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Two series of organotin(IV) carboxylates based on phenolic antioxidants RCOOH and R(CH2)2COOH (R = 3,5-di-tert-butyl-4-hydroxyphenyl) and natural bile (cholanic) acids of formulae (RCOO)2SnMe2 (1); (RCOO)2SnBu2 (2); (R(CH2)2COO)2SnMe2 (3); (R(CH2)2COO)2SnBu2 (4); (cholate)SnPh3 (5); (deoxycholate)SnPh3 (6); (lithocholate)SnPh3 (7); (cholate)SnMe3 (8); (deoxycholate)SnMe3 (9), and (lithocholate)SnMe3 (10) were synthesized and characterized by 1H, 13C NMR, IR and elemental analysis to study their antioxidant and cytotoxic potential. Compounds 1 and 2 were found by X-ray diffraction analysis to be monomers in the solid state; moreover, the carboxyl groups are coordinated bidentately through O atoms. The distorted octahedron geometry around the Sn center in the monocrystals of 1, 2 was revealed. The antioxidant activity of compounds as radical scavengers and reducing agents was evaluated in spectrophotometrical tests with stable radical DPPH, reduction of Cu2+ (CUPRAC method) and interaction with superoxide anion radical. Cytotoxicity in vitro of compounds has been estimated on human cancer (colon cancer HCT-116, lung carcinoma A549, breast cancer MCF-7, neuroblastoma SH-SY5Y) cell lines and normal fibroblasts cells. The IC50 values varied in 0.002–100 μM range for compounds 1–4 depend on the alkyl substituents at Sn center and carboxylate ligand structure. The influence on Fe3+-induced lipid peroxidation, mitochondrial potential and mitochondrial permeability and tubulin assembly have been studied for the compounds 1 and 2. It was shown that the complexes 1 and 2 slightly depolarize the mitochondria but don’t influence the calcium-induced mitochondrial permeability transition. Organotin complexes with cholic and deoxycholic acids as ligands were revealed to induce apoptosis in A549 cells. The percentage of apoptotic cells were 27.9 and 27.1% for triphenyltin complexes with cholic and deoxycholic derivatives, respectively.

Compounds that act on mitochondrial functions are considered as promising drugs for the treatment of neurodegenerative diseases and age-related dementias. As a basis for the creation of such potential drugs, bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives were selected. Derivatives of cinnamic acid have a wide range of biological activities, which can be important for drugs aimed at the treatment of neurodegenerative diseases, in particular Alzheimer′s disease. In this work, the neuroprotective activity of bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives was studied. Among the compounds studied, lead substances 3, 4, and 7 have been identified. These compounds show no intrinsic toxicity and have a neuroprotective effect on the cellular model of neurodegeneration associated with calcium stress. The mechanism of their cytoprotective activity is probably due to the influence on mitochondrial functions, because these compounds effectively suppress the calcium-induced process of mitochondrial permeability jump. In addition, one of the substances investigated (7) has antioxidant properties, showing the ability to inhibit lipid peroxidation (LPO) of rat brain homogenate, which may be an additional mechanism of neuroprotective effect. The data obtained make it possible to recommend the investigated substances as a basis for the creation of effective neuroprotective drugs capable of influencing early stages of the development of neurodegenerative diseases., Соединения, направленно действующие на митохондриальные функции, рассматриваются как перспективные лекарственные препараты для лечения нейродегенеративных заболеваний и возрастных деменций. В качестве основы для создания таких потенциальных лекарственных средств были выбраны биоизостерные аналоги коричной кислоты и производные полиметоксибензолов. Производные коричной кислоты имеют широкий спектр биологических активностей, который может иметь значение для лекарственных препаратов, направленных на лечение нейродегенеративных заболеваний, в частности болезни Альцгеймера. В данной работе исследована нейропротекторная активность биоизостерных аналогов коричной кислоты и производных полиметоксибензолов. Среди исследованных соединений выявлены вещества-лидеры 3, 4 и 7. Эти соединения не проявляют собственной токсичности и оказывают нейропротекторный эффект на клеточной модели нейродегенерации, связанной с кальциевым стрессом. Механизм их цитопротекторной активности, возможно, обусловлен влиянием на функции митохондрий, поскольку эти соединения эффективно подавляют кальций-индуцированный процесс скачка митохондриальной проницаемости. Кроме того, одно из исследованных веществ (7) обладает антиоксидантными свойствами, проявляя способность к ингибированию перекисного окисления липидов (ПОЛ) гомогената мозга крыс, что может быть дополнительным механизмом нейропротекторного эффекта. Полученные данные позволяют рекомендовать исследованные вещества в качестве основы для создания эффективных нейропротекторных препаратов, способных повлиять на ранние стадии развития нейродегенеративных заболеваний.

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

Gamma (γ) synuclein is a member of the family of synucleins, which are cytoplasmic, predominantly, neuronal, proteins found only in vertebrates. Significant quantities of γ-synuclein are found in the axons and presynaptic terminals of neurons located in brain areas responsible for forming emotions and memory. However, the involvement of γ-synucleins in controlling neuronal and synaptic processes underlying various types of behavior in humans and animals have not yet been studied. We provide the first demonstration that the absence of γ-synuclein increases orientational-investigative activity in a novel context and decreases the level of situational anxiety in animals.

Pharmacology of Korean Red ginseng gives us unique possibility to develop new class of antiepileptic drugs today and to improve one’s biological activity. The chemical structures of ginsenosides (GS) have some principal differences from well-known antiepileptic new generation drugs. The antiepileptic effect of GS was also demonstrated in all models of epilepsy in rats (young and adult), which have studied, in all models of epilepsy including status epilepticus (SE), induced by lithium - pilocarpine. In our experiments in rats new evidences on protective effects were exerted as a result of premedication by GS. Pre-treatment of several GS could induce decrease of the seizures severity and brain structural damage (by MRI), neuronal degeneration in hippocampus. Wave nature of severity of motor seizures during convulsive SE was observed during lithium-pilocarpine model of SE in rats (the first increase of seizures was 30 min after the beginning of SE and the second - 90 min after. The efficacy of treatment on SE by ginsenoside as expected was observed after no less 3 weeks by daily GS i.p. administration. It is blocked SE or significantly decrease the severity of seizures during SE. The implication of presented data is that combination of ginsenosides from Korean Red ginseng and ginseng cell culture Dan25 that could be applied for prevention of epileptical status development. However, a development of optimal ratio of different ginsenosides (Rb1 Rc, Rg, Rf,) should consummate in the new antiepileptic drug development.

A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.

Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs.

This review focuses on the modeling of status epilepticus in animal brain and modern data on the mechanisms of epileptical seizures initiation using the pilocarpine binding with the muscarinic cholinoreceptors (litium pilocarpine model). The character of epileptics seizures in developing brain and adult brain of rats were investigated. The lines of modulation and inhibition epileptics statues by sacricine and intranasal application of neuropeptide thyroliberin in ultra-low doses are demonstrated. The role of the short-term changes (signal regulated kinase signaling cascade, Kv 4.2 potassium channels, hippocampal and cortical spike-wave discharges) and the long-term changes (loss of selective type of interneurons, excitatory circuits by mossy fiber sprouting) that promotion the epileptic state and recurrent seizures in limbic structure are discussed.