Dmitrii S. Yakovlev

Platinum(II)-based drugs, such as cisplatin, are commonly used to treat various types of cancer. However, their clinical use is limited due to a number of side effects and the development of resistance. To overcome these limitations, researchers have explored the development of platinum(IV) complexes as potential prodrugs that can be selectively activated under physiological conditions. In this study, we have incorporated synthetic analogs of vitamin E into the structure of platinum(IV) complexes to further improve their safety profile. The antioxidant properties of the compounds were evaluated using DPPH and CUPRAC assays, as well as lipid peroxidation inhibition models, revealing that incorporation of phenolic ligands confers pronounced antioxidant activity. Cytotoxicity was assessed towards cancer cell lines using the MTT assay, where the novel complexes showed significantly increased cytotoxic activity compared to cisplatin, while also demonstrating less toxicity toward normal fibroblast cells under the same in vitro conditions. These results suggest that the conjugation of antioxidant ligands to platinum(IV) scaffolds can modulate both redox processes and the biological activity of the resulting complexes. This proposed design strategy has the potential to create more effective platinum-based cancer treatments with enhanced biological characteristics.

In this study, the analgesic activity of the Cl-Ala-OH-AR compound was evaluated in various models of somatogenic somatic pain. The results showed that the Cl-Ala-OH-AR compound significantly increases the latency of the reaction in tests of the formation of thermal somatic pain, such as "Hot plate" and "Tail Twitching", however, its effectiveness was lower than that of tramadol and adenosine. In the algogen-induced somatic pain model evaluated in the formalin test, Cl-Ala-OH-AR demonstrated more pronounced analgesic properties, especially in the inflammatory phase, where the reduction in pain reactions was 3.4 times greater than the effect of adenosine. These results indicate a significant analgesic potential of Cl-Ala-OH-AR in the context of somatogenic somatic pain caused by algogens, which opens up prospects for further study.

In this study, we synthesized and characterized new imidazole ligands containing pyridone groups, as well as mononuclear and binuclear ruthenium complexes, which are a new class of water-soluble metallacycles. We studied the antiproliferative activity of these compounds in vitro using the MTT assay on a panel of human cancer cell lines and on primary rat fibroblasts, where we observed a complete absence of cytotoxicity up to a concentration of 1000 µM. For the binuclear metallocycle compounds, we investigated their solubility in water, resistance to hydrolysis, and ability to induce apoptosis in tumor cells.

Aim: To study the potential of the melatonin isostere, the compound K-165, to reduce intraocular pressure in old animals with elevated ophthalmotonus, and to evaluate its local irritant effect and cytotoxic properties. Materials and methods: The study was conducted in old rats over two years of age with intraocular pressure (IOP) above 16 mmHg. The level of ophthalmotonus was measured using a portable contact tonometer Tonovet ICare (Finland). The presence of IOP-lowering activity of the tested substance was assessed by the maximum reduction in ophthalmotonus compared to baseline pressure levels. The assessment of local irritant effects was conducted using a three-point scale after applying the substance to the eye tissues of the laboratory animal. Cytotoxicity was studied on HepG2 cell lines (human hepatocellular carcinoma) (CLS Cell Lines Service). Result: The compound K-165 reduces the level of intraocular pressure (IOP) in old animals, outperforming melatonin comparator. K-165 decreases ophthalmotonus by 21 % from baseline by the third hour and does not have a local irritating effect on the eye conjunctiva. It is shown that the mean cytotoxic concentration exceeds 100 μM for the compound K-165 (R² = 0.9), indicating low cytotoxicity. Conclusion: The compound K-165 significantly reduces IOP, does not have a local irritating effect, and is classified as a compound with low cytotoxicity.

Novel organotin(IV) complexes based on losartan have been synthesized and characterized by ¹H, ¹³C, ¹¹⁹Sn NMR, IR, ESI-MS and elemental analysis. The antiproliferative activity of the complexes was assessed in vitro against human cancer cells, while their cytotoxic effects were examined on primary rat skin fibroblasts. The compounds exhibited strong activity, significantly inducing apoptosis. Additionally, they effectively suppressed the spasmogenic effect induced by angiotensin II in isolated rat portal veins.

Objective: Synthesis of new compounds, melatonin isosters, and study of their ability to reduce intraocular pressure. Materials and methods: Based on the previously made forecast and on the similarity with the selected compounds, the synthesis of new compounds was carried out – melatonin isosters having a 2,3-dihydro-1,4-benzodioxin cycle connected by a linker of various chemical structure with a nitrogen-containing heterocyclic core. The structure of the synthesized compounds was proved by 1H- and 13C- NMR spectroscopy, purity and individuality – by chromatographic methods. Intraocular pressure in laboratory animals was measured using a contact veterinary tonometer Tonovet (Finland). Cytotoxicity was assessed using MTT test on normal rat skin fibroblasts. Results: Derivatives (benzodioxane-2-yl)methanol reduced the level of IOP in varying degrees of severity. The VMA-22-37 compound showed the greatest activity. With topical application of a 0.4% solution, the compound reduced the intraocular pressure of intact rats by 26.6%, while not affecting the control eye. This compound also has low cytotoxicity. Conclusion: Derivatives (benzodioxane-2-yl)methanol is promising for the search for compounds capable of reducing increased intraocular pressure.

