Glucocorticoids (GCs) are routinely used to treat hematological malignancies; however, long-term treatment with GCs can lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRAs) with reduced side effects may act as a superior alternative to GCs. More than 30 SEGRAs have been described so far, yet none of them reached clinical trials for anti-cancer treatment. In the present work, we propose a novel approach to increase the number of potential SEGRAs by obtaining derivatives of synephrine, a molecule of natural origin. We synthesized 26 novel compounds from the class of synephrine derivatives and characterized them by HRMS, and ¹H and ¹³C NMR. We evaluated in vitro anti-cancer effects in leukemia K562 and lymphoma Granta cells using the MTT assay and studied their potential affinity for the glucocorticoid receptor (GR) in silico using the molecular docking approach. The novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico exhibited cytotoxic activity against K562 and Granta cells after 24 h of treatment at the concentration of approximately 13 µM which correlated with its highest MolDock Score. The other compound with high GR affinity, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2), demonstrated cytotoxicity in both cell lines at concentrations of 50–70 µM. Overall, our results may provide a solid rationale for developing and further investigating synephrine derivatives as SEGRAs with anti-cancer activity.

Glucocorticoids (GC) are widely used in the treatment of hematological malignancies; however, the long-term treatment lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRA) with reduced side effects could be the better GC alternative. More than 30 SEGRA were described but none of them reached clinical trials as anticancer treatment. In the present work, we proposed the novel approach to broaden the list of potential SEGRA by synthesis of derivatives of synephrine, the molecule of natural origin. We synthesized 26 compounds from the class of synephrine derivatives, and studied their anticancer effect in vitro in leukemia and lymphoma cells with MTT assay as well as their potential affinity to glucocorticoid receptor (GR) in silico using molecular docking approach. Novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico revealed the micromolar range cytotoxicity in lymphoma and leukemia cells after 24 h of treatment. The other compound, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2) with high GR affinity demonstrated cytotoxicity in the range of 50-70 µM. Overall, our results provide the rationale for the development and further investigation of synephrine derivatives as SEGRA with anticancer activity.

This work carried out the synthesis of several new synephrine analogues by universal method. Some of the synthesized compounds showed cytotoxicity on myeloid leukaemia cells K562 and lymphoma cell line Granta-519. Molecular docking using the glucocorticoid receptor (GR) model (PDB identifier 1P93) was performed to understand the possible underlying mechanism of compound action. The simulation showed the similarity of synephrine analogues’ binding to the binding of dexamethasone in the GR ligand-binding domain. The synthesized analogues exhibited cytotoxicity profiles similar to those of dexamethasone.

Синтезирован ряд производных 5-аминометил-1,2,4-триазол-3-карбоновых кислот и исследовано их антипролиферативное и противомикробное действие. На линиях опухолевых клеток аденокарциномы легкого человека A549 и эпидермоидной карциномы кожи человека А431 для некоторых представителей 5-аминометил-1,2,4-триазол-3-карбокс-амидов в концентрациях 1 мМ была выявлена тенденция к снижению клеточной пролиферации, отсутствующая для клеточной линии HEK293. На агаризованных средах показано отсутствие антимикробного действия серии аминокислотных производных ряда 5-аминометил-1,2,4-триазол-3-карбоксамидов в отношении модельных и патогенных штаммов микроорганизмов и грибов.

Therapeutic peptides are a unique drug class due to their high-specificity binding with biological targets. However, the low bioavailability of peptides, as well as the lack of enzymatic stability, imposes a number of limitations on their biomedical application. A good strategy by which to overcome these limitations is the use of peptidomimetics, which are able to imitate the binding and activity of peptides both in vitro and in vivo. Peptidomimetics can be obtained by combining natural and synthetic amino acids in a peptide sequence. Various five-membered heterocycles are often used as structural fragments of peptide imitators to fix the chain in a certain conformation and to increase proteolytic stability. The use of 5-aminomethyl-1,2,4-triazole-3-carboxylic acid derivatives as building blocks of peptidomimetic structures may be a very attractive strategy, in which the tautomeric 1,2,4-triazole fragment is capable of flexibly forming hydrogen bonds on the protein surface of the target. In this work, a number of ethyl 5-aminomethyl-1,2,4-triazole-3-carboxylates and their derivatives were synthesized as mimetics of aliphatic amino acids. Their use as building blocks for synthesizing peptidomimetics was demonstrated. In addition, through the use of a panel of pathogenic and model strains of microorganisms and fungi, we demonstrated the lack of independent activity of the amino acid 1,2,4-triazole mimetics synthesized. This similarity of the biological properties of the obtained mimetics and their natural analogues reveals their bioisosterism. The bioisosterism and geometric similarity of 1,2,4-triazole mimetics and natural amino acid highlights the potential of their use as building blocks for therapeutic peptides.

A number of new 5-aminomethyl-1,2,4-triazole-3-carboxamides, demonstrating high model affinity to the IGPD catalytic site comparable with that of the native substrate, were synthesized. The derivatives obtained were tested for antimicrobial potential against M. smegmatis, a species related to M. tuberculosis. During the initial antimicrobial activity evaluation in vitro, some compounds investigated inhibited microbial growth. Moreover, high binding energy values calculated for compounds/enzyme’s catalytic site complexes correlated with the compounds’ antimicrobial efficacy. This suggests that the probable biological action mechanism of new 5-aminomethyl-1,2,4-triazole-3-carboxamides may be based on their binding to the catalytic site of IGPD, which provides prerequisites for further study of this class of compounds as potential IGPD inhibitors.