The chemistry of heterocyclic compounds has traditionally been and remains a bright area of chemical science in Russia. This is due to the fact that many heterocycles find the widest application. These compounds are the key structural fragments of most drugs, plant protection agents. Many natural compounds are also derivatives of heterocycles. At present, more than half of the hundreds of millions of known chemical compounds are heterocycles. This collective review is devoted to the achievements of Russian chemists in this field over the last 15–20 years. The review presents the achievements of leading heterocyclists representing both RAS institutes and university science. It is worth noting the wide scope of the review, both in terms of the geography of author teams, covering the whole of our large country, and in terms of the diversity of research areas. Practically all major types of heterocycles are represented in the review. The special attention is focused on the practical applications of heterocycles in the design of new drugs and biologically active compounds, high-energy molecules, materials for organic electronics and photovoltaics, new ligands for coordination chemistry, and many other rapidly developing areas. These practical advances would not be possible without the development of new fundamental transformations in heterocyclic chemistry. Bibliography — 2237 references.

The review summarizes advances in the development of low-molecular-weight ligands for G-quadruplex (G4) nucleic acid structures published in the past five years. Main chemical classes of these ligands (polyaromatic compounds, macrocyclic systems, metal complexes and heterocyclic derivatives) are considered. The chemical structures of the ligands and their influence on the stabilization of quadruplexes are analyzed. Future prospects of design of G4 ligands and their applications are discussed. The bibliography includes 188 references.

Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and is among the top three causes of cancer-associated death worldwide. However, the clinical use of chemotherapy for HCC has been limited by various challenges, emphasizing the urgent need for novel agents with improved anticancer properties. We recently synthesized and characterized a series of 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives that exhibit potent apoptotic activity against an array of cancer cell lines, including variants with multidrug resistance. Their effect on liver cancer cells, however, was unknown. Here, we investigated three selected 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives (compounds 1–3) for their cytotoxicity and the underlying molecular mechanisms in wild-type or p53-deficient HCC cells. Cytotoxicity was determined by WST-1 assays and cell impedance measurements and apoptosis was analyzed by flow cytometry. The interaction between compounds and tumor-associated NADH oxidase (tNOX, ENOX2) was studied by cellular thermal shift assay (CETSA). We found that compound 1 and 2 induced significant cytotoxicity in both HepG2 and Hep3B lines. CETSA revealed that compounds 1 and 2 directly engaged with tNOX, leading to a decrease in the cellular NAD⁺/NADH ratio. This decreased the NAD⁺-dependent activity of Sirtuin 1 (SIRT1) deacetylase. In p53-wild-type HepG2 cells, p53 acetylation/activation was enhanced, possibly due to the reduction in SIRT1 activity, and apoptosis was observed. In p53-deficient Hep3B cells, the reduction in SIRT1 activity increased the acetylation of c-Myc, thereby reactivating the TRAIL pathway and, ultimately leading to apoptosis. These compounds thus trigger apoptosis in both cell types, but via different pathways. Taken together, our data show that derivatives 1 and 2 of 4,11-diaminoanthra[2,3-b]furan-5,10-diones engage with tNOX and inhibit its oxidase activity. This results in cytotoxicity via apoptosis through tNOX-SIRT1 axis to enhance the acetylation of p53 or c-Myc in HCC cells, depending on their p53 status.

(1) Background: This investigation aimed at developing a series of c-Met-targeting cabozantinib-based PROTACs. (2) Methods: Purification of intermediate and target compounds was performed using column chromatography, in vitro antiproliferation activity was measured using a standard MTT assay and a c-Met degradation assay was performed via the immunoblotting technique. (3) Results: Several compounds exhibited antiproliferative activity towards different cell lines of breast cancer (T47D, MDA-MB-231, SKBR3, HCC1954 and MCF7) at the same level as parent cabozantinib and 7-demethyl cabozantinib. Two target conjugates, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers, exhibited the effective inhibition of c-Met phosphorylation and an ability to decrease the level of c-Met in HCC1954 cells at micromolar concentrations. (4) Conclusions: Two compounds exhibit c-Met inhibition activity in the nanomolar range and can be considered as PROTAC molecules due to their ability to decrease the total level of c-Met in HCC1954 cells. The structures of the offered compounds can be used as starting points for further evaluation of cabozantinib-based PROTACs.