Abstract
Introduction. Glucocorticoids are the important component of combined chemotherapy of blood cancer. Therapeutic effects of glucocorticoids is realized via activation of glucocorticoid receptor transrepression, the development of side effects is associated with transactivation. We demonstrated earlier that compound belonging the class of selective glucocorticoid receptor agonists, CpdA, selectively induced transrepression in blood cancer cells. CpdA represents a mixture of two enantiomers, which can differ in interaction with the receptor. Aim. The main aim of present study was to synthesize CpdA enantiomers and to evaluate their biological properties. Materials and methods. Synthesis was carried out based on Sharpless dihydroxylation; anti-tumor activity in vitro was evaluated by antiproliferative and pro-apoptotic effects. Ligand properties were estimated by PCR-analysis of glucocorticoid- and NF-kB-dependent genes expression. Results and conclusions. We demonstrated that CpdA enantiomers revealed anti-tumor activity in vitro and did not induce transactivation. Moreover, S-enantiomer of CpdA in the most tests demonstrated more pronounced activity and is more perspective molecule for future studies in vivo.
Highlights
Glucocorticoids are the important component of combined chemotherapy of blood cancer
Therapeutic effects of glucocorticoids is realized via activation of glucocorticoid receptor transrepression, the development of side effects is associated with transactivation
We demonstrated earlier that compound belonging the class of selective glucocorticoid receptor agonists, CpdA, selectively induced transrepression in blood cancer cells
Summary
Противоопухолевый эффект энантиомеров CpdA in vitro на модели острого лимфобластного лейкоза. Терапевтическое действие глюкокортикоидов реализуется посредством активации глюкокортикоидного рецептора (GR) по механизму транс-репрессии, развитие побочных эффектов связано с транс-активацией. Что соединение класса селективных агонистов GR, CpdA, селективно запускает транс-репрессию в клетках лейкоза. CpdA представляет собой смесь 2 энантиомеров, которые могут по-разному взаимодействовать с рецептором. Цель исследования – синтез энантиомеров CpdA и оценка их биологических свойств. Синтез энантиомеров был осуществлен на основании дигидроксилирования алкенов по Шарплессу; противоопухолевую активность in vitro определяли по антипролиферативному и проапоптотическому эффекту. Продемонстрировано, что энантиомеры CpdA обладают противоопухолевым действием in vitro, а также не вызывают запуска транс-активации. S-энантиомер CpdA является более перспективным кандидатом для дальнейших исследований in vivo. Ключевые слова: глюкокортикоидный рецептор, энантиомеры, гемобластозы, транс-активация, транс-репрессия, противоопухолевая активность. Anti-tumor effect of CpdA enantiomers in vitro in the model of acute lymphoblastic leukemia. Blokhin Russian Cancer Research Center, Ministry of Health of Russia; bld. 15, 24 Kashirskoe shosse, Moscow, 115478, Russia; 2 Moscow Technological University; 78 Vernadsky av., Moscow 119454, Russia; 3 Northwestern University; 303 East Chicago аv., Chicago 60611, USA;
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