Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. X-ray Crystal Structure Analysis
2.3. Biological Evaluations
2.3.1. Anti-Proliferative Evaluations
2.3.2. Western Blot Analysis of Predicted Protein Targets
2.3.3. Apoptosis Detection
3. Materials and Methods
3.1. General
3.2. Experimental Procedures for the Synthesis of Compounds
3.2.1. General Procedure for the Synthesis of Compounds (4a–4k and 5a–5e)
3.2.2. General Procedure for the Synthesis of Compounds (6a and 6b)
3.3. X-ray Crystal Structure Analysis
3.4. In Silico
3.5. Cell Culturing
3.6. Proliferation Assay
3.7. Western Blot Analysis
3.8. Apoptosis Detection
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
- Choi, Y.J.; Anders, L. Signaling through cyclin D-dependent kinases. Oncogene 2014, 33, 1890–1903. [Google Scholar] [CrossRef]
- Diaz-Moralli, S.; Tarrado-Castellarnau, M.; Miranda, A.; Cascante, M. Targeting cell cycle regulation in cancer therapy. Pharmacol. Ther. 2013, 138, 255–271. [Google Scholar] [CrossRef] [PubMed]
- Welburn, J.P.I.; Endicott, J.A. Inhibition of the cell cycle with chemical inhibitors: A targeted approach. Semin. Cell Dev. Biol. 2005, 16, 369–381. [Google Scholar] [CrossRef] [PubMed]
- Sonawane, Y.A.; Taylor, M.A.; Napoleon, J.V.; Rana, S.; Contreras, J.I.; Natarajan, A. Cyclin dependent kinase 9 inhibitors for cancer therapy. J. Med. Chem. 2016, 59, 8667–8684. [Google Scholar] [CrossRef] [PubMed]
- Mariaule, G.; Belmont, P. Cyclin-dependent kinase inhibitors as marketed anticancer drugs: Where are we Now? A short survey. Molecules 2014, 19, 14366–14382. [Google Scholar] [CrossRef] [PubMed]
- Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 2015, 14, 130–146. [Google Scholar] [CrossRef] [PubMed]
- Palanisamy, R.P. Palbociclib: A new hope in the treatment of breast cancer. J. Cancer Res. Ther. 2016, 12, 1220–1223. [Google Scholar] [CrossRef] [PubMed]
- Wu, P.; Nielsen, T.E.; Clausen, M.H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 2015, 36, 422–439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gray, N.S.; Wodicka, L.; Thunnissen, A.M.W.; Norman, T.C.; Kwon, S.; Espinoza, F.H.; Morgan, D.O.; Barnes, G.; LeClerc, S.; Meijer, L.; et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 1998, 281, 533–538. [Google Scholar] [CrossRef] [PubMed]
- McClue, S.J.; Blake, D.; Clarke, R.; Cowan, A.; Cummings, L.; Fischer, P.M.; MacKenzie, M.; Melville, J.; Stewart, K.; Wang, S.; et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int. J. Cancer 2002, 102, 463–468. [Google Scholar] [CrossRef] [PubMed]
- Zatloukal, M.; Jorda, R.; Gucky, T.; Reznickova, E.; Voller, J.; Pospisil, T.; Malinkova, V.; Adamcova, H.; Krystof, V.; Strnad, M. Synthesis and in vitro biological evaluation of 2,6,9-trisubstituted purines targeting multiple cyclin-dependent kinases. Eur. J. Med. Chem. 2013, 61, 61–72. [Google Scholar] [CrossRef] [PubMed]
- Sharma, S.; Singh, J.; Ojha, R.; Singh, H.; Kaur, M.; Bedi, P.; Nepali, K. Design strategies, structure activity relationship and mechanistic insights for purines as kinase inhibitors. Eur. J. Med. Chem. 2016, 112, 298–396. [Google Scholar] [CrossRef] [PubMed]
