Inhibition of cardiac guanylate cyclase by doxorubicin and some of its analogs: possible relationship to cardiotoxicity.

The anthracycline antibiotic doxorubicin induces a variety of cardiotoxic effects. We have recently demonstrated that this drug also causes a selective inhibition of rat and human cardiac guanylate cyclase activity in vitro. In the present study, we examined the effect of 30 analogs of doxorubicin on cardiac guanylate cyclase activity. Structural modifications of these anthracycline antibiotics were found to alter their effect on rat cardiac guanylate cyclase activity, N-Substitutions on the sugar moiety eliminated the inhibitory action observed with the parent compound. Long-chain hydrocarbon substitutions in place of the methylketone side chain had a similar effect. Removal or substitution of the C-4 methoxy group had little or no effect on the ability of these compounds to modify guanylate cyclase activity. Substitutions of the C-9 side chain by a hydrazone derivative resulted in compounds that stimulated the enzyme. All of the anthracenedione derivatives were inhibitory. A comparison of the inhibitory effect of some of these anthracycline derivatives on in vitro cardiac guanylate cyclase activity with their cardiotoxic potency suggests a possible relationship between these two parameters.