Vol 45, No 4 (2019)

T-cell response along with humoral response compose the basis of acquired immunity. Effective activation of T lymphocytes requires at least two signals. The first signal is provided by the interaction of T-cell receptor with antigenic peptide in the context of major histocompatibility complex molecules (I or II class). The second signal required for T cell activation, proliferation and differentiation is delivered by molecules called “immune checkpoints” which determine the polarity, effectiveness and termination of the immune response. The immune checkpoint group consist of around 70 members. The first discovered molecules that control immune response belong to the B7 family of cell membrane proteins. The classical two-signal model for T cell activation was developed with their implication. Immune checkpoints have gained popularity after successful clinical trials of antibodies blocking CTLA-4 and PD-1 receptors (immune checkpoint inhibitors), in which the tremendous antitumor effects were demonstrated. Considering the importance of the immune checkpoints in therapeutic regulation of antitumor immunity, in this review we describe the functional properties of all known today molecules of the B7 family. The first part of our review discusses the structural features, functions and therapeutic applications of B7-1, B7-2, B7-H1, B7-H2, B7-DC, and their receptors.

Using the known synthesis of L-selenocystine,3,3'-diseleno-bis (2-aminopropionic acid), from β‑chloroalanine, a structural analog of natural sulfur-containing amino acids capable of accumulating selenium in the body, we synthesized a new selenium-containing amino acid 3,3'-dimethyl-L-selenocystine () from α-amino-β-chlorobutyric acid. It was shown that, similarly to the selenium released from natural L-selenocystine, the selenium from 3,3'-dimethyl-L-selenocystine accumulated in rat liver, muscles, and serum, where its concentration exceeded that of the control by 40.63, 14.07 and 22.98%, respectively. A close degree of selenium accumulation in the tissues implied a similar metabolic pathway of the amino acids and biological availability of the trace element from the synthesized amino acid. L-Selenocystine and 3,3'‑dimethyl-L-selenocystine decreased concentrations of free amino acids in rat serum by 12.17 and 11.78%, respectively. The most significant reduction, by 74.6 and 66.4% respectively, was observed for proline, a marker of organism stress. Accumulation of selenium in liver and serum indicated close metabolism of L‑selenocystine and its derivative 3,3'-dimethyl-L-selenocystine.

MTH1 (MutT homologue 1, NUDT1), a member of the Nudix phosphohydrolase superfamily of enzymes, was speculated to contribute to hampering tumor growth based on a number of validation experiments. Based on the crystal structure of MTH1, de novo design was employed to construct a series of new MTH1 inhibitors by means of fragment-based strategy. ADMET (absorption, distribution, metabolism, excretion, toxicity) were used to assess the pharmacokinetic profiles; pharmacophore screening and molecular docking were carried out to obtain 9 candidate molecules. Then, molecular dynamic (MD) simulations were performed to learn the stability of receptor–ligand complexes, which have the lowest binding energy in docking, and the binding model was analyzed. Finally, using reverse virtual screening, potential targets of query compounds, especially those enzymes participating in various cancer-related pathways, were found. The results provide theoretical basis for the design of more potent MTH1 inhibitors.

Three new Co(III) polypyridyl complexes [Co(phen)₂CIIP]³⁺ {CIIP = 2-(5-chloro-3a,H-isoindol-3-yl)-1H-imidazo[4,5-f][1,10]phenantholine} (phen = 1,10 phenanthroline), [Co(bpy)₂CIIP]³⁺ (bpy = 2,2′-bipyridine), and [Co(dmb)₂CIIP]³⁺ (dmb = 4,4′-dimethyl-2,2′-bipyridine) were synthesized and characterized by different spectral methods. The complexes interact with DNA in an intercalation mode as confirmed by spectroscopic titration and viscosity measurements. All three complexes cleaved the pBR322 DNA in photoactivated cleavage studies and exhibited good antimicrobial activity. Anticancer activity of these Co(III) complexes was evaluated on the SKOV3 cell line. Cytotoxicity by MTT assay showed growth inhibition in dose dependent manner. Cell cycle analysis by flow cytometry data showed increase in Sub G1 population. Annexin V FITC/PI staining confirmed that these complexes caused cell death by the induction of apoptosis.

A five-stage synthesis of azepanobetulin from betulin with a total yield of 47% has been carried out. The acylation of azepanobetulin with anhydrides or acid chlorides (acetic, phthalic, nicotinic) and tosylation resulted in the synthesis of О- and N-derivatives of azepanobetulin. Azepanobetulin, its 28-tosylate, 3а-N,28-О-dinicotinoate, and 3-N,28-О-diacetate showed antitumor activity toward a large panel of cancer cells, whereas mono-С28-acylates were ineffective. In contrast to azepanobetulin, its azepanone analog did not possess cytotoxicity. Leukemia and colon tumor cells were most sensitive to azepanobetulin and its bisacylates. Azepanobetulin was highly effective toward the melanoma cell line. 28-О-para-Tosylazepanobetulin exhibited antitumor activity toward nine cancer types and produced a cytocidal effect toward 31 cell lines.