Zhidkova Ekaterina M, Oleynik Evgeniya S, Mikhina Ekaterina A, Stepanycheva Daria V, Grigoreva Diana D, Grebenkina Lyubov E, Gordeev Kirill V, Savina Ekaterina D, Matveev Andrey V, Yakubovskaya Marianna G, Lesovaya Ekaterina A
Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center for Oncology, Kashirskoe Shosse 24-15, Moscow 115478, Russia.
Department of Biotechnology and Industrial Pharmacy, Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 86 Vernadsky Prospekt, Moscow 119571, Russia.
Biomolecules. 2024 Dec 24;15(1):2. doi: 10.3390/biom15010002.
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 H and C NMR. We evaluated anti-cancer effects in leukemia K562 and lymphoma Granta cells using the MTT assay and studied their potential affinity for the glucocorticoid receptor (GR) using the molecular docking approach. The novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol () with the highest GR affinity 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 (), 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.
糖皮质激素（GCs）常用于治疗血液系统恶性肿瘤；然而，长期使用GCs会导致萎缩性和代谢性不良反应。副作用较小的选择性糖皮质激素受体激动剂（SEGRAs）可能是GCs的一种更好的替代品。到目前为止，已经描述了30多种SEGRAs，但它们都没有进入抗癌治疗的临床试验。在本研究中，我们提出了一种新方法，即通过获得天然来源分子辛弗林的衍生物来增加潜在SEGRAs的数量。我们从辛弗林衍生物类别中合成了26种新化合物，并通过高分辨质谱（HRMS）、氢核磁共振（H NMR）和碳核磁共振（C NMR）对其进行了表征。我们使用MTT法评估了它们对白血病K562细胞和淋巴瘤Granta细胞的抗癌作用，并使用分子对接方法研究了它们对糖皮质激素受体（GR）的潜在亲和力。具有最高GR亲和力的新型衍生物1-[4-(苄氧基)phenyl]-2-(己基氨基)乙醇（）在浓度约为13µM处理24小时后，对K562和Granta细胞表现出细胞毒性活性，这与其最高的MolDock分数相关。另一种具有高GR亲和力的化合物2-(己基氨基)-1-(4-硝基苯基)乙醇（）在50-70µM浓度下对两种细胞系均表现出细胞毒性。总体而言，我们的结果可能为开发和进一步研究具有抗癌活性的SEGRAs辛弗林衍生物提供坚实的理论依据。
