Regulation of apoptosis in leukemic cells by analogs of dynemicin A

The naturally occurring enediyne antibiotics, which include calicheamicin, esperamicin, neocarzinostatin, kedarcidin and dynemicin, are a unique class of reactive compounds which can undergo aromatization to produce cytotoxic biradicals and can result in phosphodiester bond breakage of DNA. Synthetic enediynes designed with low molecular complexity are also highly cytotoxic, specifically to human leukemic cells, by a mechanism involving the induction of apoptosis. We have used a variety of biological assays to evaluate the cytotoxic properties of synthetic dynemicin analogs which contain a spectrum of structural modifications and reactivities. It was found that the induction of apoptosis and nuclear degradation by the synthetic compounds did not require an ability to bind or cleave DNA. Prevention of apoptosis was observed in analogs which were electronically stabilized to inhibit aromatic rearrangement and generation of diradicals. The preventive capability of the stabilized analogs was observed against a wide variety of toxic agents including topoisomerase I and II inhibitors, anti-mitotic and DNA anti-metabolite drugs, as well as alkylating agents. The structural determinants involved in inhibiting the induction of apoptosis are described. The significance of these results with respect to relevant mechanism of tumor regression are discussed.