7 research outputs found
ΠΠ»ΠΈΡΠ½ΠΈΠ΅ ΠΈΠΎΠ½ΠΎΠ² ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² Π½Π° ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠΊΠΈ ΠΊΠ°ΠΊ Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΡΠΉ ΠΌΠ΅Ρ Π°Π½ΠΈΠ·ΠΌ ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π° Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°
The article provides an overview of our own results of comparative study of influence of ions of iron, zinc and aluminium on the structure of microtubules from tubulin and microtubules associated proteins of rat brain with data on the structure of microtubules from tubulin and microtubules associated proteins from the brain of patients with Alzheimerβ²s disease (AD). A significant decrease in the amount of soluble tubulin was found in the postmortem brain of AD patients in comparison with the control group in the hippocampus, frontal cortex and substantia nigra, but not in the inferior olive. In vitro polymerization of tubulin and microtubules associated proteins from the brain of AD patients and electron micrographs of microtubules were obtained. The assembly of microtubules from brains of AD patients is disrupted, resulting in defective structures. On the other hand, the study of the influence of Al3+, Fe3+, Zn2+ on the microtubules from rat brains tubulin and microtubules associated proteins assembly and structure has shown that all studied metals are able to reduce the amount of microtubules and induce the assembly of anomal structures. According to the degree of the destructive effect on the microtubules and, accordingly, the possible significance in the pathogenesis of Alzheimer disease, metal ions can be arranged in the following sequence Al3+ > Zn2+ > Fe3+. Moreover, phosphorylation of tubulin and microtubules associated proteins in the presence of aluminum ions to the greatest extent reflects the phosphorylation of these proteins at AD. Comparison of data on the structure of microtubules after their assembly from brains of AD patients tubulin and microtubules associated proteins from brains of AD patients, and from the brain of rats, but in the presence of metal ions, confirm the conclusion about the possible role of the metals in the AD etiopathogenesis.ΠΠ±ΠΎΠ±ΡΠ΅Π½Ρ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΡΠ΅ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΡΡΠ°Π²Π½ΠΈΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΡΡΠ΅ΠΊΡΠΎΠ² ΠΈΠΎΠ½ΠΎΠ² ΠΆΠ΅Π»Π΅Π·Π°, ΡΠΈΠ½ΠΊΠ° ΠΈ Π°Π»ΡΠΌΠΈΠ½ΠΈΡ Π½Π° ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΈΡ
ΡΠ±ΠΎΡΠΊΠΈ ΠΈΠ· ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ ΠΌΠΈΠΊΡΠΎΡΡΠ±ΡΠ»Π»ΠΎΠ°ΡΡΠΎΡΠΈΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
