Role of epoxide in neocarzinostatin chromophore stability and action

To determine the role of the epoxide moiety of the nonprotein chromophore of the antitumor antibiotic neocarzinostatin in its ability to damage DNA, the diol monomethyl ether derivative was prepared, and its stability and biological properties were studied. This analogue was found to be more stable than the epoxide (about 9-fold), but to be much less active in nicking supercoiled DNA and in forming covalent adducts with poly(dA-dT). However it is able to bind noncovalently to DNA and to the neocarzinostatin apoprotein. Another analogue, the chlorohydrin derivative, is about half as active as the epoxide in the DNA scission reaction and appears to produce the same covalent adducts with poly(dA-dT) as does the epoxide, suggesting that both compounds undergo similar types of activation by thiol. These results indicate that the epoxide moiety of the neocarzinostatin chromophore is an important part of the highly unsaturated, strained bicyclo[7.3.0]dodecadiendiyne in the thiol-dependent, DNA-damaging reaction. It may be involved in the activation of the drug to its active species and/or may be the site of new bond formation in its reaction with DNA.