Login Register Cart 0
Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Cytotoxic and Antitumoral Activity of N-(9H-purin-6-yl) Benzamide Derivatives and Related Water-soluble Prodrugs

Author(s): Emeline Cros-Perrial, Steve Saulnier, Muhammad Zawwad Raza, Rémi Charmelot, David Egron, Charles Dumontet, Laurent Chaloin, Suzanne Peyrottes and Lars Petter Jordheim*

Volume 15, Issue 6, 2022

Published on: 13 January, 2022

Article ID: e141021197233 Pages: 12

DOI: 10.2174/1874467214666211014164406

Price: $65

Open Access Journals Promotions 2
Abstract

Background: The development of small molecules as cancer treatments is still of both interest and importance.

Objective: Having synthesized and identified the initial cytotoxic activity of a series of chemically related N-(9H-purin-6-yl) benzamide derivatives, we continued their evaluation on cancer cell models. We also synthesized water-soluble prodrugs of the main compound and performed in vivo experiments.

Method: We used organic chemistry to obtain compounds of interest and prodrugs. The biological evaluation included MTT assays, synergy experiments, proliferation assays by CFSE, cell cycle distribution and in vivo antitumoral activity.

Results: Our results show activities on cancer cell lines ranging from 3-39 μM for the best compounds, with both induction of apoptosis and decrease in cell proliferation. Two compounds evaluated in vivo showed weak antitumoral activity. In addition, the lead compound and its prodrug had a synergistic activity with the nucleoside analogue fludarabine in vitro and in vivo.

Conclusion: Our work allowed us to gain better knowledge on the activity of N-(9H-purin-6-yl) benzamide derivatives and showed new examples of water-soluble prodrugs. More research is warranted to decipher the molecular mechanisms of the molecules.

Keywords: Cell death, cancer cells, prodrug, in vivo, chemistry, pharmacology.

