Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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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)
  • Received : 2018.10.12
  • Accepted : 2019.02.18
  • Published : 2019.09.01
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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 $10{\mu}M$ 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.

Keywords

References

  1. Akhtar, M. J., Yar, M. S., Khan, A. A., Ali, Z. and Haider, M. R. (2017) Recent advances in the synthesis and anticancer activity of some molecules other than nitrogen containing heterocyclic moeities. Mini Rev. Med. Chem. 17, 1602-1632.
  2. Ardito, F., Giuliani, M., Perrone, D., Troiano, G. and Lo Muzio, L. (2017) The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (review). Int. J. Mol. Med. 40, 271-280. https://doi.org/10.3892/ijmm.2017.3036
  3. Buontempo, F., Orsini, E., Martins, L. R., Antunes, I., Lonetti, A., Chiarini, F., Tabellini, G., Evangelisti, C., Melchionda, F., Pession, A., Bertaina, A., Locatelli, F., McCubrey, J. A., Cappellini, A., Barata, J. T. and Martelli, A. M. (2014) Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia 28, 543-553. https://doi.org/10.1038/leu.2013.349
  4. Buontempo, F., McCubrey, J. A., Orsini, E., Ruzzene, M., Cappellini, A., Lonetti, A., Evangelisti, C., Chiarini, F., Evangelisti, C., Barata, J. T. and Martelli A. M. (2017) Therapeutic targeting of CK2 in acute and chronic leukemias. Leukemia 32, 1-10. https://doi.org/10.1038/leu.2017.301
  5. Cani, A., Simioni, C., Martelli, A. M., Zauli, G., Tabellini, G., Ultimo, S., McCubrey, J. A., Capitani, S. and Neri, L. M. (2015) Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia. Oncotarget 6, 6597-6610. https://doi.org/10.18632/oncotarget.3260
  6. Chon, H. J., Bae, K. J., Lee, Y. and Kim, J. (2015) The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies. Front. Pharmacol. 6, 70. https://doi.org/10.3389/fphar.2015.00070
  7. Cozza, G. (2017) The development of CK2 inhibitors: from traditional pharmacology to in silico rational drug design. Pharmaceuticals 10, 26. https://doi.org/10.3390/ph10010026
  8. Cozza, G., Pinna, L. A. and Moro, S. (2012) Protein kinase CK2 inhibitors: a patent review. Expert Opin. Ther. Pat. 22, 1081-1097. https://doi.org/10.1517/13543776.2012.717615
  9. Dadashpour, S. and Emami, S. (2018) Indole in the target-based design of anticancer agents: a versatile scaffold with diverse mechanisms. Eur. J. Med. Chem. 150, 9-29. https://doi.org/10.1016/j.ejmech.2018.02.065
  10. Eastman, A. (2017) Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays. Oncotarget 8, 8854-8866. https://doi.org/10.18632/oncotarget.12673
  11. Feng, J.-B. and Wu, X.-F. (2016) Potassium tert -butoxide-promoted synthesis of 1-aminoisoquinolines from 2-methylbenzonitriles and benzonitriles under catalyst-free conditions. Adv. Synth. Catal. 358, 2179-2185. https://doi.org/10.1002/adsc.201600169
  12. Gao, X., Cen, L., Li, F., Wen, R., Yan, H., Yao, H. and Zhu, S. (2018) Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 505, 761-767. https://doi.org/10.1016/j.bbrc.2018.09.120
  13. Hameed, A., Al-Rashida, M., Uroos, M., Ali, S. A., Arshia, Ishtiaq, M. and Khan, K. M. (2018) Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011-2016). Expert Opin. Ther. Pat. 28, 281-297. https://doi.org/10.1080/13543776.2018.1432596
  14. He, L., Chang, H. X., Chou, T. C., Savaraj, N. and Cheng, C. C. (2003) Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern - synthesis and biological activity studies of 11H-indolo[3.2-c]quinoline derivatives. Eur. J. Med. Chem. 38, 101-107. https://doi.org/10.1016/S0223-5234(02)01420-4
  15. Hotchkiss, R. S., Strasser, A., McDunn, J. E. and Swanson, P. E. (2009) Cell death. N. Engl. J. Med. 361, 1570-1583. https://doi.org/10.1056/NEJMra0901217
  16. Karki, S. S., Hazare, R., Kumar, S., Bhadauria, V. S., Balzarini, J. and De Clercq, E. (2009) Synthesis, anticancer and cytostatic activity of some 6H-indolo[2,3-b]quinoxalines. Acta Pharm. 59, 431-440. https://doi.org/10.1111/j.1600-0773.1986.tb02795.x
  17. Kazandjian, D., Blumenthal, G. M., Yuan, W., He, K., Keegan, P. and Pazdur, R. (2016) FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin. Cancer Res. 22, 1307-1312. https://doi.org/10.1158/1078-0432.CCR-15-2266
