Seven-membered N-heterocycles as approved drugs and promising leads in medicinal chemistry as well as the metal-free domino access to their scaffolds.

Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are often found in nature (e.g. alkaloids), the natural compounds of this group are rather rare as approved therapeutics. Thus, recently studied and approved azepane or azepine-congeners predominantly consist of semi-synthetically or synthetically-obtained scaffolds. In this review a comparison of approved drugs and recently investigated leads was proposed taking into regard their structural aspects (stereochemistry), biological activities, pharmacokinetic properties and confirmed molecular targets. The 7-membered N-heterocycles reveal a wide range of biological activities, not only against CNS diseases, but also as e.g. antibacterial, anticancer, antiviral, antiparasitic and against allergy agents. As most of the approved or investigated potential drugs or lead structures, belonging to 7-membered N-heterocycles, are synthetic scaffolds, this report also reveals different and efficient metal-free cascade approaches useful to synthesize both simple azepane or azepine-containing congeners and those of oligocyclic structures. Stereochemistry of azepane/azepine fused systems, in view of biological data and binding with the targets, is discussed. Apart from the approved drugs, we compare advances in SAR studies of 7-membered N-heterocycles (mainly from 2018 to 2023), whereas the related synthetic part concerning various domino strategies is focused on the last ten years.

Inhibition of the glutamate-cysteine ligase catalytic subunit with buthionine sulfoximine enhances the cytotoxic effect of doxorubicin and cyclophosphamide in Burkitt lymphoma cells.

Burkitt lymphoma (BL) is a highly aggressive lymphoma that mainly affects children and young adults. Chemotherapy is effective in young BL patients but the outcome in adults is less satisfactory. Therefore, there is a need to enhance the cytotoxic effect of drugs used in BL treatment. Glutathione (GSH) is an important antioxidant involved in processes such as regulation of oxidative stress and drug detoxification. Elevated GSH levels have been observed in many cancers and were associated with chemoresistance. We previously identified GCLC, encoding an enzyme involved in GSH biosynthesis, as an essential gene in BL. We now confirm that knockout of GCLC decreases viability of BL cells and that the GCLC protein is overexpressed in BL tissues. Moreover, we demonstrate that buthionine sulfoximine (BSO), a known inhibitor of GCLC, decreases growth of BL cells but does not affect control B cells. Furthermore, we show for the first time that BSO enhances the cytotoxicity of compounds commonly used in BL treatment, doxorubicin, and cyclophosphamide. Given the fact that BSO itself was not toxic to control cells and well-tolerated in clinical trials, combination of chemotherapy with BSO may allow reduction of the doses of cytotoxic drugs required to obtain effective responses in BL patients.

Cascade Transformation of the Ansamycin Benzoquinone Core into Benzoxazole Influencing Anticancer Activity and Selectivity.

The metal-free cascade transformation of geldanamycin benzoquinone core is proposed at relatively mild conditions. This approach yields new benzoxazole ansamycin antibiotics and enables their functionalization in an atom-economic manner, irrespective of the type of amine used. The analysis of the heterocyclization course reveals the dependence of its rate on the nature of the para-substituent within the benzylamine moiety (EDG/EWG) and the strength of the base. The reduction of the ansamycin core enables an increase in anticancer potency and selectivity.

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology.

Oncologic patients are subjected to four major treatment types: surgery, radiotherapy, chemotherapy, and immunotherapy. All nonsurgical forms of cancer management are known to potentially violate the structural and functional integrity of the cardiovascular system. The prevalence and severity of cardiotoxicity and vascular abnormalities led to the emergence of a clinical subdiscipline, called cardiooncology. This relatively new, but rapidly expanding area of knowledge, primarily focuses on clinical observations linking the adverse effects of cancer therapy with deteriorated quality of life of cancer survivors and their increased morbidity and mortality. Cellular and molecular determinants of these relations are far less understood, mainly because of several unsolved paths and contradicting findings in the literature. In this article, we provide a comprehensive view of the cellular and molecular etiology of cardiooncology. We pay particular attention to various intracellular processes that arise in cardiomyocytes, vascular endothelial cells, and smooth muscle cells treated in experimentally-controlled conditions in vitro and in vivo with ionizing radiation and drugs representing diverse modes of anti-cancer activity.

Modifications of geldanamycin via CuAAC altering affinity to chaperone protein Hsp90 and cytotoxicity.

Functionalization of alkyne (1) and azide (2) derivatives of geldanamycin (GDM) via dipolar cycloaddition CuAAC yielded 35 new congeners (3-37) with C(17)-triazole arms bearing caps of different nature (basic vs. acidic, hydrophilic vs. hydrophobic). Confrontation of biological data (anticancer activity vs. toxicity in normal cells) with lipophilicity (clogP), dissociation constants (Kd) of complexes with Hsp90 and binding modes to Hsp90 revealed SAR in specific subgroups of GDM derivatives. The most potent GDM congeners 14-16, bearing C(17)-triazole-benzyl-halogen arms exhibited the most optimal clogP values of 2.7-3.1 at favourable binding to Hsp90 (KdHsp90 at µM level). The anticancer activity of 14-16 (IC50 = 0.23-0.41 µM) is higher than those of GDM (IC50 = 0.58-0.64 µM) and actinomycin D (ActD, IC50 = 0.62-0.71 µM) in SKBR-3, SKOV-3 and PC-3 cell lines, with a comparable cytotoxicity in healthy cells. The relationship between structure and attractive anticancer potency (IC50 = 0.53-0.74 µM) is also observed for congeners with C(17)-triazole-saccharide or C(17)-triazole-unsaturated arms. In the former, the absolute configuration at C(4) (ᴅ-glucose vs. ᴅ-galactose) whereas in the latter the length of the unsaturated arm influences the cytotoxic effects due to different binding strength (Kd, ΔE) and modes with Hsp90. Among all triazole congeners of GDM that are biologically attractive and exhibit lower toxicity in normal cells than GDM and ActD, the derivative 22, bearing the C(17)-triazole-cinnamyl arm, shows the lowest Kd (Hsp90), optimal clogP = 2.82, the best pro-apoptotic properties in SKBR-3 and SKOV-3 and the best selectivity indices (SI). For the most potent GDM derivatives with C(17)-triazole arm, the docking studies have suggested the importance of the intermolecular stabilization between the arm and the D57 or Y61 of Hsp90.