Background:: A number of studies demonstrate the efficacy of ribavirin against various cancer types in in vitro and in vivo models. However, ribavirin induces the development of multiple side effects, suggesting a high demand for ribavirin analogues with improved therapeutic indexes. Objective:: This study was focused on the analysis of ribavirin, its aglycon 1,2,4-triazole-3-carboxamide, and several of its derivatives activities in blood cancer cells in vitro. Methods:: Four 1,2,4-triazole-3-carboxamide derivatives were designed and synthesized. Antiproliferative effects were evaluated in chronic myeloid leukemia cells К562 and acute lymphoblastic leukemia cells CCRF-SB as well as in the cells of whole blood mononuclear fraction of healthy volunteers by cell counting using the trypan blue exclusion method. Cell cycle distribution and apoptosis under the influence of the compounds were analyzed by flow cytometry with PI staining, and then apoptosis data were confirmed by Western blot analysis for PARP1 and caspase-3 cleavage. Results:: We demonstrated the significant antiproliferative effect of 5-(tetrahydropyran-2-yl)-1,2,4-triazole-3- carboxamide and 1-(tetrahydropyran-2-yl)-1,2,4-triazol-3-carboxamide in leukemia cell lines in vitro in comparison to non-transformed monocytes, providing the rationale for further studies of 1,2,4-triazole-3-carboxamide derivatives as anti-leukemia drugs. Conclusion:: These results implied that the 1,2,4-triazole-3-carboxamide derivatives exhibited their antiproliferative activities by induction of cell cycle arrest. Consequently, 5-(tetrahydropyran-2-yl)-1,2,4-triazole-3-carboxamide and 1-(tetrahydrofuran-2-yl)-1,2,4-triazol-3-carboxamide may present antimetabolites with potential anticancer efficacy.

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin’s aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments.

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.

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work we studied the biological activities of a number of oxymethyl derivatives of ribavirin’s aglycon – 1,2,4-triazole-3-carboxamide. Oxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitu-tions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series the presence of an antiproliferative effect was inves-tigated and in the case of 1-oxymethyl derivatives was shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low mi-cromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited cell cy-cle progression and induced accumulation of leukemia cells in subG1-phase. The molecular docking results suggest that oxymethyl derivatives may act by inhibiting translation initiation due to interfering with eIF4E assembly. The outcome results relived that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anti-cancer treatments.

Background/Objectives: Glucocorticoids (GCs) present effective anti-cancer drugs for the treatment of hematological malignancies but their clinical use is limited due to their multiple adverse effects. Selective glucocorticoid receptor agonists/modulators (SEGRAMs) modify glucocorticoid receptor (GR) function shifting it towards therapeutically important transrepression and, therefore, could be safer alternative to GCs. Here we report on biological activity of four novel ligands of glucocorticoid receptor (GR), derivatives of natural origin molecule, synephrine. Methods: We demonstrated the affinity of synephrine derivatives in silico and in vitro by molecular dynamics simulation and radioligand binding assay, correspondingly. Further, we tested the induction of apoptosis in cultured cells and cytotoxic effects in primary lymphoblasts from the patients with acute lymphoblastic leukemia. Therapeutically important GR transrepression was evaluated by luciferase reporter assay and Q-PCR of transrepression marker genes, while GR transactivation associated with side effects was evaluated by Q-PCR analysis and by the level of GR phosphorylation at Ser211. Anti-cancer effects of leader compound, 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2), was studied on murine transplantable lymphoma P388 model. 10S-E2 potential to avoid the development of atrophic complication was evaluated on the murine model of glucocorticoid-induced osteoporosis. Results: All studied synephrine derivatives demonstrated high GR affinity; the effects on GR function were controversial. The leader compound, 10S-E2 revealed SEGRAM properties in vitro and demonstrated anti-cancer effects in vivo. Conclusion: Although the anti-cancer effect of 10S-E2 was less pronounced to the reference drug dexamethasone, non-atrophogenic properties of 10S-E2 make this molecule an attractive candidate for long-term GR-associated therapies.