8-Hydroxyquinoline Glycoconjugates Containing Sulfur at the Sugar Anomeric Position—Synthesis and Preliminary Evaluation of Their Cytotoxicity

One of the main factors limiting the effectiveness of many drugs is the difficulty of their delivery to their target site in the cell and achieving the desired therapeutic dose. Moreover, the accumulation of the drug in healthy tissue can lead to serious side effects. The way to improve the selectivity of a drug to the cancer cells seems to be its conjugation with a sugar molecule, which should facilitate its selective transport through GLUT transporters (glucose transporters), whose overexpression is seen in some types of cancer. This was the idea behind the synthesis of 8-hydroxyquinoline (8-HQ) derivative glycoconjugates, for which 1-thiosugar derivatives were used as sugar moiety donors. It was expected that the introduction of a sulfur atom instead of an oxygen atom into the anomeric position of the sugar would increase the stability of the obtained glycoconjugates against untimely hydrolytic cleavage. The anticancer activity of new compounds was determined based on the results of the MTT cytotoxicity tests. Because of the assumption that the activity of this type of compounds was based on metal ion chelation, the effect of the addition of copper ions on cell proliferation was tested for some of them. It turned out that cancer cells treated with glycoconjugates in the presence of Cu2+ had a much slower growth rate compared to cells treated with free glycoconjugates in the absence of copper. The highest cytotoxic activity of the compounds was observed against the MCF-7 cell line.

Solution region synthesis methodology of planar eight-bar linkage for four specified positions of a 4R chain

The solution region methodology for solving the problem of four-bar linkage synthesis with four specified positions was extended to solve the problem of eight-bar linkage synthesis. The processes to build solution regions for synthesizing different types of eight-bar linkages are described, and the methods of building solution regions are divided into five types. First, the synthesis equation is derived, and the curve expressed by the synthesis equation is called the solution curve. Second, the process to build the spatial solution regions from the solution curves is detailed, and a new defect identification method is developed for building the spatial feasible solution region, which is a set of linkage solutions meeting four positions and excluding defects. Finally, linkage solutions that do not meet practical engineering requirements are eliminated from the spatial feasible solution region to obtain the useful spatial solution region. The examples demonstrate the feasibility of the proposed method. The proposed synthesis methodology is simple and easy to program, and provides reference for four specified position synthesis of other multi-bar linkages.

Drug design: 4-thiazolidinones applications. Part 1. Synthetic routes to the drug-like molecules

4-Thiazolidinones, as examples of privileged scaffolds, have been the focus of medicinal chemistry since 60th. Among them, 5-substituted thiazolidinones with a C5 exocyclic bond (5-ene derivatives) are of special interest due to chemical characteristics and pharmacological profiles, possessing anticancer, antimicrobial, and antiviral properties, as well as being high-affinity ligands to a number of biological targets. A new medicinal chemistry trend claims that the aforementioned compounds are frequent hitters or pan assay interference compounds, which are useless because of the possible low selectivity. This is argued by the Michael acceptor property of 5-ene-4-thiazolidinones, which is actively discussed in the literature and requires further investigation. Based on SAR analysis, the main vectors for the design of 5-ene-4-thiazolidinone-based molecules were proposed: complication of C5 fragment; introduction of the substituents in the N3 position; synthesis of isosteric heterocycles; combination with other pharmacologically attractive fragments; annealing of thiazolidinone core; utilisation of 5-ene-thiazolidinones in synthesis of other compounds. The affinity of 5-ene-4-thiazolidinones toward various targets can be regarded as an advantage in polypharmacological approaches. Michael acceptors are considered as the “new old tool” for new drug creation, especially anticancer agents. One of the possible solutions within privileged substructure-based diversity-oriented synthesis is the fixation of 5-ene-4-thiazolidinone fragment in the fused heterocycles, for example, thiopyrano[2,3-d]thiazoles obtained from 5-ene-thiazolidinones.