A.E. Chichibabin Laboratory of Heterocyclic Compounds (№ 3)

● Chemistry of heterocyclic compounds;

● Photochemical transformations;

● Synthesis and study of organic radicals;

● Molecular design of magnetic materials.

✓ We have synthesized the first stable tetraradical with a quintet ground state. The tetraradical exhibits good thermal stability: in an inert atmosphere, its decomposition starts at approximately 125 °C; in an airsaturated toluene solution, no decomposition is observed after several hours of heating at 90 °C. The magnetic properties of the tetraradical were investigated using: SQUID magnetometry of polycrystalline samples; Evans method in solution; EPR spectroscopy in various matrices. The experimental data, supported by highlevel quantumchemical calculations, confirm that the tetraradical possesses a highspin quintet ground state. This tetraradical, featuring an unprecedented combination of magnetic and thermal properties, holds promise for the development of purely organic magnetic materials. DOI: 10.1021/jacs.4c04391

✓ Organic nitroxyl radicals — in particular, chloro-, bromo-, and iodosubstituted nitronyl nitroxide radicals — exhibit selfassembly in the crystalline state through the combined action of halogen bonds (Hal···O_NO) and hydrogen bonds (O_NO···H_Me). The halogen bond brings together atoms carrying spin densities of opposite signs, thereby promoting ferromagnetic intermolecular exchange interactions. This work demonstrates for the first time that halogen bonds can create pathways facilitating ferromagnetic intermolecular exchange between paramagnetic centres in organic nitronyl nitroxide radicals. DOI: 10.1016/j.matchemphys.2024.130252

✓ Nitronyl nitroxide radicals, being stable paramagnets with delocalized spin density, serve as convenient building blocks for the design of highspin systems. One of the most efficient methods to introduce a nitronyl nitroxide moiety into organic molecules is the palladiumcatalyzed crosscoupling reaction of aryl halides with organogold derivatives of nitronyl nitroxide. However, the high cost of organogold compounds limits their widespread use in the synthesis of highspin systems. We have developed the first silver(I) nitronyl nitroxide derivatives stabilized by sterically hindered Nheterocyclic carbene (NHC) ligands. In crosscoupling reactions, the synthesized organosilver compounds prove to be as effective as their organogold counterparts. This has been demonstrated through the synthesis of a broad range of: aryl and hetarylsubstituted nitronyl nitroxides; various mono, bi, tri, and tetraradical derivatives. DOI: 10.1021/acs.organomet.5c00042

✓ The naphthoquinone moiety is a structural component of numerous natural compounds and pharmaceuticals; however, the reactivity of its polyfluorinated analogues remains largely unexplored. In this work, we investigated a multicomponent condensation of hexafluoro1,4naphthoquinone with various nitrogencontaining heterocycles and methyleneactive compounds. It was demonstrated that this interaction leads to the formation of a previously unknown type of zwitterionic products. At the same time, an analogous condensation with αsubstituted pyridines afforded previously unreported salts. The resulting betaines can serve as starting materials for the synthesis of novel fluorinated polycyclic compounds, including: pyrido[1,2a]indole6,11diones; naphto[2,3b]furan4,9diones. DOI: 10.1002/ajoc.202400751

✓ We have discovered a previously unknown photochemical rearrangement of substituted 3arylamino pyrazoles containing an allomaltool fragment. It has been shown that upon UV irradiation, such systems undergo an ESIPTinduced contraction of the pyran4one ring, leading to the formation of an unstable αhydroxy1,2diketone. For the first time, this intermediate was successfully trapped via intramolecular cyclization involving the arylamino moiety, resulting in the formation of a new class of tricyclic derivatives: cyclopenta[4,5]pyrrolo[2,3c]pyrazoles. The discovered cascade process proceeds under mild conditions and provides a straightforward and convenient approach to the synthesis of structurally complex heterocyclic systems. This study continues our series of works on photochemical transformations of 3hydroxypyran4one derivatives and expands the synthetic potential of photochemistry involving ESIPTactive systems. DOI 10.1039/D5OB00796H

✓ In this study, we have thoroughly investigated the photoinduced transformations of 2aminothiazole derivatives (terarylenes) containing an allomaltool fragment. It has been demonstrated that the photochemical transformations of the studied compounds can proceed via two distinct pathways, with the specific route determined by the structure of the starting material. By varying the structure of the initial terarylene, one can direct the process either towards: the classical 6πelectrocyclization of the 1,3,5hexatriene system, or the ESIPTinduced contraction of the pyranone ring. This discovery opens up fundamentally new possibilities for finetuning photoresponsive systems based on allomaltoolcontaining terarylenes. The relationship between the chemical structure of the starting compounds and their photochemical behaviour was analysed using: theoretical modelling methods; UV spectroscopy. As a result of this work, we have proposed new photochemical approaches to the synthesis of: polyaromatic products; thiazolecontaining salts. Furthermore, we have demonstrated the potential of the studied compounds as convenient starting materials for the development of photoacid generators (PAGs), which are in high demand in microelectronics and photolithography. DOI: 10.1039/D5OB00264H