- Le Tourneau, C.; Faivre, S.; Laurence, V.; Delbaldo, C.; Vera, K.; Girre, V.; Chiao, J.; Armour, S.; Frame, S.; Green, S.R.; et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur. J. Cancer 2010, 46, 3243–3250. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Kalyan, K.; Sorokinas, A.; Stankunas, E.; Levy, J.; Meskinyte, I.; Stankevicius, V.; Kaupinis, A.; Valius, M. Roscovitine in cancer and other diseases. Ann. Transl. Med. 2015, 3, 135. [Google Scholar] [CrossRef] [PubMed]
- Kryštof, V.; Moravcová, D.; Paprskářová, M.; Barbier, P.; Peyrot, V.; Hlobilková, A.; Havlíček, L.; Strnad, M. Synthesis and biological activity of 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin. Eur. J. Med. Chem. 2006, 41, 1405–1411. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.K.; Dessalew, N.; Bharatam, P.V. 3D-QSAR CoMFA study on indenopyrazole derivatives as cyclin dependent kinase 4 (CDK4) and cyclin dependent kinase 2 (CDK2) inhibitors. Eur. J. Med. Chem. 2006, 41, 1310–1319. [Google Scholar] [CrossRef] [PubMed]
- Jorda, R.; Paruch, K.; Krystof, V. Cyclin-dependent kinase inhibitors inspired by roscovitine: Purine bioisosteres. Curr. Pharm. Des. 2012, 18, 2974–2980. [Google Scholar] [CrossRef] [PubMed]
- Paruch, K.; Dwyer, M.P.; Alvarez, C.; Brown, C.; Chan, T.Y.; Doll, R.J.; Keertikar, K.; Knutson, C.; McKittrick, B.; Rivera, J.; et al. Discovery of dinaciclib (SCH 727965): A potent and selective inhibitor of cyclin-dependent kinases. ACS Med. Chem. Lett. 2010, 1, 204–208. [Google Scholar] [CrossRef] [PubMed]
- Parry, D.; Guzi, T.; Shanahan, F.; Davis, N.; Prabhavalkar, D.; Wiswell, D.; Seghezzi, W.; Paruch, K.; Dwyer, M.P.; Doll, R.; et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther. 2010, 9, 2344–2353. [Google Scholar] [CrossRef] [PubMed]
- Flynn, J.; Jones, J.; Johnson, A.J.; Andritsos, L.; Maddocks, K.; Jaglowski, S.; Hessler, J.; Grever, M.R.; Im, E.; Zhou, H.; et al. Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia 2015, 29, 1524–1529. [Google Scholar] [CrossRef] [PubMed]
- Feldmann, G.; Mishra, A.; Bisht, S.; Karikari, C.; Garrido-Laguna, I.; Rasheed, Z.; Ottenhof, N.A.; Dadon, T.; Alvarez, H.; Fendrich, V.; et al. Cyclin-dependent kinase inhibitor dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol. Ther. 2011, 12, 598–609. [Google Scholar] [CrossRef] [PubMed]
- Gelbert, L.M.; Cai, S.; Lin, X.; Sanchez-Martinez, C.; Del Prado, M.; Lallena, M.J.; Torres, R.; Ajamie, R.T.; Wishart, G.N.; Flack, R.S.; et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: In vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Investig. New Drugs 2014, 32, 825–837. [Google Scholar] [CrossRef] [PubMed]
- Barroso-Sousa, R.; Shapiro, G.I.; Tolaney, S.M. Clinical development of the CDK4/6 inhibitors ribociclib and abemaciclib in breast cancer. Breast Care 2016, 11, 167–173. [Google Scholar] [CrossRef] [PubMed]
- Syed, Y.Y. Ribociclib: First global approval. Drugs 2017, 77, 799–807. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.X.; Sicinska, E.; Czaplinski, J.T.; Remillard, S.P.; Moss, S.; Wang, Y.; Brain, C.; Loo, A.; Snyder, E.L.; Demetri, G.D.; et al. Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. Mol. Cancer Ther. 2014, 13, 2184–2193. [Google Scholar] [CrossRef] [PubMed]
