ABSTRACT
A comparison of more important physical, chemical and biological properties of the nitric oxide (NO) and free stable nitroxyl radicals (nitroxides) on the base of their structural similarity is made in the article. The active moiety in the nitroxide molecule represents a sterically hindered nitric oxide. The mechanisms of biological action of the nitroxides and especially of their derivatives with antitumor agents from the groups of nitrogen mustards, nitrosoureas, aziridines and triazenes (spin-labeled compounds) is explained through the biological activities of sterically hindered NO. Similarly to NO, nitroxides also can react with superoxide anion radical (O(2)(-)), they possess superoxide dismutase (SOD) mimetic action. While the interaction of NO with O(2)(-)yields very toxic peroxynitrite (ONOO(-)), its formation is strongly limited in the presence of a nitroxide. It is known that the nitrosourea antitumor drugs, like lomustine (CCNU) and carmustine (BCNU), showed high general toxicity, one of the reasons for that probability is the formation of NO, and subsequently of ONOO(-), during their metabolism. The biological investigations of the nitroxides showed their considerably lower general toxicity that could be explained with the SOD-mimetic action of the nitroxide present in their molecule.
Subject(s)
Nitric Oxide/metabolism , Nitrogen Oxides/metabolism , Superoxide Dismutase/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Spin LabelsABSTRACT
We studied the formation of a free radical induced by UV irradiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in benzene. It was determined a stable nitroxide radical by ESR spectroscopy. We confirmed that sterically hindered cyclic amine 2,2,6,6-tetramethyl-4-piperidone (TMPone) was transformed into a corresponding stable free nitroxyl radical during UV irradiation. When CCNU was present, the rate of free radical formation from TMPone increased considerably.
Subject(s)
Lomustine/radiation effects , Benzene , Electron Spin Resonance Spectroscopy , Free Radicals , Lomustine/chemistry , Triacetoneamine-N-Oxyl , Ultraviolet RaysABSTRACT
1-Methyl-1-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, 1,1-di-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide and 1,1-di-(2-bromoethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, which are a novel class of nitrosoureas containing hydrazinomustard residue, have been synthesized. A dose-dependent antitumour activity was found with the three tested compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Nitrosourea Compounds/chemical synthesis , Semicarbazides/chemical synthesis , Tumor Cells, Cultured/drug effects , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Mice , Mice, Inbred Strains , Nitrosourea Compounds/pharmacology , Semicarbazides/pharmacologyABSTRACT
A hypothesis is suggested, which emphasizes the role in carcinogenesis of the attack on low molecular nucleophilic substances (LMN) by electrophilic agents - chemical carcinogens, phisical factors, and antitumor alkylating agents. The significance of the degree of nucleophilicity (electronic charge, order of bonds, index of valence) as a locus minoris resistentiae of the LMN in the electrophilic attack on the latter is emphasized as well as the probable role of the hydrogenated pteridines in influencing carcinogenesis by means of ascorbate, tocopherol, SH-containing compounds etc. In support of this hypothesis the preference of electrophilic agents (derivatives of nitrogen mustard and nitrosoureas) for the places with highest degree of nucleophilicity as targets, in experiments in vitro with nucleic bases and pteridines is emphasized.