Aim.Glaucoma is a whole group of diseases caused by increased intraocular pressure (IOP), leading to atrophy of the optic nerve and irreversible blindness. Melatonin has a wide range of biological activity, including antioxidant and antiglaucoma, but its use is limited by insufficient stability and duration of action. To search for new, more effective antiglaucoma agents among derivatives of 3-arylidene-2-oxindole, melatonin analogues, a search for quinonoxidoreductase 2 (NQO2) inhibitors was performed, antioxidant activity was determined and the effect of active compounds on intraocular pressure was studied.Materials and methods.The study of inhibitory activity against NQO2 was evaluated kinetically using menadione and N-benzyl-dihydronicotinamide assubstrate and co-substrate, respectively. Antiradical activity was studied for reducing superoxide-dependentluminescence in a reaction medium containing hemoglobin, luminol and hydrogen peroxide using the Infinite M200 PRO microplate reader (Tecan, Austria), as well as for free radical binding tests OH•-, ABTS and DPPH. Cytotoxicity assessment was carried out using a standard MTT test on MCF-7 and HepG2 line cells. Intraocular pressure in laboratory animals was measured using a contactveterinary tonometer Tonovet (Finland).Results.Derivatives of 3-arylidene-2-oxindole have demonstrated significant antioxidant activity. A number of NQO2 inhibitors have also been identified. The most active compound inhibits human NQO2 with an IC50of 0,4 μM. The compound also showed anti-radical activity, binding the superoxide anion to IC50of 6,1 μM, superior to melatonin on both counts, and low cytotoxicity. With topical application of a 0,4% solution, the compound reduced the intraocular pressure of intact rats by (40,9 ± 6,4) %, while not having a systemic hypotensive effect.Conclusion.Derivatives of 3-arylidene-2-oxindole are promising for drug discovery for the treatment of eye diseases associatedwith increased intraocular pressure or oxidative stress, such as glaucoma, uveitis and diabetic retinopathy.

A novel polydentate chelating antioxidant ligand and series of organotin complexes on its base were synthesized and characterized by NMR ¹H, ¹³C, ¹¹⁹Sn, IR spectroscopy, X-ray, and elemental analysis. Their antioxidant activity was evaluated in DPPH and NBT-tests, and as lipoxygenase inhibitory activity. It was shown that ligand alone is a radical scavenger, while introducing tin in the structure of the compound significantly decreases its activity. For the ligand alone the ability to strongly suppress the formation of advanced glycation end products (AGEs) was shown, which may be associated with the established antiradical activity. All synthesized compounds appeared to be moderate lipoxygenase inhibitors. The stability of compounds to hydrolysis under different pH was estimated. The ligand undergoes decomposition after about an hour, while organotin complexes on its base demonstrate vast stability, showing signs of decomposition only after 5 h of experimentation. Cytotoxicity of compounds was studied by standard MTT-test, which showed unorthodox results: the ligand itself demonstrated noticeable cytotoxicity while the introduction of organotin moiety either did not affect the toxicity levels or reduced them instead of increasing. Organotin complexes possess luminescence both as powders and DMSO solutions, its quantum yields reaching 67% in DMSO. The combination of luminescence with unique cytotoxic properties allows us to propose the synthesized compounds as perspective theranostic agents.

Six compounds of the 5(7)-alkylamino-6-nitroazolopyrimidine and 8-alkylazolo[5,1- b ]purine series were selected based on the structural analysis of A ₁ adenosine receptor inhibitors and the role of this biological target in the modulation of intraocular pressure, an important factor in the pathogenesis of glaucoma. These heterocycles were shown to exhibit a weak affinity towards the A ₁ adenosine receptor on an in vitro model of the adenosine-dependent change of the chronotropic effect on isolated atria of white mice. On the other hand, thiadiazolo[3,2- a ]pyrimidines and triazolo[5,1- b ]purine displayed an in vivo hypotensive effect in rats . The leading compound, 5-methyl-8-(hydroxyethyl)triazolo[5,1- b ]purine) (0.2% solution), caused a 34% reduction of ophthalmotonus in 3 h without an adverse resorptive effect. In addition, using the MTT-test it was shown on the human HepG2 cell line that the heterocycles affecting the intraocular pressure were by one to two orders of magnitude less cytotoxic than the reference doxorubicin.