- Casimiro, M.C.; Velasco-Velázquez, M.; Aguirre-Alvarado, C.; Pestell, R.G. Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin. Investig. Drugs 2014, 23, 295–304. [Google Scholar] [CrossRef] [PubMed]
- Maračić, S.; Kraljević, T.G.; Paljetak, H.Č.; Perić, M.; Matijašić, M.; Verbanac, D.; Cetina, M.; Raić-Malić, S. 1,2,3-Triazole pharmacophore-based benzofused nitrogen/sulfur heterocycles with potential anti-Moraxella catarrhalis activity. Bioorg. Med. Chem. 2015, 23, 7448–7463. [Google Scholar] [CrossRef] [PubMed]
- Gregorić, T.; Sedić, M.; Grbčić, P.; Paravić, A.T.; Pavelić, S.K.; Cetina, M.; Vianello, R.; Raić-Malić, S. Novel pyrimidine-2,4-dione-1,2,3-triazole and furo[2,3-d]pyrimidine-2-one-1,2,3-triazole hybrids as potential anti-cancer agents: Synthesis, computational and X-ray analysis and biological evaluation. Eur. J. Med. Chem. 2017, 125, 1247–1267. [Google Scholar] [CrossRef] [PubMed]
- Sharma, A.; Luxami, V.; Paul, K. Purine-benzimidazole hybrids: Synthesis, single crystal determination and in vitro evaluation of antitumor activities. Eur. J. Med. Chem. 2015, 93, 414–422. [Google Scholar] [CrossRef] [PubMed]
- Abbot, V.; Sharma, P.; Dhiman, S.; Noolvi, M.N.; Patelc, H.M.; Varun Bhardwaj, V. Small hybrid heteroaromatics: Resourceful biological tools in cancer research. RSC Adv. 2017, 7, 28313–28349. [Google Scholar] [CrossRef]
- Carbone, A.; Parrino, B.; Di Vita, G.; Attanzio, A.; Spanò, V.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Livrea, M.A.; Diana, P.; et al. Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues. Mar. Drugs 2015, 13, 460–492. [Google Scholar] [CrossRef] [PubMed]
- Singh, M.; Tandon, V. Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-Aryl-substituted 2-bis-1H-benzimidazoles. Eur. J. Med. Chem. 2011, 46, 659–669. [Google Scholar] [CrossRef] [PubMed]
- Kode, N.; Chen, L.; Murthy, D.; Adewumi, D.; Phadtare, S. New bis-N9-(methylphenylmethyl)purine derivatives: Synthesis and antitumor activity. Eur. J. Med. Chem. 2007, 42, 327–333. [Google Scholar] [CrossRef] [PubMed]
- Alpan, A.S.; Zencir, S.; Zupkó, I.; Coban, G.; Réthy, B.; Gunes, H.S.; Topcu, Z. Biological activity of bis-benzimidazole derivatives on DNA topoisomerase I and HeLa, MCF7 and A431 cells. J. Enzyme Inhib. Med. Chem. 2009, 24, 844–849. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.H.; Cheng, M.S.; Wang, Q.H.; Nie, H.; Liao, N.; Wang, J.; Chen, H. Design, synthesis, and anti-tumor evaluation of novel symmetrical bis-benzimidazoles. Eur. J. Med. Chem. 2009, 44, 1808–1812. [Google Scholar] [CrossRef] [PubMed]
- Huang, S.T.; Hsei, I.J.; Chen, C. Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles. Bioorg. Med. Chem. 2006, 14, 6106–6119. [Google Scholar] [CrossRef] [PubMed]
- Auffinger, P.; Hays, F.A.; Westhof, E.; Ho, P.S. Halogen bonds in biological molecules. Proc. Natl. Acad. Sci. USA 2004, 101, 16789–16794. [Google Scholar] [CrossRef] [PubMed]
- Lu, Y.; Shi, T.; Wang, Y.; Yang, H.; Yan, X.; Luo, X.; Jiang, H.; Zhu, W. Halogen bondings—A novel interaction for rational drug design? J. Med. Chem. 2009, 52, 2854–2862. [Google Scholar] [CrossRef] [PubMed]