  18. Kretzschmar, C., Roolf, C., Langhammer, T.-S., Sekora, A., Pews-Davtyan, A., Beller, M., Frech, M. J., Eisenloffel, C., Rolfs, A. and Junghanss, C. (2014) The novel arylindolylmaleimide PDA-66 displays pronounced antiproliferative effects in acute lymphoblastic leukemia cells. BMC Cancer 14, 71. https://doi.org/10.1186/1471-2407-14-71
  19. Li, Z., Luo, M., Cai, B., Haroon-Ur-Rashid, Huang, M., Jiang, J., Wang, L. and Wu, L. (2018) Design, synthesis, biological evaluation and structure-activity relationship of sophoridine derivatives bearing pyrrole or indole scaffold as potential antitumor agents. Eur. J. Med. Chem. 157, 665-682. https://doi.org/10.1016/j.ejmech.2018.08.021
  20. Maletzki, C., Klier, U., Marinkovic, S., Klar, E., Andra, J. and Linnebacher, M. (2014) Host defense peptides for treatment of colorectal carcinoma - a comparative in vitro and in vivo analysis. Oncotarget 5, 4467-4479. https://doi.org/10.18632/oncotarget.2039
  21. Mantu, D., Antoci, V., Moldoveanu, C., Zbancioc, G. and Mangalagiu, I. I. (2016) Hybrid imidazole (benzimidazole)/pyridine (quinoline) derivatives and evaluation of their anticancer and antimycobacterial activity. J. Enzyme Inhib. Med. Chem. 31, 96-103.
  22. Martell, R. E., Brooks, D. G., Wang, Y. and Wilcoxen, K. (2013) Discovery of novel drugs for promising targets. Clin. Ther. 35, 1271-1281. https://doi.org/10.1016/j.clinthera.2013.08.005
  23. Miller, B. W., Przepiorka, D., de Claro, R. A., Lee, K., Nie, L., Simpson, N., Gudi, R., Saber, H., Shord, S., Bullock, J., Marathe, D., Mehrotra, N., Hsieh, L. S., Ghosh, D., Brown, J., Kane, R. C., Justice, R., Kaminskas, E., Farrell, A. T. and Pazdur, R. (2015) FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin. Cancer Res. 21, 1525-1529. https://doi.org/10.1158/1078-0432.CCR-14-2522
  24. Moore, D. E., Weise, K., Zawydiwski, R. and Thompson, E. B. (1985) The karyotype of the glucocorticoid-sensitive, lymphoblastic human T-cell line CCRF-CEM shows a unique deleted and inverted chromosome 9. Cancer Genet. Cytogenet. 14, 89-94. https://doi.org/10.1016/0165-4608(85)90219-5
  25. Mphahlele, M., Mmonwa, M., Aro, A., McGaw, L. and Choong, Y. (2018) Synthesis, biological evaluation and molecular docking of novel indole-aminoquinazoline hybrids for anticancer properties. Int. J. Mol. Sci. 19, 2232. https://doi.org/10.3390/ijms19082232
  26. Mukherjee, S. and Pal, M. (2013) Medicinal chemistry of quinolines as emerging anti-inflammatory agents: an overview. Curr. Med. Chem. 20, 4386-4410. https://doi.org/10.2174/09298673113209990170
  27. Musiol, R. (2017) An overview of quinoline as a privileged scaffold in cancer drug discovery. Expert Opin. Drug Discov. 12, 583-597. https://doi.org/10.1080/17460441.2017.1319357
  28. Musiol, R., Serda, M., Hensel-Bielowka, S. and Polanski, J. (2010) Quinoline-based antifungals. Curr. Med. Chem. 17, 1960-1973. https://doi.org/10.2174/092986710791163966
  29. Naeem, A., Badshah, S., Muska, M., Ahmad, N. and Khan, K. (2016) The current case of quinolones: synthetic approaches and antibacterial activity. Molecules 21, 268. https://doi.org/10.3390/molecules21040268
  30. Neri, L. M., Cani, A., Martelli, A. M., Simioni, C., Junghanss, C., Tabellini, G., Ricci, F., Tazzari, P. L., Pagliaro, P., McCubrey, J. A. and Capitani, S. (2014) Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia 28, 739-748. https://doi.org/10.1038/leu.2013.226
  31. Paubelle, E., Zylbersztejn, F. and Thomas, X. (2017) The preclinical discovery of vosaroxin for the treatment of acute myeloid leukemia. Expert Opin. Drug Discov. 12, 747-753. https://doi.org/10.1080/17460441.2017.1331215
  32. Piazza, F., Manni, S., Ruzzene, M., Pinna, L.A., Gurrieri, C. and Semenzato, G. (2012) Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways. Leukemia 26, 1174-1179. https://doi.org/10.1038/leu.2011.385
  33. Rahman, A. F. M. M., Korashy, H. M. and Kassem, M. G. (2014) Gefitinib. Profiles Drug Subst. Excip. Relat. Methodol. 39, 239-264. https://doi.org/10.1016/B978-0-12-800173-8.00005-2
  34. Richter, A., Roolf, C., Sender, S., Kong, W., Knubel, G., Sekora, A., Gladbach, Y. S., Hamed, M., Fuellen, G., Vollmar, B., Jeremias, I., Panse, J. P., Escobar, H. M. and Junghanss, C. (2017) Casein kinase II inhibition by CX-4945 and epigenetic modulation by decitabine demonstrate significant antiproliferative activity as single agents as well as in combination in acute b-lymphoblastic leukemia cells. Blood 130, 3887.
