Biomolecules & Therapeutics

  • 제27권5호
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  • Pages.492-501
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  • 2019
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells

  • Roolf, Catrin (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Saleweski, Jan-Niklas (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Stein, Arno (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Richter, Anna (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Maletzki, Claudia (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Sekora, Anett (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Escobar, Hugo Murua (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center) ;
  • Wu, Xiao-Feng (Leibniz-Institute for Catalysis at the University of Rostock) ;
  • Beller, Matthias (Leibniz-Institute for Catalysis at the University of Rostock) ;
  • Junghanss, Christian (Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center)
  • 투고 : 2018.10.12
  • 심사 : 2019.02.18
  • 발행 : 2019.09.01
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초록

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 $10{\mu}M$ 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 $1.94{\mu}M$. 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.

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참고문헌

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