{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T11:46:31Z","timestamp":1764157591922,"version":"3.46.0"},"reference-count":73,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-15-00321"],"award-info":[{"award-number":["23-15-00321"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glucocorticoids (GCs) represent 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 the biological activity of four novel glucocorticoid receptor (GR) ligands, derivatives of synephrine, a natural-origin molecule. 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 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 the leader compound, 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2), were studied using a murine transplantable lymphoma P388 model. The potential of 10S-E2 to prevent the development of atrophic complication was evaluated using a murine model of glucocorticoid-induced osteoporosis. All studied synephrine derivatives demonstrated high GR affinity, with the IC50 value of the most active derivative 10S-E2 being 0.56 \u00b5M; the effects on GR function were cell-type-specific. The leader compound, 10S-E2, revealed SEGRAM properties in vitro and demonstrated anti-cancer effects in vivo, inhibiting tumor growth by more than 60%. Although the anti-cancer effect of 10S-E2 was less pronounced than that of the reference drug dexamethasone, non-atrophogenic properties of 10S-E2 make this molecule an attractive candidate for long-term GR-associated therapies.<\/jats:p>","DOI":"10.3390\/ijms262311404","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:29:47Z","timestamp":1764084587000},"page":"11404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-9391","authenticated-orcid":false,"given":"Ekaterina M.","family":"Zhidkova","sequence":"first","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina D.","family":"Savina","sequence":"additional","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0056-6040","authenticated-orcid":false,"given":"Daria V.","family":"Migaleva","sequence":"additional","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1498-849X","authenticated-orcid":false,"given":"Olga A.","family":"Vlasova","sequence":"additional","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1469-2365","authenticated-orcid":false,"given":"Timur T.","family":"Valiev","sequence":"additional","affiliation":[{"name":"Department of Hemoblastosis Chemotherapy, Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adel D.","family":"Enikeev","sequence":"additional","affiliation":[{"name":"Oncogene Regulation Department, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-8432","authenticated-orcid":false,"given":"Gennadii A.","family":"Badun","sequence":"additional","affiliation":[{"name":"Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskiye Gory 1, Moscow 119991, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5040-9937","authenticated-orcid":false,"given":"Maria G.","family":"Chernysheva","sequence":"additional","affiliation":[{"name":"Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskiye Gory 1, Moscow 119991, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-3082","authenticated-orcid":false,"given":"Svetlana A.","family":"Dodonova","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Kursk State Medical University, Karl Marx St. 3, Kursk 305041, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-7828","authenticated-orcid":false,"given":"Alexey A.","family":"Kryukov","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Kursk State Medical University, Karl Marx St. 3, Kursk 305041, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6383-0077","authenticated-orcid":false,"given":"Pavel A.","family":"Kusov","sequence":"additional","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4040-4803","authenticated-orcid":false,"given":"Kirill V.","family":"Gordeev","sequence":"additional","affiliation":[{"name":"Laboratory of Biologically Active Nanostructures, Gamaleya Research Institute of Epidemiology and Microbiology, Gamalei St. 18, Moscow 123098, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-0980","authenticated-orcid":false,"given":"Ekaterina A.","family":"Yurchenko","sequence":"additional","affiliation":[{"name":"Laboratory for Biological Testing and the Mechanism of Action of Biologically Active Substances, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, 159 Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0830-3036","authenticated-orcid":false,"given":"Andrey V.","family":"Matveev","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Industrial Pharmacy, Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 86 Vernadsky Prospekt, Moscow 119571, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9710-8178","authenticated-orcid":false,"given":"Marianna G.","family":"Yakubovskaya","sequence":"additional","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"},{"name":"Institute of Medicine, Peoples\u2019 Friendship University of Russia, Miklukho-Maklaya St. 6, Moscow 117198, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1967-9637","authenticated-orcid":false,"given":"Ekaterina A.","family":"Lesovaya","sequence":"additional","affiliation":[{"name":"Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia"},{"name":"Institute of Medicine, Peoples\u2019 Friendship University of Russia, Miklukho-Maklaya St. 6, Moscow 117198, Russia"},{"name":"Oncology Department, I.P. Pavlov Ryazan State Medical University, Ministry of Health of Russia, Ryazan 390026, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41584-020-0370-z","article-title":"Views on Glucocorticoid Therapy in Rheumatology: The Age of Convergence","volume":"16","author":"Buttgereit","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.pharmthera.2015.05.001","article-title":"Selective Glucocorticoid Receptor Modulation: New Directions with Non-Steroidal Scaffolds","volume":"152","author":"Sundahl","year":"2015","journal-title":"Pharmacol. 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