The Effect of Nitroxyalkyl Succinimides on Activity of Cyclic Guanosine Monophosphate Phosphodiesterase.

The effect of N-nitroxymethyl succinimide (1), N-(2-nitroxyethyl) succinimide (2) and N-(3-nitroxypropyl) succinimide (3) on enzymatic activity of cyclic guanosine monophosphate (cGMP) phosphodiesterase was studied and crystal structure of compound (2) was determined. It was shown that all studied N-nitroxy succinimides inhibited cGMP phosphodiesterase in a concentration range of 0.1-0.001 mM. Compound (2) noncompetitively and reversibly inhibited hydrolytic function of enzyme with Ki=1.7×10-5 М. Inhibition constant for the reference compound N-(2-nitroethyl) nicotinamide (nicorandil) was 3×10-5 М.

Action of Iron Nitrosyl Complexes, NO Donors, on the Activity of Sarcoplasmic Reticulum Ca2+-ATPase and Cyclic Guanosine Monophosphate Phosphodiesterase.

The effect of iron nitrosyl complexes, NO donors, of a general formula [Fe2(L)2(NO)4] with functional sulfur-containing ligands (L-3-nitro-phenol-2-yl, 4-nitro-phenol-2-yl, or 1-methyl-tetrazol-5-yl) on the activity of sarcoplasmic reticulum Ca2+-ATPase and cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) was studied. The test complexes uncoupled the hydrolytic and transport functions of Ca2+- ATPase, thus disturbing the balance of Ca2+ ions in cells, which may affect the formation of thrombi and adhesion of metastatic cells to the endothelium of capillaries. They also inhibited the activity of cGMP PDE, thereby contributing to the accumulation of the second messenger cGMP. The studied iron nitrosyl complexes can be considered as potential drugs.

Effects of Fullerene Derivatives on Activity of Ca2+-ATPase of the Sarcoplasmic Reticulum and cGMP Phosphodiesterase.

We studied the effects of new water-soluble polysubstituted fullerene C60 (PFD) derivatives on activity of Ca2+-Mg2+ ATPase of the sarcoplasmic reticulum and cGMP phosphodiesterase. All examined fullerene derivatives inhibited activity of both enzymes. For instance, PFD-I, PFD-II, PFD-III, PFD-V, PFD-IX, PFD-X, and PFD-XI in a concentration of 5×10-5 M completely inhibited hydrolytic and transport functions of Ca2+-ATPase. These compounds in a concentration of 5×10-6 suppressed active transport of calcium ions by 51±5, 77±8, 52±5, 52±5, 100±10, 80±8, and 100±10%, respectively, and inhibited ATP hydrolysis by 31±3, 78±8, 18±2, 29±3, 78±8, 63±7, and 73±9%, respectively, uncoupling the hydrolytic and transport functions of the enzyme. PFD-I noncompetitive and reversibly reduced activity of Ca2+-ATPase (Ki=2.3×10-6 M). All the studied fullerene derivatives (except for PFD-VII) inhibited cGMP phosphodiesterase by more than 80% in concentration of 10-4 M and higher and by more than 50% in concentration of 10-5 M. PFD-I is a non-competitive reversible inhibitor of cGMP phosphodiesterase (Ki=7×10-6 M). These results allow us to expect antimetastatic, antiaggregatory, antihypertensive and vasodilative activity of the studied compounds.