Version 1
: Received: 28 June 2024 / Approved: 1 July 2024 / Online: 1 July 2024 (07:34:30 CEST)
How to cite:
Zhidkova, E. M.; Tilova, L. R.; Fetisov, T. I.; Kirsanov, K. I.; Kulikov, E. P.; Enikeev, A. D.; Budunova, I. V.; Badun, G. A.; Chernysheva, M. G.; Shirinian, V. Z.; Yakubovskaya, M. G.; Lesovaya, E. A. Synthesis and Anti-Cancer Activity of Novel Selective Glucocorticoid Receptor Agonists of Phenylethanolamine Series. Preprints2024, 2024070030. https://doi.org/10.20944/preprints202407.0030.v1
Zhidkova, E. M.; Tilova, L. R.; Fetisov, T. I.; Kirsanov, K. I.; Kulikov, E. P.; Enikeev, A. D.; Budunova, I. V.; Badun, G. A.; Chernysheva, M. G.; Shirinian, V. Z.; Yakubovskaya, M. G.; Lesovaya, E. A. Synthesis and Anti-Cancer Activity of Novel Selective Glucocorticoid Receptor Agonists of Phenylethanolamine Series. Preprints 2024, 2024070030. https://doi.org/10.20944/preprints202407.0030.v1
Zhidkova, E. M.; Tilova, L. R.; Fetisov, T. I.; Kirsanov, K. I.; Kulikov, E. P.; Enikeev, A. D.; Budunova, I. V.; Badun, G. A.; Chernysheva, M. G.; Shirinian, V. Z.; Yakubovskaya, M. G.; Lesovaya, E. A. Synthesis and Anti-Cancer Activity of Novel Selective Glucocorticoid Receptor Agonists of Phenylethanolamine Series. Preprints2024, 2024070030. https://doi.org/10.20944/preprints202407.0030.v1
APA Style
Zhidkova, E. M., Tilova, L. R., Fetisov, T. I., Kirsanov, K. I., Kulikov, E. P., Enikeev, A. D., Budunova, I. V., Badun, G. A., Chernysheva, M. G., Shirinian, V. Z., Yakubovskaya, M. G., & Lesovaya, E. A. (2024). Synthesis and Anti-Cancer Activity of Novel Selective Glucocorticoid Receptor Agonists of Phenylethanolamine Series. Preprints. https://doi.org/10.20944/preprints202407.0030.v1
Chicago/Turabian Style
Zhidkova, E. M., Marianna G. Yakubovskaya and Ekaterina A. Lesovaya. 2024 "Synthesis and Anti-Cancer Activity of Novel Selective Glucocorticoid Receptor Agonists of Phenylethanolamine Series" Preprints. https://doi.org/10.20944/preprints202407.0030.v1
Abstract
Glucocorticoids (GCs) are widely used in blood cancer treatment despite their multiple adverse effects. Biological response to GCs is mediated by glucocorticoid receptor (GR) by transactivation (TA), associated with side effects, and transrepression (TR), mediating anticancer effects. Selective GR agonists (SEGRAs) preferentially activating GR TR could be better option for cancer treatment. One of well-characterized SEGRAs is 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium-chloride (CpdA), demonstrated anticancer activity in vitro and in vivo, however its translational potential is limited due to chemical instability. CpdA derivatives CpdA-01-08 were designed by two synthetic strategies. Derivative CpdA-03 demonstrated superior GR affinity and stability compared to CpdA. Analysis of CpdA-03 ligand properties in lymphoma Granta and leukemia CEM cell lines revealed its SEGRA profile: it induced GR TR without triggering GR TA, as evidenced by changes in expression of GR target genes. Effects of CpdA-03 on cell viability, growth, and apoptosis were similar to reference GR ligand, dexamethasone (Dex), and the proto-type compound CpdA. In vivo testing of CpdA-03 anti-lymphoma activity in transplantable P388 murine lymphoma model showed that CpdA-03 reduced tumor volume threefold, outperforming Dex and CpdA. In conclusion, this work introduces CpdA-03 as promising new SEGRA with potential for further development as anti-lymphoma drug with fewer side effects.
Medicine and Pharmacology, Oncology and Oncogenics
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