Roolf Catrin, Saleweski Jan-Niklas, Stein Arno, Richter Anna, Maletzki Claudia, Sekora Anett, Escobar Hugo Murua, Wu Xiao-Feng, Beller Matthias, Junghanss Christian
Department of Medicine, Clinic III ? Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock 18057, Germany.
Leibniz-Institute for Catalysis at the University of Rostock, Rostock 18059, Germany.
Biomol Ther (Seoul). 2019 Sep 1;27(5):492-501. doi: 10.4062/biomolther.2018.199.
Nitrogen-containing heterocycles such as quinoline, quinazolinones and indole are scaffolds of natural products and have broad biological effects. During the last years those structures have been intensively synthesized and modified to yield new synthetic molecules that can specifically inhibit the activity of dysregulated protein kinases in cancer cells. Herein, a series of newly synthesized isoquinolinamine (FX-1 to 8) and isoindoloquinazolinone (FX-9, FX-42, FX-43) compounds were evaluated in regards to their anti-leukemic potential on human B- and T- acute lymphoblastic leukemia (ALL) cells. Several biological effects were observed. B-ALL cells (SEM, RS4;11) were more sensitive against isoquinolinamine compounds than T-ALL cells (Jurkat, CEM). In SEM cells, metabolic activity decreased with 10 μM up to 26.7% (FX-3), 25.2% (FX-7) and 14.5% (FX-8). The 3-(p-Tolyl) isoquinolin-1-amine FX-9 was the most effective agent against B- and T-ALL cells with IC50 values ranging from 0.54 to 1.94 μM. None of the tested compounds displayed hemolysis on erythrocytes or cytotoxicity against healthy leukocytes. Anti-proliferative effect of FX-9 was associated with changes in cell morphology and apoptosis induction. Further, influence of FX-9 on PI3K/AKT, MAPK and JAK/STAT signaling was detected but was heterogeneous. Functional inhibition testing of 58 kinases revealed no specific inhibitory activity among cancer related kinases. In conclusion, FX-9 displays significant antileukemic activity in B- and T-ALL cells and should be further evaluated in regards to the mechanisms of action. Further compounds of the current series might serve as templates for the design of new compounds and as basic structures for modification approaches.
含氮杂环，如喹啉、喹唑啉酮和吲哚，是天然产物的骨架，具有广泛的生物学效应。在过去几年中，这些结构已被广泛合成和修饰，以产生能够特异性抑制癌细胞中失调蛋白激酶活性的新合成分子。在此，对一系列新合成的异喹啉胺（FX-1至8）和异吲哚并喹唑啉酮（FX-9、FX-42、FX-43）化合物在人B细胞和T细胞急性淋巴细胞白血病（ALL）细胞上的抗白血病潜力进行了评估。观察到了几种生物学效应。B-ALL细胞（SEM、RS4;11）比T-ALL细胞（Jurkat、CEM）对异喹啉胺化合物更敏感。在SEM细胞中，10 μM时代谢活性下降高达26.7%（FX-3）、25.2%（FX-7）和14.5%（FX-8）。3-(对甲苯基)异喹啉-1-胺FX-9是对B-ALL和T-ALL细胞最有效的药物，IC50值范围为0.54至1.94 μM。所测试的化合物均未对红细胞显示溶血作用或对健康白细胞显示细胞毒性。FX-9的抗增殖作用与细胞形态变化和凋亡诱导有关。此外，检测到FX-9对PI3K/AKT、MAPK和JAK/STAT信号传导有影响，但存在异质性。对58种激酶的功能抑制测试显示在癌症相关激酶中没有特异性抑制活性。总之，FX-9在B-ALL和T-ALL细胞中显示出显著的抗白血病活性，应进一步评估其作用机制。本系列中的其他化合物可能作为新化合物设计的模板和修饰方法的基本结构。