  35. Schneider, U., Schwenk, H. U. and Bornkamm, G. (1977) Characterization of EBV-genome negative "null" and "T" cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non-Hodgkin lymphoma. Int. J. Cancer 19, 621-626. https://doi.org/10.1002/ijc.2910190505
  36. Schult, C., Dahlhaus, M., Ruck, S., Sawitzky, M., Amoroso, F., Lange, S., Etro, D., Glass, A., Fuellen, G., Boldt, S., Wolkenhauer, O., Neri, L. M., Freund, M. and Junghanss, C. (2010) The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells. BMC Cancer 10, 560. https://doi.org/10.1186/1471-2407-10-560
  37. Schult, C., Dahlhaus, M., Glass, A., Fischer, K., Lange, S., Freund, M. and Junghanss, C. (2012) The dual kinase inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells. Anticancer Res. 32, 463-474.
  38. Shen, C., Man, N. Y. T., Stewart, S. and Wu, X.-F. (2015) Palladium-catalyzed dicarbonylative synthesis of tetracycle quinazolinones. Org. Biomol. Chem. 13, 4422-4425. https://doi.org/10.1039/C5OB00368G
  39. Shen, C., Spannenberg, A. and Wu, X.-F. (2016) Palladium-catalyzed carbonylative four-component synthesis of thiochromenones: the advantages of a reagent capsule. Angew. Chemie Int. Ed. 55, 5067-5070. https://doi.org/10.1002/anie.201600953
  40. Solomon, V. R. and Lee, H. (2011) Quinoline as a privileged scaffold in cancer drug discovery. Curr. Med. Chem. 18, 1488-1508. https://doi.org/10.2174/092986711795328382
  41. Stansfield, L. C. and Pollyea, D. A. (2017) Midostaurin: a new oral agent targeting FMS-like tyrosine kinase 3-mutant acute myeloid leukemia. Pharmacother. J. Hum. Pharmacol. Drug Ther. 37, 1586-1599. https://doi.org/10.1002/phar.2039
  42. Stumpel, D. J. P. M., Schneider, P., van Roon, E. H. J., Boer, J. M., de Lorenzo, P., Valsecchi, M. G., de Menezes, R. X., Pieters, R. and Stam, R. W. (2009) Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options. Blood 114, 5490-5498. https://doi.org/10.1182/blood-2009-06-227660
  43. Terwilliger, T. and Abdul-Hay, M. (2017) Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 7, e577. https://doi.org/10.1038/bcj.2017.53
  44. Vandekerckhove, S. and D'hooghe, M. (2015) Quinoline-based antimalarial hybrid compounds. Bioorg. Med. Chem. 23, 5098-5119. https://doi.org/10.1016/j.bmc.2014.12.018
  45. Wei, A. H. and Tiong, I. S. (2017) Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood 130, 2469-2474. https://doi.org/10.1182/blood-2017-08-784066
  46. Wu, P., Nielsen, T. E. and Clausen, M. H. (2015) FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 36, 422-439. https://doi.org/10.1016/j.tips.2015.04.005
  47. Yanamandra, M., Mitra, S. and Giri, A. (2015) Development and application of PI3K assays for novel drug discovery. Expert Opin. Drug Discov. 10, 171-186. https://doi.org/10.1517/17460441.2015.997205
  48. Yang, D., Tong, D., Zhang, Q., Wang, Y., Sun, J., Zhang, F. and Zhao, G. (2017) Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold. Chem. Biol. Drug Des. 90, 791-803. https://doi.org/10.1111/cbdd.13000

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