Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.

A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC50,MCF-7 < 10 µM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC50 < 5 µM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.

Electrochemical Properties and Structure of Multi-Ferrocenyl Phosphorus Thioesters.

The reaction of triferrocenylthiophosphite with elemental sulfur leads to triferrocenyltetrathiophosphate. The molecule of tetrathiophosphate adopts propeller-like all synclinal-conformation of the ferrocenyl fragments respective to the P=S bond. All ferrocenyl groups have nearly ideal eclipsed conformation of the cyclopentadienyl fragments. The Fc3S3P (1), Fc3S3P=O, (2) and Fc3S3P=S (3) demonstrate three reversible and well-separated ferrocenyl-based redox events. The electronic structures of 1-3 have been studied quantum-chemically; the energies and composition of frontier orbitals have been calculated.

Excellent supercapacitor and sensor performance of robust cobalt phosphinate ferrocenyl organic framework materials achieved by intrinsic redox and structure properties.

A new redox active coordination polymer [Co(H2O)2(Fc(PHOO)2)·2H2O]n (Fc = ferrocene) was synthesized by the diffusion method and characterized by single-crystal X-ray diffraction. Phosphinate fragments formed infinite chains connected through ferrocene fragments to 2D PCP associated with cobalt atoms. Additional strong hydrogen bonding via the participation of coordinated and lattice water molecules resulted in the formation of a 3D network. The polymer exhibited water-induced crystal-to-amorphous transformation with chromotropism, as confirmed by spectroscopic techniques, elemental analysis, TGA and XRPD. The explosion of the amorphous phase [Co(Fc(PHOO)2)]n to form water vapor readily led to its conversion into the initial crystalline [Co(H2O)2(Fc(PHOO)2)·2H2O]n with a reverse change of color. The dehydrated form of the polymer selectively sorbed water and could be used as a material with the function of an express dehydrator. Moreover, a modified electrode could qualitatively determine the water content in the solvent at a concentration of 0.05%. Both hydrated and dehydrated forms were evaluated as electrode materials for supercapacitors. The [Co(Fc(PHOO)2)]n (dehydrated form) electrode exhibited high specific capacitance and excellent cycling stability. Its maximum specific capacitance was 2517 F g-1 at a current density of 2 A g-1, and the specific capacitance retention was about 90.1% after 1000 cycles.

Zn and Co redox active coordination polymers as efficient electrocatalysts.

New redox active 1D helical coordination polymers M(fcdHp) (M(ii) = Zn(1), Co(2)) have been obtained by utilizing the 1,1'-ferrocenylenbis(H-phosphinic) acid (H2fcdHp) ligand and Zn or Co nitrate salts. Complexes 1 and 2 are isomorphic, crystallizing in the chiral space groups P4122 and P4322, respectively. Their redox, electrocatalytic and other properties are described. These compounds incorporated into carbon paste electrodes and exhibited reversible redox reactions, arising from the ferrocenyl moiety. These coordination polymers are efficient as electrocatalysts for the reduction of protons to hydrogen. Using N,N-dimethylformamidium ([DMF(H)+]) as the acid in the acetonitrile solution, Co CP (2) displays a turnover frequency of 300 s-1, which is among the fastest rates reported for any CP electrocatalyst in CH3CN. This high rate of catalytic reaction comes at the cost of the 820-840 mV overpotential at the potential of catalysis. As the hydrogen evolution reaction (HER) catalysts, the CPs exhibited in 0.5 M H2SO4 the overpotential η10 of 340 or 450 mV, onset overpotential of 220 or 300 mV (vs. RHE), Tafel slope of 110 or 120 mV dec-1, correspondingly for 1 and 2, and considerable long-term stability for the HER.

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.