycin (41) was used in an antibody-directed enzyme-prodrug therapy (O Scheme 16) [53],... 

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. 

Kratz F, Wamecke A, Schmid B, et al. Prodrugs of anthracyclines in cancer chemotherapy. Curr Med Chem 2006 13 477-523. 

PRODRUGS OF NATURAL ANTHRACYCLINES SUITED FOR ANTIBODY DIRECTED ENZYME PRODRUG THERAPY (ADEPT) AND PRODRUG MONOTHERAPY... 

An important point for non-toxic prodrug design is the choice of the substitution site of the drug by the enzyme substrate. The type and stereochemistry of the substituents at C-9 on the A-ring of anthracyclines has been shown to have a dramatic influence on activity of these antibiotics [1-4]. Efficient detoxification could therefore be expected by glycosidation of the 14-OH group of doxorubicin by a bulky sugar unit. 

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]. 

The articles contained in this volume include the interaction of alkaloids with neuroreceptors and ion channels, anthracyclines suited for antibody-directed enzyme prodrug therapy and metabolites from soilborne fungi. Several articles are concerned with bioactive natural products from marine sources. The other areas covered include natural products with polyene amide structures, potential hypoglycemic agents, biological activity of essential oils, bioactive saponins and biologically active diterpenoids. 

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