- Wilcken, R.; Zimmermann, M.O.; Lange, A.; Joerger, A.C.; Boeckler, F.M. Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J. Med. Chem. 2013, 56, 1363–1388. [Google Scholar] [CrossRef] [PubMed]
- Raić-Malić, S.; Meščić, A. Recent trends in 1,2,3-triazolo-nucleosides as promising anti-infective and anticancer agents. Curr. Med. Chem. 2015, 22, 1462–1499. [Google Scholar] [CrossRef] [PubMed]
- Kerru, N.; Singh, P.; Koorbanally, N.; Raj, R.; Kumar, V. Recent advances (2015–2016) in anticancer hybrids. Eur. J. Med. Chem. 2017. [Google Scholar] [CrossRef] [PubMed]
- Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Shahar Yar, M. Structureactivity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem. 2017, 125, 143–189. [Google Scholar] [CrossRef] [PubMed]
- Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem. 2017, 71, 30–54. [Google Scholar] [CrossRef] [PubMed]
- Yan, R.; Sander, K.; Galante, E.; Rajkumar, V.; Badar, A.; Robson, M.; El-Emir, E.; Lythgoe, M.F.; Pedley, R.B.; Årstad, E. A one-pot three-component radiochemical reaction for rapid assembly of 125I-labeled molecular probes. J. Am. Chem. Soc. 2013, 135, 703–709. [Google Scholar] [CrossRef] [PubMed]
- Chittepu, P.; Sirivolu, V.R.; Seela, F. Nucleosides and oligonucleotides containing 1,2,3-triazole residues with nucleobase tethers: Synthesis via the azide-alkyne ‘click’ reaction. Bioorg. Med. Chem. 2008, 16, 8427–8439. [Google Scholar] [CrossRef] [PubMed]
- Kraljević, T.G.; Harej, A.; Sedić, M.; Pavelić, S.K.; Stepanić, V.; Drenjančević, D.; Talapko, J.; Raić-Malić, S. Synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole-coumarin hybrids. Eur. J. Med. Chem. 2016, 124, 794–808. [Google Scholar] [CrossRef] [PubMed]
- Filimonov, D.A.; Poroikov, V.V. Chemoinformatics Approaches to Virtual Screening; Varnek, A., Tropsha, A., Eds.; RSC Publishing: Cambridge, UK, 2008; pp. 182–216. [Google Scholar]
- Sumi, N.J.; Kuenzi, B.M.; Knezevic, C.E.; Rix, L.L.R.; Rix, U. Chemoproteomics reveals novel protein and lipid kinase targets of clinical CDK4/6 inhibitors in lung cancer. ACS Chem. Biol. 2015, 10, 2680–2686. [Google Scholar] [CrossRef] [PubMed]
- Kretz, A.L.; Schaum, M.; Richter, J.; Kitzig, E.F.; Engler, C.C.; Leithäuser, F.; Henne-Bruns, D.; Knippschild, U.; Lemke, J. CDK9 is a prognostic marker and therapeutic target in pancreatic cancer. Tumor Biol. 2017, 39, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Zhang, W.; Liu, H.T. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002, 12, 9–18. [Google Scholar] [CrossRef] [PubMed]
- Wilkinson, M.G.; Millar, J.B. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J. 2000, 14, 2147–2157. [Google Scholar] [CrossRef] [PubMed]
- Oxford Diffraction. Xcalibur CCD System, CrysAlisPro; Agilent Technologies: Abingdon, UK, 2015. [Google Scholar]
- Burla, M.C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G.L.; De Caro, L.; Giacovazzo, C.; Polidori, G.; Spagna, R. SIR2004: An improved tool for crystal structure determination and refinement. J. Appl. Crystallogr. 2005, 38, 381–388. [Google Scholar] [CrossRef]
- Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. 2015, C71, 3–8. [Google Scholar] [CrossRef]
