T. P. Trofimova

Synthesis and study of NOS-inhibiting activity of 2-N-acylamino-5,6-dihydro-4H-1,3-thiazine

The synthesis and results of in vitro and in vivo testing of 2-N-acetylamino-, 2-N-benzoylamino-,2-N-cyclohexanecarbonylamino-, and 2-N-(1-adamantanecarbonyl)amino-5,6-dihydro-4H-1,3-thiazines for NOS-inhibiting activity have been described.

The relationship between NO-synthase inhibitory activity of N,S-containing heterocycles and their radioprotective and antileukemic properties

The effect of NO-synthase (NOS) activator and inhibitors on leukemic cell lines HL-60, K-562, and MOLT-4 and bone marrow cells of untreated patients diagnosed with B-cell acute lymphoblastic leukemia compared with lymphocytes from healthy donors is examined. The obtained data on the relationships between the radioprotective, NOS inhibitory, and cytotoxic properties of a number of thiazine, thiazoline, and thiourea derivatives indicates their potential for use as agents for complex radio- and chemotherapy.

Nitric oxide inhibitor activity of 2-amino-2-thiazoline derivatives

A series of 2-amino-2-thiazoline derivatives have been synthesized and characterized with respect to NOS-inhibitor activity in vivo. It was established that the dimensions of the substituents in 2-N-mono-and 2-N,N-disubstituted 2-amino-2-thiazolines are not significant for the biological activity of the products.

Zinc-containing derivatives of 2-aminopyrimidine

A platform containing three anticancer components is proposed. The components are a radioactive 69mZn isotope and zinc complexes, where both zinc and ligand exhibit anticancer properties. Two zinc-containing complexes, namely (2-AP)2ZnCl2 and (2-AP)2Zn(Sal)2 (AP is 2-aminopyrimidine, Sal is salicylate) were synthesized and characterized. Their cytotoxicity with respect to some leukemia cell lines is demonstrated. Their stability in physiological solution and percentage of apoptosis (by flow cytometry) are investigated. Stable complexes of compounds with the isotope 69mZn were characterized by TLC and autoradiography.

Sorption and cytotoxicity of zinc on hydroxyapatite

The preparation, physicochemical properties, and cytotoxicity of zinc-containing hydroxyapatites (HAP) were considered for further using HAP as carriers for zinc-containing drugs and radiopharmaceuticals.

Prospects of new approaches to impact leukemia cells

Two new approaches to impact leukemia cells of different types are considered. The effect of heterocycles serving as NO synthase inhibitors or activators and the possibilities of the use of the zinc-related magnetic isotope effect are described.

Effect of the thiazine and thiourea derivatives as NO-synthase effectors on the survival of leukemic cells

The effector activity of thiazine and thiourea derivatives towards various forms of NO-synthase (NOS) in vitro and ex vivo was compared with their cytotoxic effect on human lymphocytes and leukemic cells. A thiazine derivative was revealed that exhibits a selective effect only on malignant cells and is an inhibitor of inducible and neuronal NOS.

The complex of zinc with N-(5,6-dihydro-4H-1,3-thiazine-2-yl)benzamide

A complex of zinc with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (L) ligand, LZnCl2, was synthesized for subsequent medical trials. The molar extinction coefficients were determined for LHBr solutions in water and physiological saline, and for LZnCl2 ethanol solution. The ligand stability in various solvents was evaluated and the value of its protonation constant was found for the physiological saline solution, logK = 5.3±0.2. The impossibility of determination of the complex stability constant by the potentiometric titration method was demonstrated. The complex exhibited an insufficient stability in aqueous and physiological saline solutions, but was stable as the solution in alcohol. There was no sorption observed upon the treatment of ligand with hydroxyapatite nanoparticles, which could be a potential carrier for the therapeutic form of LZnCl2, providing additional degrees of freedom for the interaction of ligand with cell membranes and a prolonged action of zinc ions.

Synthesis and studies of biological activity of N -(4- tert -butylbenzyl)- N -(pyridin-3-ylmethyl)-2-aminothiazolines as potential multifunctional agents for treatment of neurodegenerative diseases

A number of N-(4-tert-butylbenzyl)-N-(pyridin-3-ylmethyl)-2-aminothiazolines with different substituents at position 5 of thiazoline ring was synthesized and their inhibitory activity against human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), horse serum butyrylcholinesterase (BChE, EC 3.1.1.8), and porcine liver carboxylesterase (CaE, EC 3.1.1.1) was studied, as well as their antioxidant properties in DPPH and ABTS tests (DPPH is the 2,2-diphenyl-1-picrylhydrazyl, ABTS is the 2,2´-azinobis(3-ethylbenzthiazolino-6-sulfonic acid)). All the studied compounds virtually do not inhibit AChE, whereas the inhibition degree of BChE and CaE depends on the substituent structure. The presence of radical-binding activity comparable with the standard antioxidant ascorbic acid was shown for compounds containing a iodomethyl substituent. The found lead compound (R1 = H, R2 = CH2I) combines the antioxidant properties and the ability to efficiently inhibit BChE, simultaneously possessing an optimal esterase profile. The performed studies showed that N-(4-tert-butylbenzyl)-N-(pyridin-3-ylmethyl)-2-aminothiazolines are a new promising class of compounds, which can be used for the development of multifunctional agents for treatment of neurodegenerative diseases.

Role of NO and NO synthases in oncogenesis

The review focuses on the role of NO and NO synthases in the signaling pathways responsible for the occurrence and development of leukemias. Some classes of inhibitors of different NO synthase isoforms that exhibit cytotoxic activity against leukemia cells are described.