Pharmacological characterization of a new Ca2+ sensitizer

The benzimidazole molecule was modified to synthesize a Ca(2+) sensitizer devoid of additional effects associated with Ca(2+) overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 microM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na(+)/K(+)-ATPase, sarcolemmal Ca(2+)-ATPase, Na(+)/Ca(2+) exchange carrier, or sarcoplasmic reticulum Ca(2+) pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca(2+)

Studies on the mechanism of action of mitomycin C.

The in vitro formation and properties of the molecular complex between mitomycin C and native DNA were examined by means of various experimental methods; the data obtained indicate that the complex is extremely weak and that the chromophoric moiety of the antibiotic is not involved in its formation. The alkylating activity of mitomycin C was also studied using 3H-mitomycin C; while monofunctional alkylation increases almost in parallel with the concentration of the antibiotic, the difunctional alkylation, causing inter-strand cross-linkages in DNA, rapidly reaches a maximum and then remains constant even when increasing the concentration of the antibiotic and monofunctional alkylation. On the basis of these results, the currently accepted molecular model of the mitomycin--DNA interaction must be revised; a new model of this interaction is presented, which is in better agreement with the properties of mitomycin C and with the latest findings on the subject

A search for potential antitumor agents: biological effects and DNA binding of a series of anthraquinone derivatives.

none5nonePalù G;Palumbo M;Antonello C;Meloni GA;Marciani-Magno SPalu', Giorgio; Palumbo, Manlio; Antonello, C; Meloni, Ga; Marciani Magno, S