In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Using the methodology of “click” chemistry, a singular method has been developed for the synthesis of unique conjugates based on sesquiterpene lactones: dehydrocostuslactone and alantolactone with polyalkoxybenzenes. To expand the structural range of the resulting conjugates, the length of the 1,2,3-triazole spacer was varied. For all synthesized compounds, the cytotoxic profile was determined on the cell lines of tumor origin (SH-SY5Y, HeLa, Hep-2, A549) and normal Hek 293 cells. It was found that the compounds based on alantolactone 7a–d with a long spacer and substances containing dehydrocostuslactone 10a–d with a short spacer have the greatest toxic effect. The decrease in cell survival under the action of these conjugates may be due to their ability to cause dissipation of the transmembrane potential of mitochondria and inhibit the process of glycolysis, leading to cell death. The obtained results confirm the assumption that the development of conjugates based on sesquiterpene lactones and polyalkoxybenzenes can be considered as a promising strategy for the search for potential antitumor agents.

Experimental and theoretical conformational analysis of N-methyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide, N-butyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide, and N-octyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide was carried out by the methods of dipole moments, IR spectroscopy, and Density Functional Theory (DFT) B3PW91/6-311++G(df,p) calculations. In solution, these N,N-dialkyl substituted bisphosphorylated acetamides exist as a conformational equilibrium of several forms divided into two groups—with Z- or E-configuration of the carbonyl group and alkyl substituent, and syn or anti arrangement of the phosphoryl-containing fragments relative to the amide plane. The substituents at the phosphorus atoms have eclipsed cis- or staggered gauche-orientation relative to the P=O groups, and cis orientation of the substituents is due to the presence of intramolecular H-contacts P=O...H−C_phenyl or p,π conjugation between the phosphoryl group and the phenyl ring. Preferred conformers of acetamides molecules are additionally stabilized by various intramolecular hydrogen contacts with the participation of oxygen atoms of the P=O or C=O groups and hydrogen atoms of the methylene and ethylene bridges, alkyl substituents, and phenyl rings. However, steric factors, such as a flat amide fragment, the bulky phenyl groups, and the configuration of alkyl bridges, make a significant contribution to the realization of preferred conformers.

The creation of new potential metal-based therapeutics largely relies on the development of useful ligand scaffolds. In recent years, our research group has introduced thiophosphoryl-functionalized carboxamides as a convenient framework for obtaining biologically active cyclopalladated derivatives. In continuation of these studies, β-(aminoalkyl)phosphine sulfides bearing additional substituents in the ethylene backbone were synthesized for the first time and reacted with picolinic acid to afford a series of new functionalized amide ligands. The latter readily underwent direct cyclopalladation under the action of PdCl₂(NCPh)₂ under mild reaction conditions. The resulting S,N,N-complexes were studied for in vitro cytotoxicity against several solid and hematopoietic cancer cell lines, as well apoptosis induction and DNA damage ability, which showed their promising anticancer properties. In addition, moderate antibacterial activity was observed for a representative palladocycle of the β-thiophosphorylated derivatives.

Parahydrogen-induced nuclear polarization offers a significant increase in the sensitivity of NMR spectroscopy to create new probes for medical diagnostics by magnetic resonance imaging. As precursors of the biocompatible hyperpolarized probes, unsaturated derivatives of phosphoric acid, propargyl and allyl phosphates, are proposed. The polarization transfer to ¹H and ³¹P nuclei of the products of their hydrogenation by parahydrogen under the ALTADENA and PASADENA conditions, and by the PH-ECHO-INEPT+ pulse sequence of NMR spectroscopy, resulted in a very high signal amplification, which is among the largest for parahydrogen-induced nuclear polarization transfer to the ³¹P nucleus.

In this study, a simple and efficient method for the synthesis of conjugates of N-acyl derivatives of 3,5-bis(benzylidene)-4-piperidones and phenothiazine was developed. The method was based on the acylation of 3,5-bis(benzylidene)-4-piperidones with chloroacetic acid chloride, followed by treatment of the product with sodium azide and an azide-alkyne [3+2] cycloaddition reaction between the resulting azide and 10-(prop-2-yn-1-yl)-10H-phenothiazine in the final step. Using this method, a series of seven compounds 23–29 were synthesized. The structure of synthesized compounds 23–29 was studied using ¹H, ¹³C, and ¹⁹F NMR spectroscopy and ESI-MS mass spectrometry. The cytotoxicity of compounds 23–29 and their hydrochloride salts 30–36 towards pancreatic adenocarcinoma Panc-1, bladder cancer T-24, glioblastoma T98G, breast adenocarcinoma BT-20, and normal dermal fibroblast DF-1 cells was studied using an MTT assay. Compound 29, containing 3,4,5-trimethoxyl radicals at the aromatic ring, and its hydrochloride salt 36, demonstrated the best cytotoxicity against Panc-1, T-24, T98G, and BT-20 cancer cells. Hydrochloride salts were found to exhibit superior cytotoxicity against Panc-1, T-24, T98G, and BT-20 cancer cells compared to the original 3,5-bis(benzylidene)-4-piperidones and free bases. Selective cytotoxic action against Panc-1, T-24, T98G, and BT-20 cancer cells compared to normal DF-1 cells was also observed for all the obtained compounds and their salts.