Π±Π΅Π»ΠΊΠΎΠ² ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡΡ Ρ Π΄Π°Π½Π½ΡΠΌΠΈ ΠΏΠΎ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΈΡ
ΡΠ±ΠΎΡΠΊΠΈ ΠΈΠ· ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ Π±Π΅Π»ΠΊΠΎΠ², Π°ΡΡΠΎΡΠΈΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
Ρ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠΊΠ°ΠΌΠΈ (ΠΠΠ ΠΎΡ Π°Π½Π³Π». microtubules associated proteins), ΠΌΠΎΠ·Π³Π° Π±ΠΎΠ»ΡΠ½ΡΡ
Π±ΠΎΠ»Π΅Π·Π½ΡΡ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° (ΠΠ). Π ΠΌΠΎΠ·Π³Π΅ Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΠ Π²ΡΡΠ²Π»Π΅Π½ΠΎ Π·Π½Π°ΡΠΈΡΠ΅Π»ΡΠ½ΠΎΠ΅ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π° ΡΠ°ΡΡΠ²ΠΎΡΠΈΠΌΠΎΠ³ΠΎ ΡΡΠ±ΡΠ»ΠΈΠ½Π°, ΠΏΠΎ ΡΡΠ°Π²Π½Π΅Π½ΠΈΡ Ρ ΠΊΠΎΠ½ΡΡΠΎΠ»ΡΠ½ΠΎΠΉ Π³ΡΡΠΏΠΏΠΎΠΉ, Π² Π³ΠΈΠΏΠΏΠΎΠΊΠ°ΠΌΠΏΠ΅, Π»ΠΎΠ±Π½ΠΎΠΉ ΠΊΠΎΡΠ΅ ΠΈ ΡΡΡΠ½ΠΎΠΉ ΡΡΠ±ΡΡΠ°Π½ΡΠΈΠΈ, Π½ΠΎ Π½Π΅ Π² Π½ΠΈΠΆΠ½Π΅ΠΉ ΠΎΠ»ΠΈΠ²Π΅. ΠΡΡΠ°Π±ΠΎΡΠ°Π½Ρ ΡΡΠ»ΠΎΠ²ΠΈΡ, ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΠ²ΡΠΈΠ΅ Π²ΠΏΠ΅ΡΠ²ΡΠ΅ ΠΏΡΠΎΠ²Π΅ΡΡΠΈ in vitro ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠΈΠ·Π°ΡΠΈΡ ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP ΠΌΠΎΠ·Π³Π° Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΠ ΠΈ ΠΏΠΎΠ»ΡΡΠΈΡΡ ΡΠ»Π΅ΠΊΡΡΠΎΠ½Π½ΡΠ΅ ΠΌΠΈΠΊΡΠΎΡΠΎΡΠΎΠ³ΡΠ°ΡΠΈΠΈ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π²ΡΠΈΡ
ΡΡ ΡΡΡΡΠΊΡΡΡ. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΡΠΎ ΠΏΡΠΈ ΠΠ Π½Π°ΡΡΡΠ΅Π½ ΠΏΡΠΎΡΠ΅ΡΡ ΡΠ±ΠΎΡΠΊΠΈ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ, Π² ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ΅ ΡΠ΅Π³ΠΎ ΠΎΠ±ΡΠ°Π·ΡΡΡΡΡ Π΄Π΅ΡΠ΅ΠΊΡΠ½ΡΠ΅ ΡΡΡΡΠΊΡΡΡΡ. Π‘ Π΄ΡΡΠ³ΠΎΠΉ ΡΡΠΎΡΠΎΠ½Ρ, ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ Π²Π»ΠΈΡΠ½ΠΈΡ ΠΈΠΎΠ½ΠΎΠ² Al3+, Fe3+, Zn2+ Π½Π° ΡΠ±ΠΎΡΠΊΡ ΠΈ ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ ΠΈΠ· ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡΡ ΠΏΠΎΠΊΠ°Π·Π°Π»ΠΎ, ΡΡΠΎ Π»ΡΠ±ΠΎΠΉ ΠΈΠ· ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π½ΡΡ
Π½Π°ΠΌΠΈ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² ΡΠΏΠΎΡΠΎΠ±Π΅Π½ ΡΠ½ΠΈΠΆΠ°ΡΡ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²ΠΎ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ ΠΈ Π²ΡΠ·ΡΠ²Π°ΡΡ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠ΅ Π°Π½ΠΎΠΌΠ°Π»ΡΠ½ΡΡ