Graphical Abstract

[1]
Jordheim, L.P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat. Rev. Drug Discov., 2013, 12(6), 447-464.
[http://dx.doi.org/10.1038/nrd4010] [PMID: 23722347]
[2]
Savic, D.; Stankovic, T.; Lavrnja, I.; Podolski-Renic, A.; Bankovic, J.; Pekovic, E.; Stojiljkovic, M.; Takic, L.; Ruzdijic, S.; Pesic, M. Purine nucleoside analogs in the therapy of cancer and neuroinflammation. Motth, 2015, 1, 3-14.
[http://dx.doi.org/10.1515/motth-2015-0002]
[3]
Bhatia, S.; Landier, W.; Hageman, L.; Chen, Y.; Kim, H.; Sun, C.L.; Kornegay, N.; Evans, W.E.; Angiolillo, A.L.; Bostrom, B.; Casillas, J.; Lew, G.; Maloney, K.W.; Mascarenhas, L.; Ritchey, A.K.; Termuhlen, A.M.; Carroll, W.L.; Wong, F.L.; Relling, M.V. Systemic exposure to thiopurines and risk of relapse in children with acute lymphoblastic leukemia: A children’s oncology group study. JAMA Oncol., 2015, 1(3), 287-295.
[http://dx.doi.org/10.1001/jamaoncol.2015.0245] [PMID: 26181173]
[4]
Bostrom, B.; Erdmann, G. Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am. J. Pediatr. Hematol. Oncol., 1993, 15(1), 80-86.
[http://dx.doi.org/10.1097/00043426-199302000-00010] [PMID: 8447563]
[5]
Robak, P.; Robak, T. Older and new purine nucleoside analogs for patients with acute leukemias. Cancer Treat. Rev., 2013, 39(8), 851-861.
[http://dx.doi.org/10.1016/j.ctrv.2013.03.006] [PMID: 23566572]
[6]
Amemiya, S.; Yamaguchi, T.; Sakai, T.; Hashimoto, Y.; Noguchi-Yachide, T. Structure-activity relationship study of N(6)-benzoyladenine-type BRD4 inhibitors and their effects on cell differentiation and TNF-α production. Chem. Pharm. Bull. (Tokyo), 2016, 64(9), 1378-1383.
[http://dx.doi.org/10.1248/cpb.c16-00410] [PMID: 27581642]
[7]
Noguchi-Yachide, T.; Sakai, T.; Hashimoto, Y.; Yamaguchi, T. Discovery and structure-activity relationship studies of N6-benzoyladenine derivatives as novel BRD4 inhibitors. Bioorg. Med. Chem., 2015, 23(5), 953-959.
[http://dx.doi.org/10.1016/j.bmc.2015.01.022] [PMID: 25678016]
[8]
Kucukdumlu, A.; Tuncbilek, M.; Bilget Guven, E.; Cetin Atalay, R. Synthesis of some substituted 6-phenyl purine analogues and their biological evaluation as cytotoxic agents. Acta Chim. Slov., 2017, 64(3), 621-632.
[http://dx.doi.org/10.17344/acsi.2017.3419] [PMID: 28862295]
[9]
Marton, Z.; Guillon, R.; Krimm, I.; Preeti, ; Rahimova, R.; Egron, D.; Jordheim, L.P.; Aghajari, N.; Dumontet, C.; Périgaud, C.; Lionne, C.; Peyrottes, S.; Chaloin, L. Identification of noncompetitive inhibitors of cytosolic 5′-nucleotidase II using a fragment-based approach. J. Med. Chem., 2015, 58(24), 9680-9696.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01616] [PMID: 26599519]
[10]
Guillon, R.; Rahimova, R.; Preeti, ; Egron, D.; Rouanet, S.; Dumontet, C.; Aghajari, N.; Jordheim, L.P.; Chaloin, L.; Peyrottes, S. Lead optimization and biological evaluation of fragment-based cN-II inhibitors. Eur. J. Med. Chem., 2019, 168, 28-44.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.040] [PMID: 30798051]
[11]
Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 1984, 22, 27-55.
[http://dx.doi.org/10.1016/0065-2571(84)90007-4] [PMID: 6382953]
[12]
Jordheim, L.P.; Marton, Z.; Rhimi, M.; Cros-Perrial, E.; Lionne, C.; Peyrottes, S.; Dumontet, C.; Aghajari, N.; Chaloin, L. Identification and characterization of inhibitors of cytoplasmic 5′-nucleotidase cN-II issued from virtual screening. Biochem. Pharmacol., 2013, 85(4), 497-506.
[http://dx.doi.org/10.1016/j.bcp.2012.11.024] [PMID: 23220537]
[13]
Jordheim, L.P.; Puy, J.Y.; Cros-Perrial, E.; Peyrottes, S.; Lefebvre, I.; Périgaud, C.; Dumontet, C. Determination of the enzymatic activity of cytosolic 5′-nucleotidase cN-II in cancer cells: development of a simple analytical method and related cell line models. Anal. Bioanal. Chem., 2015, 407(19), 5747-5758.
