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Structural Analogs of Dehydrozingerone Containing a Pyridoxine Fragment Exhibit Membrane-Modulating Properties and Synergistically Enhance the Antitumor Activity of Cytostatics

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An Erratum to this article was published on 23 November 2023

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Abstract

Previously we synthesized 10 novel structural analogs of dehydrozingerone based on the pyridoxine (vitamin B6) scaffold. Two lead compounds (compound (I) and compound (II)) expressed good cytotoxic activity against tumor cells and have shown higher selectivity than doxorubicin. In the present study, the mechanism of action of the leading analogues of dehydrozingerone, as well as the efficiency of their combinations with known cytostatics, was studied in more detail. We revealed a synergistic effect of leader dehydrozingerone analogs combinations with known cytostatics—doxorubicin, vinblastine and paclitaxel. It was established, that test compounds (I) and (II), as well as curcumin and dehydrozingerone, possess membrane-damaging activity: cause cytoplasmic membrane depolarization and reduction in its microviscosity, which can explain the increase in toxicity of cytostatics. In addition, the test compounds were found to increase the ATPase activity of P-glycoproteins, likely acting as their substrates. It was also revealed that the test compounds increase the expression of BAX and E-cadherin, decrease the expression of Bcl-2 in cancer cells. Compound (I) does not cause blood cells hemolysis, does not possess DNA-damaging and mutagenic activity, and when administered intravenously to mice, the LD50 was 65 mg/kg. The investigated compounds are promising drug candidates to be further tested on animals with grafted tumors.

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Funding

Cytotoxicity study was performed by the subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities, project no. 0671-2020-0053. All other experiments of the study were funded by RFBR, project no. 20-33-70175.

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Authors and Affiliations

  1. Scientific and Educational Center of Pharmaceutics, Kazan Federal University, 420008, Kazan, Russia

    O. V. Bondar, R. Karwt, T. Mohammad, R. S. Pavelyev, M. V. Pugachev, Be. B. Ygaiev, A. M. Aimaletdinov & Y. G. Shtyrlin

  2. Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008, Kazan, Russia

    A. R. Kayumov

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  1. O. V. Bondar
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  2. R. Karwt
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Conflict of interest. The authors declare that they have no conflicts of interest.

Statement on the welfare of animals. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Kazan (Volga region) Federal University (protocol code 24 and date of approval 22.09.2020) for studies involving animals.

All manipulations with animals were carried out in accordance with GOST 33215-2014 of Russian Federation “Guidelines for the maintenance and care of laboratory animals. Rules for equipping premises and organizing procedures for working with laboratory animals”. Additionally, this research was carried out in accordance with the ARRIVE guidelines [55]. The acute toxicity study of compound (I) was agreed with the local ethics committee of the Kazan (Volga region) Federal University, protocol no. 24 of 22.09.2020.

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Bondar, O.V., Karwt, R., Mohammad, T. et al. Structural Analogs of Dehydrozingerone Containing a Pyridoxine Fragment Exhibit Membrane-Modulating Properties and Synergistically Enhance the Antitumor Activity of Cytostatics. Russ J Bioorg Chem 49, 797–814 (2023). https://doi.org/10.1134/S106816202304009X

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