ΡΡΡΡΠΊΡΡΡ. ΠΠΎ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ Π΄Π΅ΡΠΎΡΠΌΠΈΡΡΡΡΠ΅Π³ΠΎ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΡ Π½Π° ΠΌΠΈΠΊΡΠΎΡΡΠ±ΡΠ»ΡΡΠ½ΡΡ ΡΠΈΡΡΠ΅ΠΌΡ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΌΠΎΠ·Π³Π° ΠΈ, ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²Π΅Π½Π½ΠΎ, Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΠΉ Π·Π½Π°ΡΠΈΠΌΠΎΡΡΠΈ Π² ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π΅ ΠΠ, ΠΈΠΎΠ½Ρ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² ΠΌΠΎΠΆΠ½ΠΎ ΡΠ°ΡΠΏΠΎΠ»ΠΎΠΆΠΈΡΡ Π² ΡΠ»Π΅Π΄ΡΡΡΠ΅ΠΉ ΠΏΠΎΡΠ»Π΅Π΄ΠΎΠ²Π°ΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ Al3+ > Zn2+ > Fe3+. ΠΠΎΠ»Π΅Π΅ ΡΠΎΠ³ΠΎ, ΡΠΏΠ΅ΠΊΡΡ ΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP Π² ΠΏΡΠΈΡΡΡΡΡΠ²ΠΈΠΈ ΠΈΠΎΠ½ΠΎΠ² Π°Π»ΡΠΌΠΈΠ½ΠΈΡ Π² Π½Π°ΠΈΠ±ΠΎΠ»ΡΡΠ΅ΠΉ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ ΠΎΡΡΠ°ΠΆΠ°Π΅Ρ ΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΡΡΠΈΡ
Π±Π΅Π»ΠΊΠΎΠ² ΠΏΡΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°. Π‘ΠΎΠΏΠΎΡΡΠ°Π²Π»Π΅Π½ΠΈΠ΅ Π΄Π°Π½Π½ΡΡ
ΠΎ Π½Π°ΡΡΡΠ΅Π½ΠΈΡΡ
ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ, Π½Π°Π±Π»ΡΠ΄Π°Π΅ΠΌΡΡ
ΠΏΡΠΈ ΠΈΡ
ΡΠ±ΠΎΡΠΊΠ΅ ΠΈΠ· ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP ΠΈΠ· ΠΌΠΎΠ·Π³Π° Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΠ, ΠΈ ΠΈΠ· ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡ, Π½ΠΎ Π² ΠΏΡΠΈΡΡΡΡΡΠ²ΠΈΠΈ ΠΈΠΎΠ½ΠΎΠ² ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ², ΠΏΠΎΠ΄ΡΠ²Π΅ΡΠΆΠ΄Π°ΡΡ Π²ΡΠ²ΠΎΠ΄ ΠΎ Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΠΉ ΡΠΎΠ»ΠΈ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² Π² ΡΡΠΈΠΎΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π΅ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°
ΠΠΈΡΠΎΡ ΠΎΠ½Π΄ΡΠΈΠΈ ΠΊΠ°ΠΊ Π²Π°ΠΆΠ½Π°Ρ ΠΌΠΈΡΠ΅Π½Ρ ΠΏΡΠΈ ΠΏΠΎΠΈΡΠΊΠ΅ Π½ΠΎΠ²ΡΡ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° ΠΈ ΡΡΠ°ΡΡΠ΅ΡΠΊΠΈΡ Π΄Π΅ΠΌΠ΅Π½ΡΠΈΠΉ
The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimerβ²s disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimerβ²s disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest β both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.ΠΠ±ΠΎΠ±ΡΠ΅Π½Ρ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΡΠ΅ ΠΈ Π»ΠΈΡΠ΅ΡΠ°ΡΡΡΠ½ΡΠ΅ Π΄Π°Π½Π½ΡΠ΅, ΠΎΠ±ΠΎΡΠ½ΠΎΠ²ΡΠ²Π°ΡΡΠΈΠ΅ ΡΠΎΠ»Ρ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ ΠΊΠ°ΠΊ Π²Π°ΠΆΠ½Π΅ΠΉΡΠ΅ΠΉ ΠΌΠΈΡΠ΅Π½ΠΈ ΠΏΡΠΈ ΠΏΠΎΠΈΡΠΊΠ΅ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. Π‘ΡΠ°ΡΠ΅Π½ΠΈΠ΅ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΎΡΠ½ΠΎΠ²Π½ΡΠΌ ΡΠ°ΠΊΡΠΎΡΠΎΠΌ ΡΠΈΡΠΊΠ° ΡΠΏΠΎΡΠ°Π΄ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΎΡΠΌ ΡΠ°Π·Π»ΠΈΡΠ½ΡΡ
Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, Π² ΡΠΎΠΌ ΡΠΈΡΠ»Π΅ ΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° (ΠΠ). ΠΠ΄Π½ΠΎΠΉ ΠΈΠ· Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ Π°ΡΠ³ΡΠΌΠ΅Π½ΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΠΈ ΠΏΡΠΈΠ½ΡΡΡΡ
