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

• Published in: Russian journal of bioorganic chemistry 2023-08, Vol.49 (4), p.797-814
• Main Authors: Bondar, O. V., Karwt, R., Mohammad, T., Pavelyev, R. S., Pugachev, M. V., Ygaiev, Be. B., Kayumov, A. R., Aimaletdinov, A. M., Shtyrlin, Y. G.
• Format: Article
• Language: English
• Subjects: Analogs; Anticancer properties; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Blood cells; Depolarization; Doxorubicin; Glycoproteins; Lead compounds; Life Sciences; Membranes; Organic Chemistry; Pyridoxine; Substrates; Synergistic effect
• ISSN: 1068-1620; 1608-330X
• DOI: 10.1134/S106816202304009X

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.