Information on the thesis

The interaction of calf thymus DNA (ST DNA) with the cluster rhenium
compounds with phosphate, adamantyl and ferrulate ligands was studied by the
electron spectroscopy for the first time. During the spectrophotometric titration
of CT-DNA with the compounds of direnium Re tetraphosph, Re cis-Adam, Re trans-Adam,
Re Ferul , the hyperchromic effect in the region of 260 nm of DNA was observed, it
is much higher than that shown for binuclear alkyl carboxylates of rhenium (III).
The DNA-ligand complexes formation in the long-wavelength region of the
spectrum, which is due to the interaction of π-electron clouds of nucleic bases and
biologically active ligands, was shown for the first time. The dependence of the
interaction mechanism of rhenium compounds and DNA in the presence of
hydrogen peroxide and cisplatin in solutions was shown. Spectrophotometric
titration of rhenium compounds in the presence of cisplatin was performed for the
first time and binding constants were obtained This constants exceed the values
of the basic constants, especially for ReFerul (almost 12 times). For the first time,
the method of competitive complexation with propidium iodide showed that
cluster rhenium (III) compounds of different structural types are able to interact
with oligonucleotides with the intensity which exceeding the intensity of cisplatin
binding, depending on the structure of the ligands, the intensity of the interaction
reaches 73.2%. The cytotoxic activity of a new cluster compound of rhenium with
beta-alanine ligands [Re 2 Cl 6 (C 3 H 7 NO 2 ) 2 ]·1.5H 2 O (Re cis-βAla) in solutions and
nanoliposomes separately and together with cisplatin on leukemic T-cells of the
Jurkat line was studied for the first time. It is shown, that Recis-βAla solution has
a cytotoxicity close to the IC 50 value to cisplatin (IC 50 = 2,06·10 -6 M). The
administration of the rhenium-platinum system with Re cis-βAla showed even
greater cytotoxicity against cells, especially high when both components of the
system were in the form of mixed liposomes (IC 50 = 4,93·10 -10 M). Loaded with
both cytostatics liposomes (nanobins) were used in experiments with cancer cell
culture first time and showed high efficacy. It is shown that in the presence of
Re cis-βAla by different methods of administration, even at significant (necrotic)
concentrations of cisplatin, the apoptotic pathway of leukemic T-cells of the
Jurkat line death are predominates. This is very important for therapeutic
measures and side effects, as necrosis activates inflammation and the immune
response, which is not inherent in apoptosis. The anticancer, DNA-binding and
antioxidant activities of the rhenium cluster compound with β-alanine ligands
have been studied.. The high solubility and stability of the substance in aqueous
solutions, in contrast to alkylcarboxylates, revealed the effect of its aqueous
solution and the rhenium-platinum system based on it on the growth of Guerin’s
carcinoma without the use of liposomes. The introduction of both the solution and
the liposomal form of the compound direnium Re cis-βAla led to a decrease in tumor
mass almost equally, which makes it possible to use water-resistant compounds
of direnium in experimental work and practice. It was found that the newly
synthesized cluster compound of rhenium Re cis-βAla, regardless of the method of
administration has antioxidant and antianemic properties in vivo, stabilizing a red
blood cell counts, as was the case with other rhenium (III) cluster compounds. In
general, elucidation of the anticancer, DNA-binding, and antioxidant properties
of such compounds opens up new, broader prospects for the introduction of amino
acid derivatives of rhenium (III) cluster compounds into medical practice. The
antitumor activity of two derinium (III) dicarboxylates with 1-
adamantanecarboxylic acid ligands, with cis- and trans-orientation of carboxyl
groups around the cluster fragment of cis- and trans-diadamants of dirhenium
separately and together with cisplatin in vivo was studied. The antitumor activity
was almost identical to the minor benefits for the cis analog in vivo. The attempt
to explain the differences in the possible mechanism of antitumor activity of
substances taking into account the antiradical and DNA-binding properties of the
studied compounds was made.
Key words: dirhenium(III) cluster compounds, biologically active ligands, ,
cisplatin, model of tumor growth, Calf Thymus DNA, oligonucleotides, pro-drug,
antiradical activity, beta-alanine, adamantanecarboxylic acid.