Biomedical Chemistry: Research and Methods, 2018, 1(3), e00052
The 40th Anniversary of the Institute of Physiologically Active Compounds of the Russian Academy of Sciences

Bioisosteric Analogues of Cinnamic Acid as Effective Neuroprotectors

M.E. Neganova1*, V. Semenov2, M. Semenova3, O.M. Redkozubova4, Yu.R. Aleksandrova5, E.A. Lysova1, S.G. Klochkov1, E.F. Shevtsova1

1Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia,*e-mail: neganova83@mail.ru
2Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky av., Moscow, 119991 Russia
3Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilova str., Moscow, 119334 Russia
4OOO Neurobotics, Directions 4922, 4-2, Southern Industrial Area, Zelenograd, 124498 Russia
4Ivanovo State University, School of Biology and Chemistry, Department of General Biology and Physiology, 136 Lenina av., Ivanovo, Russia

Key words: cinnamic acid; neuroprotectors; neurodegenerative diseases; mitochondria; antioxidants

DOI: 10.18097/BMCRM00052

The whole version of this paper is available in Russian.

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.

Figure 1. Antioxidant activity of bioisosteric cinnamic acid analogues and polymethoxybenzenes (effect on the LPO of rat brain homogenate, initiated by Fe3+ ions). The concentration of test compounds was 30 μM. DMSO (≤1%) was used as negative control. * - p≤0.05 as compared with the control (T-test).

Figure 2. Influence of bioisosteric cinnamic acid analogues and polymethoxybenzenes on mitochondrial characteristics.
A - effect on the membrane potential of rat liver mitochondria.
B - change in the rate of Ca2+ induced swelling of rat liver mitochondria. The concentration of test compounds was 30 μM. The concentration of Ca2+ ions was 12.5 μM. DMSO (≤1%) was used as negative control. * - p≤0.05 as compared with the control (T-test).

Figure 3. Influence of bioisosteric cinnamic acid analogues and polymethoxybenzenes on the viability of neuroblastoma cells SH-SY5Y. A - own toxicity. B - effect on ionomycin (IM) -induced toxicity. The concentration of test compounds is 30 μM. Concentration of IM - 3 μM. DMSO (≤1%) was used as negative control. * - p≤0.05 as compared with the control (T-test).

CLOSE
Table 1. Structures of test compounds.

ACKNOWLEDGEMENTS

The work was financially supported by RFBR grant No. 16-03-00079 and within the framework of the State Task of 2018 (topic No. 0090-2017-0019).

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