- Farrugia, L.J. WinGX and ORTEP for Windows: An update. J. Appl. Crystallogr. 2012, 45, 849–854. [Google Scholar] [CrossRef]
- Spek, A.L. Structure validation in chemical crystallography. Acta Crystallogr. Sect. D Biol. Crystallogr. 2009, 65, 148–155. [Google Scholar] [CrossRef] [PubMed]
- Macrae, C.F.; Bruno, I.J.; Chisholm, J.A.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P.A. Mercury CSD 2.0—New features for the visualization and investigation of crystal structures. J. Appl. Crystallogr. 2008, 41, 466–470. [Google Scholar] [CrossRef]
- Gazivoda, T.; Raić-Malić, S.; Krištafor, V.; Makuc, D.; Plavec, J.; Kraljević-Pavelić, S.; Pavelić, K.; Naesens, L.; Andrei, G.; Snoeck, R.; et al. Synthesis, cytostatic and anti-HIV evaluations of the new unsaturated acyclic C-5 pyrimidine nucleoside analogues. Bioorg. Med. Chem. 2008, 16, 5624–5634. [Google Scholar] [CrossRef] [PubMed]
Compd | R | IC50 a (µM) | ClogP b | |||
---|---|---|---|---|---|---|
A549 | CFPAC-1 | HeLa | SW620 | |||
4a | –(CH2)7CH3 | >100 | >100 | >100 | 77.8 ± 4.25 | 4.9 |
4b | –(CH2)3Cl | >100 | 86.0 ± 2.13 | 85.5 ± 5.61 | 75.9 ± 3.41 | 2.6 |
4c | >100 | >100 | 75.5 ± 3.94 | 99.1 ± 8.36 | 4.0 | |
4d | >100 | >100 | >100 | 80.5 ± 5.84 | 3.6 | |
4e | >100 | >100 | 98.5 ± 0.54 | >100 | 3.7 | |
4f | >100 | >100 | 77.2 ± 18.04 | >100 | 5.2 | |
4g | >100 | >100 | 9.5 ± 1.76 | 16.8 ± 1.97 | 5.7 | |
4h | >100 | 8.1 ± 0.84 | 7.4 ± 0.19 | 6.9 ± 1.79 | 5.1 | |
4i | >100 | >100 | >100 | >100 | 2.6 | |
4j | >100 | 60.8 ± 4.70 | 64.0 ± 1.70 | 86.0 ± 2.03 | 2.2 | |
4k | 86.2 ± 3.75 | 41.6 ± 3.24 | 25.6 ± 3.03 | 65.1 ± 7.34 | 2.7 | |
5a | 82.9 ± 2.35 | 77.5 ± 0.17 | >100 | >100 | 2.8 | |
5b | >100 | 84.2 ± 5.43 | 84.1 ± 0.02 | >100 | 2.0 | |
5c | 38.4 ± 1.04 | 31.4 ± 8.45 | 15.9 ± 2.09 | 28.4 ± 3.04 | 3.6 | |
5d | 75.6 ± 7.29 | 60.6 ± 5.52 | 53.2 ± 5.68 | 75.8 ± 1.81 | 3.7 | |
5e | >100 | 9.8 ± 0.20 | 5.3 ± 2.69 | 36.5 ± 1.43 | 5.4 | |
6a | 9.4 ± 1.16 | 3.6 ± 2.02 | 7.0 ± 0.64 | 40.8 ± 3.83 | 4.9 | |
6b c | 4.2 ± 1.39 | 0.95 ± 0.28 | 2.3 ± 0.99 | 6.8 ± 0.69 | 4.9 | |
Roscovitine c | 24.7 ± 1.15 | 25.3 ± 2.63 | 27.2 ± 1.79 | 28.0 ± 1.83 | - |
CFPAC-1 | Untreated Cells (%) | 6b (%) |
---|---|---|
secondary necrotic cells | 10.44 | 20.72 |
late apoptotic/primary necrotic cells | 5.78 | 18.02 |
viable cells | 78.04 | 58.56 |
early apoptotic cells | 5.78 | 2.70 |
© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Bistrović, A.; Harej, A.; Grbčić, P.; Sedić, M.; Kraljević Pavelić, S.; Cetina, M.; Raić-Malić, S. Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases. Int. J. Mol. Sci. 2017, 18, 2292. https://doi.org/10.3390/ijms18112292
Bistrović A, Harej A, Grbčić P, Sedić M, Kraljević Pavelić S, Cetina M, Raić-Malić S. Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases. International Journal of Molecular Sciences. 2017; 18(11):2292. https://doi.org/10.3390/ijms18112292
Chicago/Turabian StyleBistrović, Andrea, Anja Harej, Petra Grbčić, Mirela Sedić, Sandra Kraljević Pavelić, Mario Cetina, and Silvana Raić-Malić. 2017. "Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases" International Journal of Molecular Sciences 18, no. 11: 2292. https://doi.org/10.3390/ijms18112292