Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells
Catrin Roolf1, Jan-Niklas Saleweski1, Arno Stein1, Anna Richter1, Claudia Maletzki1, Anett Sekora1, Hugo Murua Escobar1, Xiao-Feng Wu2, Matthias Beller2 and Christian Junghanss1,*
1Department of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock 18057, 2Leibniz-Institute for Catalysis at the University of Rostock, Rostock 18059, Germany
E-mail: christian.junghanss@med.uni-rostock.de
Tel: +49-381-494-7420, Fax: +49-381-494-7422
Received: October 12, 2018; Revised: January 20, 2019; Accepted: February 18, 2019; Published online: April 2, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
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.
Keywords: Acute lymphoblastic leukemia, Heterocycles, Isoquinolinamine, Isoindoloquinazolinone, Apoptosis, Kinase inhibitor


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