✓ Cancer remains one of the most serious challenges for modern medicine. Consequently, the development of new antitumor drugs — particularly those based on natural compounds with reduced toxicity and high efficacy — is a pressing task for contemporary science. We have proposed a photochemical method for synthesizing analogues of the natural alkaloid isocryptolepine from acyloximes derived from 3acetyl2arylinoles. The key intermediate in this process is a nitrogencentered iminyl radical. Evaluation of the antiproliferative activity of the obtained isocryptolepines revealed that they exhibit (sub)micromolar inhibitory activity against tested breast cancer (BC) cell lines. Notably, the antiproliferative properties of the lead compound significantly surpassed those of 4hydroxytamoxifen — a wellknown drug used to treat hormonedependent breast cancers. Further investigation showed that the synthesized indoloquinolines display antiestrogenic activity. This finding suggests that these compounds may exhibit selectivity toward BC cells expressing the estrogen receptor α (ERα). Additionally, the studied isocryptolepines were found to produce synergistic effects when combined with the chemotherapeutic agent 5fluorouracil. These results provide a foundation for further research into isocryptolepine analogues, with the aim of discovering effective drugs for treating aggressive forms of breast cancer. DOI: 10.1016/j.bioorg.2024.107942

✓ The first representatives of the azaoxa[5]helicenes in the furolinoquinoline series have been synthesized, and their structural and photophysical properties have been investigated. Using Xray crystallography and DFT calculations, it was established that luminescent furanfused aza[5]helicenes — unlike their carbon analogues — do not undergo Mallorytype photocyclization. This is due to an increased distance between the terminal carbon atoms, which confers greater stability toward UV light. A study of the acidochromic properties of the synthesized compounds revealed that protonation with trifluoroacetic acid leads to an increase in fluorescence intensity for most of the obtained azahelicenes. The best fluorescence enhancement was observed for the fluorophore containing a methoxy substituent in the peripheral phenyl moiety, which exhibited a 10fold increase in quantum yield. The incorporation of a furolinoquinoline moiety into the helicene skeleton results in: improved fluorescent properties; the ability to modulate these properties using acidic agents. DOI: 10.1016/j.dyepig.2024.112032

✓ Irreversible phototransformations of ortho-bihetarylchalcones irradiated with visible light have been studied. Isosteric replacement of one of the aryl residues with a chalcone moiety in diarylethenes (terarylenes) molecules significantly expands the synthetic potential of these compounds, thereby opening up a wide range of new functional materials. It has been discovered for the first time that protonation of the carbonyl group in the chalcone moiety of ortho-bihetarylchalcones exclusively facilitates 6π-photocyclization, leading to the formation of oxathia[5]helicenes, whereas photolysis in toluene in the presence of triethylamine preferentially yields 1,2,3,4-tetrasubstituted cyclobutanes. The formation of the helicene framework is due to visible light-induced 6π-electrocyclization of the hexatriene system of bigetaryl chalcones, and [2+2]-photocycloaddition is facilitated by the aggregation of chalcone molecules, which is a consequence of the formation of a head-to-head excimer due to the π–π-stacking interaction of the polyaromatic systems of naphthofuranes. The obtained results can be used to develop new efficient protocols for the synthesis of fused heteroaromatic frameworks and promising materials with wide application in material chemistry, molecular electronics, and medicine. DOI: 10.1039/D5OB00490J

✓ Gossypol, 2,2'-bis(1,6,7-trihydroxy-5-isopropyl-3-methyl-8-formylnaphthalene, is a large-scale byproduct of the cotton ginning industry. Given its availability, large volumes, and potential use as a base for developing various promising biologically active products, the use of this compound is an attractive challenge in modern chemistry. We have synthesized previously unknown imine derivatives of gossypol containing bioactive fragments, a drug, or a spin label.

1. Polyfunctional hydrazones of oxamic acid thiohydrazides are convenient substrates for the creation of new classes of drugs, such as promising inhibitors of the type 3 secretion system of Gram-negative bacteria and next-generation antibacterial agents. We have obtained gossypol derivatives containing thiohydrazide fragments.

2. A conjugate of gossypol with Doxorubicin, a well-known anticancer antibiotic, was obtained. Screening results showed that the conjugate at micromolar concentrations inhibits tumor cell proliferation. DOI: 10.2174/0113852728358616241226064825

3. The first example of a spin-labeled gossypol derivative is described, which was obtained using nitronyl nitroxide – amino-Tempo. The introduction of paramagnetic radical particles into gossypol is of interest both for the production of products with altered pharmacological characteristics and stable radicals promising for magnetic resonance imaging studies in pharmacology or biochemistry. DOI: 10.3390/molecules29204966

✓ A promising direction in the chemistry of organic radicals is the targeted design of functional systems containing a paramagnetic group and a fluorophore fragment. We have developed methods for the synthesis of hybrid chromones containing radicals located in furan ring or in the acyl group of chromone. DOI: 10.1016/j.mencom.2024.10.019