Information on the thesis

Dissertation is dedicated to the research of the role of free radical processes in the
mechanisms of thiazole derivatives anti-neoplastic activity. It has been investigated that
newly synthesized thiazole derivatives such as (N-(5-benzyl-1,3-thiazol- 2-yl)-3,5-dime-
thyl-1-benzofuran-2-carboxamide and 8-methyl-2-Me-7-[trifluoromethyl-phenylmethyl]-
pyrazolo-[4,3-e]-[1,3]-thiazolo-[3,2-a]-pyrimidin-4(2H)-one) exhibit high cytotoxic activ-
ity towards some lines of tumor cells and are not toxic towards healthy cells. At the same
time, it was found that the tested substances lose their cytotoxic properties in the presence
of scavengers of reactive Oxygen species (ROS). According to the results of two-factor
dispersion analysis, it was found that in the cytoxic effect the influence of scavengers,
tested substances, and unknown factors are 50–70%, 9%, and < 7%, respectively. These
data suggest that ROS are involved in the mechanism of action of thiazole derivatives
towards tumor cells.
For the first time, the influence of the thiazole derivatives on cellular ultrastructure of
lymphoma cells were investigated. It has been shown that the substances result in irrevers-
ible changes , such as the swelling of mitochondria, the blebbing of the plasma membrane,
the disturbances in the shape of the nucleus until it disappears, etc. Such changes indicate
the induction of apoptosis and necrosis in lymphoma cells by the studied substances.
The influence of thiazole derivatives on lipid peroxidation products was studied. At
the action of the substances at concentrations of 1, 10 and 50 μM, the level of primary
products of lipid peroxidation (hydroperoxides) either increases or does not change. This
indicates a violation of the activity of some enzymes of the antioxidant system (catalase,
glutathione-peroxidase). The level of secondary products of lipid peroxidation by the
action of the test substances is either unchanged or diminished. The influence of thiazole
derivatives on the content of a superoxide radical in lymphoma cells was also studied.
The investigated substances at concentrations of 10 and 50 μM decrease the level of su-
peroxide radical, that may be due to the activation of superoxide dismutase activity.
The effect of thiazole derivatives on the activity of key enzymes of the antioxidant
system in lymphoma cells has been investigated. The substances at concentrations of 10
and 50 µM activate superoxide dismutase and decrease the activity of catalase and glu-
tathione peroxidase. This effect suggests that the change in the activity of enzymes leads
to the accumulation of H
2
O
2
in the cells.
The effect of thiazole derivatives on respiratory processes and oxidative phospho-
rylation in mitochondria of lymphoma cells has been studied. It was established that the
parameters of respiration and oxidative phosphorylation are not statistically different for
the studied substances. For the first time the mitochondria membrane potential in lym –
phoma cells has been registered. The FCCP protonor reduces the membrane potential of
lymphoma mitochondria, which suggests that the mitochondria in lymphoma cells are
functionally active. It has been established that at still one of the substances at a concentra-
tion of 50 µM decreases membrane potential of mitochondria, which indirectly suggests
that the mitochondria of lymphoma cells may be involved in the cytotoxic processes.
It was found that the thiazole derivatives do not change the level of lipid peroxida-
tion products, level of superoxide radical and the activity of antioxidant enzymes in
mouse liver cells. It has been found that in liver cells of mouse possessing lymphoma the
content of secondary products of lipid peroxidation and superoxide radical is signifi-
cantly higher than in liver cells of healthy mice. Increased activity of catalase in liver
cells of mouse with lymphoma compared to the activity of the enzyme in liver cells of
healthy mice was observed. Such changes may be due to the growth of the tumor in the
body and the influence of tumor metabolites spreaded by blood flow .
The influence of thiazole derivatives on respiration and oxidative phosphorylation
in mitochondria of liver cells of mouse was studied. It has been established that the pa-
rameters of respiration and oxidative phosphorylation on the action of substances basi-
cally do not change.
The obtained results expand the understanding of the mechanism of anti-neoplastic
action of thiazole derivatives on tumor cells in vitro. Data can be used to carry out further
preclinical studies of thiazole derivatives as potential antitumor drugs with minimal side
effects.
Key words: free radical processes, cytotoxicity, tumors, thiazole derivatives, anti-
oxidant enzymes, respiration and oxidative phosphorylation