[http://dx.doi.org/10.1007/s00216-015-8757-4] [PMID: 25998135]
[14]
Jornada, D.H.; dos Santos Fernandes, G.F.; Chiba, D.E.; de Melo, T.R.; dos Santos, J.L.; Chung, M.C. The prodrug approach: A successful tool for improving drug solubility. Molecules, 2015, 21(1), 42.
[http://dx.doi.org/10.3390/molecules21010042] [PMID: 26729077]
[15]
Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov., 2008, 7(3), 255-270.
[http://dx.doi.org/10.1038/nrd2468] [PMID: 18219308]
[16]
Rautio, J.; Meanwell, N.A.; Di, L.; Hageman, M.J. The expanding role of prodrugs in contemporary drug design and development. Nat. Rev. Drug Discov., 2018, 17(8), 559-587.
[http://dx.doi.org/10.1038/nrd.2018.46] [PMID: 29700501]
[17]
Meyer, J.A.; Wang, J.; Hogan, L.E.; Yang, J.J.; Dandekar, S.; Patel, J.P.; Tang, Z.; Zumbo, P.; Li, S.; Zavadil, J.; Levine, R.L.; Cardozo, T.; Hunger, S.P.; Raetz, E.A.; Evans, W.E.; Morrison, D.J.; Mason, C.E.; Carroll, W.L. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat. Genet., 2013, 45(3), 290-294.
[http://dx.doi.org/10.1038/ng.2558] [PMID: 23377183]
[18]
Tzoneva, G.; Perez-Garcia, A.; Carpenter, Z.; Khiabanian, H.; Tosello, V.; Allegretta, M.; Paietta, E.; Racevskis, J.; Rowe, J.M.; Tallman, M.S.; Paganin, M.; Basso, G.; Hof, J.; Kirschner-Schwabe, R.; Palomero, T.; Rabadan, R.; Ferrando, A. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat. Med., 2013, 19(3), 368-371.
[http://dx.doi.org/10.1038/nm.3078] [PMID: 23377281]
[19]
Itoh, R. Enzymatic properties and physiological roles of cytosolic 5′-nucleotidase II. Curr. Med. Chem., 2013, 20(34), 4260-4284.
[http://dx.doi.org/10.2174/0929867311320340006] [PMID: 23992315]
[20]
Pesi, R.; Allegrini, S.; Balestri, F.; Garcia-Gil, M.; Cividini, F.; Colombaioni, L.; Jordheim, L.P.; Camici, M.; Tozzi, M.G. Cytosolic 5′-Nucleotidase II Is a Sensor of Energy Charge and Oxidative Stress: A Possible Function as Metabolic Regulator. Cells, 2021, 10(1), 182.
[http://dx.doi.org/10.3390/cells10010182] [PMID: 33477638]
[21]
Brouwer, C.; Vogels-Mentink, T.M.; Keizer-Garritsen, J.J.; Trijbels, F.J.; Bökkerink, J.P.; Hoogerbrugge, P.M.; van Wering, E.R.; Veerman, A.J.; De Abreu, R.A. Role of 5′-nucleotidase in thiopurine metabolism: enzyme kinetic profile and association with thio-GMP levels in patients with acute lymphoblastic leukemia during 6-mercaptopurine treatment. Clin. Chim. Acta, 2005, 361(1-2), 95-103.
[http://dx.doi.org/10.1016/j.cccn.2005.05.006] [PMID: 15990089]
[22]
Tzoneva, G.; Dieck, C.L.; Oshima, K.; Ambesi-Impiombato, A.; Sánchez-Martín, M.; Madubata, C.J.; Khiabanian, H.; Yu, J.; Waanders, E.; Iacobucci, I.; Sulis, M.L.; Kato, M.; Koh, K.; Paganin, M.; Basso, G.; Gastier-Foster, J.M.; Loh, M.L.; Kirschner-Schwabe, R.; Mullighan, C.G.; Rabadan, R.; Ferrando, A.A. Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia. Nature, 2018, 553(7689), 511-514.
[http://dx.doi.org/10.1038/nature25186] [PMID: 29342136]
[23]
Meanwell, N.A.; Krystal, M.R.; Nowicka-Sans, B.; Langley, D.R.; Conlon, D.A.; Eastgate, M.D.; Grasela, D.M.; Timmins, P.; Wang, T.; Kadow, J.F. Inhibitors of HIV-1 attachment: The discovery and development of temsavir and its prodrug fostemsavir. J. Med. Chem., 2018, 61(1), 62-80.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01337] [PMID: 29271653]
[24]
Oslob, J.D.; Heumann, S.A.; Yu, C.H.; Allen, D.A.; Baskaran, S.; Bui, M.; Delarosa, E.; Fung, A.D.; Hashash, A.; Hau, J.; Ivy, S.; Jacobs, J.W.; Lew, W.; Maung, J.; McDowell, R.S.; Ritchie, S.; Romanowski, M.J.; Silverman, J.A.; Yang, W.; Zhong, M.; Fuchs-Knotts, T. Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg. Med. Chem. Lett., 2009, 19(5), 1409-1412.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.043] [PMID: 19186057]

Rights & Permissions Print Cite
Article Metrics
27
1
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy