Antitumor antibiotic streptonigrin and its derivatives as inhibitors of nitric oxide-dependent activation of soluble guanylyl cyclase

Abstract

The influence of streptonigrin on the activity of human platelet guanylyl cyclase was investigated. Streptonigrin (0.1–5 μM) had no effect on the basal activity of the enzyme, but inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet soluble guanylyl cyclase with an IC 50 value of 4.16 μM. Streptonigrin (10 μM) also inhibited (by 28%) the activation of the enzyme by the direct nitric oxide (NO) donor–spermine–NONO (100 μM), but had no influence on the stimulation of soluble guanylyl cyclase by protoporphyrin IX. The absence of a correlation between the inhibition of NO-stimulated guanylyl cyclase activity by streptonigrin ( I) and its derivatives (streptonigrone ( IV), streptonigrone-2′-imine ( V), amide of 1 and 2′-deoxy-2′-amino- d-glucose ( VI), amide of 1 and 2′-deoxy-2′-amino-2′- d-galactose ( VII), amide of 1 and 1- O-methyl-6-deoxy-6-amino- d-glucose ( VIII), diphenylmethyl ester of I ( IX), conjugate of I and daunorubicin ( X)), and the level of cytotoxic effects of these compounds excludes the involvement of guanylyl cyclase in the mechanism of antitumor action of streptonigrin. Inhibition of guanylyl cyclase activation by NO donors but not by protoporphyrin IX represents a new biochemical effect of streptonigrin, which should be taken into account in addition to its antitumor action.