Π² Π½Π°ΡΡΠΎΡΡΠ΅Π΅ Π²ΡΠ΅ΠΌΡ ΡΠ²Π»ΡΠ΅ΡΡΡ ΡΠ²ΠΎΠ±ΠΎΠ΄Π½ΠΎΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ½Π°Ρ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½Π°Ρ ΡΠ΅ΠΎΡΠΈΡ ΡΡΠ°ΡΠ΅Π½ΠΈΡ. ΠΠΌΠ΅Π½Π½ΠΎ Ρ Π½Π΅ΠΉ ΡΠ΅ΡΠ½ΠΎ ΡΠ²ΡΠ·Π°Π½Ρ ΠΈ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΡΠ΅ Π³ΠΈΠΏΠΎΡΠ΅Π·Ρ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠΏΠΎΡΠ°Π΄ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΎΡΠΌ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΈ, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ, ΠΠ. ΠΠ°ΡΡΡΠ΅Π½ΠΈΠ΅ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΡΡ
ΡΡΠ½ΠΊΡΠΈΠΉ ΠΏΡΠΈΠ²ΠΎΠ΄ΠΈΡ ΠΊ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΡ ΠΈΡ
ΡΠΏΠΎΡΠΎΠ±Π½ΠΎΡΡΠΈ ΡΠ΅Π³ΡΠ»ΠΈΡΠΎΠ²Π°ΡΡ Π³ΠΎΠΌΠ΅ΠΎΡΡΠ°Π· ΠΊΠ°Π»ΡΡΠΈΡ Π² ΠΊΠ»Π΅ΡΠΊΠ΅ ΠΈ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΡ ΠΏΠΎΡΠΎΠ³Π° Π΄Π»Ρ ΠΈΠ½Π΄ΡΠΊΡΠΈΠΈ ΠΏΠΎΡΡ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΠΎΠΉ ΠΏΡΠΎΠ½ΠΈΡΠ°Π΅ΠΌΠΎΡΡΠΈ (ΠΠ Π’). ΠΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΡ ΠΠ Π’ ΠΌΠΎΠΆΠ½ΠΎ ΡΠ°ΡΡΠΌΠ°ΡΡΠΈΠ²Π°ΡΡ ΠΊΠ°ΠΊ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ ΠΊ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, ΡΠ°ΠΊ ΠΊΠ°ΠΊ ΡΡΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ ΠΌΠΎΠ³ΡΡ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ ΠΏΡΠΎΡΠ²Π»ΡΡΡ ΡΠ²ΠΎΠΉΡΡΠ²Π° Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠΎΠ², Π½ΠΎ ΠΈ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠΈΠ²Π°ΡΡ Π½ΠΎΡΠΌΠ°Π»ΠΈΠ·Π°ΡΠΈΡ ΡΠΈΠ½Π°ΠΏΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ Π±Π»Π°Π³ΠΎΠ΄Π°ΡΡ ΡΠ²Π΅Π»ΠΈΡΠ΅Π½Π½ΠΎΠΉ ΠΊΠ°Π»ΡΡΠΈΠ΅Π²ΠΎΠΉ ΡΠΌΠΊΠΎΡΡΠΈ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ. Π ΠΎΠ±Π·ΠΎΡΠ΅ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½Ρ Π΄Π°Π½Π½ΡΠ΅ ΠΎ ΡΡΠ΄Π΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΠΎΠ² ΠΠ Π’, Π²ΠΊΠ»ΡΡΠ°Ρ ΡΠ½Π΄ΠΎΠ³Π΅Π½Π½ΡΠ΅ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ β ΠΌΠ΅Π»Π°ΡΠΎΠ½ΠΈΠ½, N-Π°ΡΠ΅ΡΠΈΠ»ΡΠ΅ΡΠΎΡΠΎΠ½ΠΈΠ½, ΠΈΡ
Π±ΠΈΠΎΠΈΠ·ΠΎΡΡΠ΅ΡΠ½ΡΠΉ Π°Π½Π°Π»ΠΎΠ³ Π΄ΠΈΠΌΠ΅Π±ΠΎΠ½ ΠΈ ΡΡΠ΄ Π΄ΡΡΠ³ΠΈΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ. ΠΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ ΠΊΠ°ΠΊ ΠΎΡΠ½ΠΎΠ²Ρ Π΄Π»Ρ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΠΊΡΠΈΠ½ΠΈΠ½Π³ΠΎΠ²ΠΎΠΉ ΡΡΡΠ°ΡΠ΅Π³ΠΈΠΈ ΠΏΠΎΠΈΡΠΊΠ° ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΠ΅Ρ ΠΎΡΠΎΠ±ΡΠΉ ΠΈΠ½ΡΠ΅ΡΠ΅Ρ ΠΈ ΠΊΠ°ΠΊ ΡΠ΅ΡΡΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΠΈΡ
ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΠΎΠΉ ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ, ΠΈ ΠΊΠ°ΠΊ ΠΎΡΠ½ΠΎΠ²Π° Π΄Π»Ρ ΡΠΎΠ·Π΄Π°Π½ΠΈΡ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΡΠΈΠΌΡΠ»ΡΡΠΎΡΠΎΠ² ΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΠΎΠ±Π»Π°Π΄Π°ΡΡΠΈΡ
Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½ΡΠΌ ΠΈ ΠΊΠΎΠ³Π½ΠΈΡΠΈΠ²Π½ΠΎ-ΡΡΠΈΠΌΡΠ»ΠΈΡΡΡΡΠΈΠΌ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ΠΌ
