Synthesis and in vitro antitumor activity of novel alkenyl derivatives of pyridoxine, bioisosteric analogs of feruloyl methane

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 22; pp. 5824 - 5837
• Main Authors: Pavelyev, Roman S., Bondar, Oksana V., Nguyen, Thi N.T., Ziganshina, Alisa A., Al Farroukh, Mohammad, Karwt, Rawdah, Alekbaeva, Gulnaz D., Pugachev, Mikhail V., Yamaleeva, Zilya R., Kataeva, Olga N., Balakin, Konstantin V., Shtyrlin, Yurii G.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2018; Elsevier
• Subjects: Alkenes - chemical synthesis; Alkenes - chemistry; Alkenes - pharmacology; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Dehydrozingerone; Dose-Response Relationship, Drug; Drug discovery; Drug Screening Assays, Antitumor; Feruloyl methane; Humans; Life Sciences & Biomedicine; Methane - analogs & derivatives; Methane - pharmacology; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Pyridoxine; Pyridoxine - chemical synthesis; Pyridoxine - chemistry; Pyridoxine - pharmacology; Science & Technology; Structure-Activity Relationship; Vitamin B6; Pyridoxine; Drug discovery; Dehydrozingerone; Vitamin B6; Feruloyl methane; Anticancer activity; ANTICANCER; ANTIOXIDANT; CHEMISTRY; ASSAYS; CURCUMIN ANALOGS; CELL-CYCLE; AGENTS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.10.031

[Display omitted] •Twelve pyridoxine-based bioisosteric analogs of dehydrozingerone are synthesized.•At least 8 compounds possess high in vitro antitumor activity and selectivity.•The active compounds inhibit migration of tumor cells and arrest their cell cycle.•They also increase the level of reactive oxygen species and initiate apoptosis.•The leading compound also affects the functional activity of mitochondria. Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase. Similar to DZG, but with higher efficiency, the leading compound was able to inhibit migration activity and, therefore, invasiveness of tumor cells. It also increased concentration of reactive oxygen species in tumor cells, induced depolarization of mitochondrial membranes and initiated apoptosis accompanied by disruption of integrity of cytoplasmic cell membranes. By contrast to DZG, the leading compound did not possess antioxidant properties. The obtained data make the described chemotype a promising starting point for the development of new anticancer agents.