Effect of hemoglobin on the NO-donor ability of μ2-S-bis(pyrimidine-2-thiolato)tetranitrosyldiiron

Abstract

The hydrolysis of the iron nitrosyl complex [Fe 2 (μ 2 SC 4 H 3 N 2 ) 2 (NO) 4 ] (C 4 H 3 N 2 S -is pyri midine 2 thiolate) in the presence of hemoglobin (Hb) is accompanied by the NO release into a solution. In the absence of Hb, the starting complex is oxidized by nitric oxide that is released into a solution, which leads to further transformations of NO, nitric oxide being present in the solution only partially. The effective rate constant for the decomposition of the complex is high and depends on its concentration. On the one hand, in the presence of Hb, NO molecules rapidly and irreversibly bind to Hb to form HbNO, which is the intermediate in the nitric oxide metabolism. On the other hand, the reversible binding of the iron nitrosyl complex to the surface functional groups of Hb leads to a decrease in its concentration in a solution and deceleration of the formation of NO. Therefore, Hb can ensure the complete and more pro longed assimilation of NO.The iron thiolate nitrosyl complexes [Fe 2 (SR) 2 (NO) 4 ], like S nitrosothiolates 1 and diazeniumdiolates, 2,3 are hydrolyzed in protic media to form nitric oxide 4 and be long to a new class of NO donors holding promise for the pharmacology. 5-10 Previously, we have found that iron sulfur nitrosyl complexes are decomposed with the NO release in protic media without additional activation, 4,11 the rate constants for this reaction being dependent on the molecular structures of the complexes. In the present study, we investigated the new dinuclear iron tetranitrosyl complex with the pyrimidine 2 thiolate ligand [Fe 2 (μ 2 SC 4 H 3 N 2 ) 2 (NO) 4 ] (1) exhibiting high antitumor activity (86-88% of the growth retardation in human tumor cells, the ovarian cancer cell line SCOV3). 7 The pyrimidine 2 thiolate ligand C 4 H 3 N 2 S -can be considered as the struc tural analog of antimetabolites (6 mercaptopurine, etc.), which are used for the synthesis of antitumor agents, 12-17 and NO is a key agent in the cancer genesis. 18 The direct determination of the NO concentration in a solution by the electrochemical method with the use of a sensor electrode showed that the maximum NO concen tration after the hydrolysis of complex 1 in a protic medi um is substantially lower than the stoichiometrically pos sible yield, the decomposition of complex 1 occurring rap idly. 19 By contrast, a larger amount of NO is released in the presence of hemoglobin (Hb) (one NO molecule per molecule of the complex), and the decomposition occurs more slowly. In our opinion, this fact is important both in terms of the insight into the mechanisms of reactions of heme proteins with new exogenic NO donors and from the point of view of drug design. Thus, the pharmacologically active agent (NO donor) should have the period of perfor mance sufficient for the NO delivery to target sites.The formation of Hb(NO) 4 in the reaction with Hb can serve as a convenient method for the estimation of the NO donor ability of iron nitrosyl complexes. 4 Due to the high rate constant for the reaction of Hb with NO (k...