ΠΠΈΠΎΠΈΠ·ΠΎΡΡΠ΅ΡΠ½ΡΠ΅ Π°Π½Π°Π»ΠΎΠ³ΠΈ ΠΊΠΎΡΠΈΡΠ½ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΡΡ Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠΎΠ²
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 Alzheimerβ²s 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.Π‘ΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ, Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½ΠΎ Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΠ΅ Π½Π° ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΡΠ΅ ΡΡΠ½ΠΊΡΠΈΠΈ, ΡΠ°ΡΡΠΌΠ°ΡΡΠΈΠ²Π°ΡΡΡΡ ΠΊΠ°ΠΊ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΡΠ΅ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΠ΅ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΈ Π²ΠΎΠ·ΡΠ°ΡΡΠ½ΡΡ
Π΄Π΅ΠΌΠ΅Π½ΡΠΈΠΉ. Π ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΎΡΠ½ΠΎΠ²Ρ Π΄Π»Ρ ΡΠΎΠ·Π΄Π°Π½ΠΈΡ ΡΠ°ΠΊΠΈΡ
ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΡΠ΅Π΄ΡΡΠ² Π±ΡΠ»ΠΈ Π²ΡΠ±ΡΠ°Π½Ρ Π±ΠΈΠΎΠΈΠ·ΠΎΡΡΠ΅ΡΠ½ΡΠ΅ Π°Π½Π°Π»ΠΎΠ³ΠΈ ΠΊΠΎΡΠΈΡΠ½ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ ΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΠ΅ ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠΎΠΊΡΠΈΠ±Π΅Π½Π·ΠΎΠ»ΠΎΠ². ΠΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΠ΅ ΠΊΠΎΡΠΈΡΠ½ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ ΠΈΠΌΠ΅ΡΡ ΡΠΈΡΠΎΠΊΠΈΠΉ ΡΠΏΠ΅ΠΊΡΡ Π±ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠ΅ΠΉ, ΠΊΠΎΡΠΎΡΡΠΉ ΠΌΠΎΠΆΠ΅Ρ ΠΈΠΌΠ΅ΡΡ Π·Π½Π°ΡΠ΅Π½ΠΈΠ΅ Π΄Π»Ρ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½ΡΡ
Π½Π° Π»Π΅ΡΠ΅Π½ΠΈΠ΅ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°. Π Π΄Π°Π½Π½ΠΎΠΉ ΡΠ°Π±ΠΎΡΠ΅ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π° Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½Π°Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π±ΠΈΠΎΠΈΠ·ΠΎΡΡΠ΅ΡΠ½ΡΡ
Π°Π½Π°Π»ΠΎΠ³ΠΎΠ² ΠΊΠΎΡΠΈΡΠ½ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ ΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΡ
ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠΎΠΊΡΠΈΠ±Π΅Π½Π·ΠΎΠ»ΠΎΠ². Π‘ΡΠ΅Π΄ΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π½ΡΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ Π²ΡΡΠ²Π»Π΅Π½Ρ Π²Π΅ΡΠ΅ΡΡΠ²Π°-Π»ΠΈΠ΄Π΅ΡΡ 3, 4 ΠΈ 7. ΠΡΠΈ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ Π½Π΅ ΠΏΡΠΎΡΠ²Π»ΡΡΡ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΠΎΠΉ ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ ΠΈ ΠΎΠΊΠ°Π·ΡΠ²Π°ΡΡ Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½ΡΠΉ ΡΡΡΠ΅ΠΊΡ Π½Π° ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠΉ ΠΌΠΎΠ΄Π΅Π»ΠΈ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠΈ, ΡΠ²ΡΠ·Π°Π½Π½ΠΎΠΉ Ρ ΠΊΠ°Π»ΡΡΠΈΠ΅Π²ΡΠΌ ΡΡΡΠ΅ΡΡΠΎΠΌ. ΠΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌ ΠΈΡ
ΡΠΈΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ, Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎ, ΠΎΠ±ΡΡΠ»ΠΎΠ²Π»Π΅Π½ Π²Π»ΠΈΡΠ½ΠΈΠ΅ΠΌ Π½Π° ΡΡΠ½ΠΊΡΠΈΠΈ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ, ΠΏΠΎΡΠΊΠΎΠ»ΡΠΊΡ ΡΡΠΈ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎ ΠΏΠΎΠ΄Π°Π²Π»ΡΡΡ ΠΊΠ°Π»ΡΡΠΈΠΉ-ΠΈΠ½Π΄ΡΡΠΈΡΠΎΠ²Π°Π½Π½ΡΠΉ ΠΏΡΠΎΡΠ΅ΡΡ ΡΠΊΠ°ΡΠΊΠ° ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΠΎΠΉ ΠΏΡΠΎΠ½ΠΈΡΠ°Π΅ΠΌΠΎΡΡΠΈ. ΠΡΠΎΠΌΠ΅ ΡΠΎΠ³ΠΎ, ΠΎΠ΄Π½ΠΎ ΠΈΠ· ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π½ΡΡ
Π²Π΅ΡΠ΅ΡΡΠ² (7) ΠΎΠ±Π»Π°Π΄Π°Π΅Ρ Π°Π½ΡΠΈΠΎΠΊΡΠΈΠ΄Π°Π½ΡΠ½ΡΠΌΠΈ ΡΠ²ΠΎΠΉΡΡΠ²Π°ΠΌΠΈ, ΠΏΡΠΎΡΠ²Π»ΡΡ ΡΠΏΠΎΡΠΎΠ±Π½ΠΎΡΡΡ ΠΊ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΏΠ΅ΡΠ΅ΠΊΠΈΡΠ½ΠΎΠ³ΠΎ ΠΎΠΊΠΈΡΠ»Π΅Π½ΠΈΡ Π»ΠΈΠΏΠΈΠ΄ΠΎΠ² (ΠΠΠ) Π³ΠΎΠΌΠΎΠ³Π΅Π½Π°ΡΠ° ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡ, ΡΡΠΎ ΠΌΠΎΠΆΠ΅Ρ Π±ΡΡΡ Π΄ΠΎΠΏΠΎΠ»Π½ΠΈΡΠ΅Π»ΡΠ½ΡΠΌ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠΎΠΌ Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½ΠΎΠ³ΠΎ ΡΡΡΠ΅ΠΊΡΠ°. ΠΠΎΠ»ΡΡΠ΅Π½Π½ΡΠ΅ Π΄Π°Π½Π½ΡΠ΅ ΠΏΠΎΠ·Π²ΠΎΠ»ΡΡΡ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄ΠΎΠ²Π°ΡΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π½ΡΠ΅ Π²Π΅ΡΠ΅ΡΡΠ²Π° Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΎΡΠ½ΠΎΠ²Ρ Π΄Π»Ρ ΡΠΎΠ·Π΄Π°Π½ΠΈΡ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΡΡ
Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½ΡΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΡΠΏΠΎΡΠΎΠ±Π½ΡΡ
ΠΏΠΎΠ²Π»ΠΈΡΡΡ Π½Π° ΡΠ°Π½Π½ΠΈΠ΅ ΡΡΠ°Π΄ΠΈΠΈ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ
Ru(III) complexes with lonidamine-modified ligands
A series of bifunctional Ru(III) complexes with lonidamine-modified ligands (lonidamine is a selective inhibitor of aerobic glycolysis in cancer cells) was described. Redox properties of Ru(III) complexes were characterized by cyclic voltammetry. An easy reduction suggested a perspective for these agents as their whole mechanism of action seems to be based on activation by metal atom reduction. New compounds demonstrated a more pronounced antiproliferative potency than the parental drug; individual new agents were more cytotoxic than cisplatin. Stability studies showed an increase in the stability of complexes along with the linker length. A similar trend was noted for antiproliferative activity, cellular uptake, apoptosis induction, and thioredoxin reductase inhibition. Finally, at concentrations that did not alter water solubility, the selected new complex evoked no acute toxicity in Balb/c mice. Β© 2021 by the authors. Licensee MDPI, Basel, Switzerland