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

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.

Anticancer Potential of Pyridoxine-Based Doxorubicin Derivatives: An In Vitro Study.

Doxorubicin (DOX) is a prevalent anticancer agent; however, it is unfortunately characterized by high cardiotoxicity, myelosuppression, and multiple other side effects. To overcome DOX limitations, two novel pyridoxine-derived doxorubicin derivatives were synthesized (DOX-1 and DOX-2). In the present study, their antitumor activity and mechanism of action were investigated. Of these two compounds, DOX-2, in which the pyridoxine fragment is attached to the doxorubicin molecule via a C3 linker, revealed higher selectivity against specific cancer cell types compared to doxorubicin and a promising safety profile for conditionally normal cells. However, the compound with a C1 linker (DOX-1) was not characterized by selectivity of antitumor action. It was revealed that DOX-2 obstructs cell cycle progression, induces apoptosis via the mitochondrial pathway without the development of necrosis, and showcases antioxidant capabilities, underlining its cell-regulatory roles. In contrast to doxorubicin's DNA-centric mechanism, DOX-2 does not interact with nuclear DNA. Given these findings, DOX-2 presents a new promising direction in cancer therapeutics, which is deserving of further in vivo exploration.