Prodrugs of enediyne compounds, cyclopropylindoles and their seco precursors: potential new anticancer agents

A major problem with cancer chemotherapy is its lack of selectivity for killing tumour cells over that for normal tissue. ADEPT (antibody-directed enzyme prodrug therapy) and GDEPT (gene-directed enzyme prodrug therapy) attempt to overcome this problem by either localising or expressing a prodrug activating enzyme selectively at the tumour site. These patents lay claim to prodrugs of enediyne compounds and the seco precursors of cyclopropylindoles which can be activated by either the enzyme carboxypeptidase G2 or the enzyme nitroreductase and form active agents that are much more cytotoxic than those presently in use for ADEPT or GDEPT applications. Novel prodrugs activated by nitroreductase are demonstrated. These represent a new class of bioreductive agent and are of particular interest in GDEPT strategies.