Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Anti-proliferative Activities
Compd. | R1 | R2 | Ar | IN a at 40 μM (%) | ||||
---|---|---|---|---|---|---|---|---|
SW620 | A549 | SKOV-3 | HepG2 | HeLa | ||||
3a | H | — | Phenyl | 9 ± 2.3 | 10 ± 2.6 | NT b | NT | 37 ± 3.0 |
3b | H | — | 4-Cl-Ph- | 8 ± 1.4 | 3 ± 1.5 | 12 ± 2.2 | NT | 18 ± 2.1 |
3c | H | — | 3,4-di MeO-Ph- | 11 ± 0.9 | 22 ± 0.5 | NT | 29 ± 2.8 | 29 ± 2.1 |
3d | H | — | 3-MeO-4-OH-Ph- | 13 ± 3.0 | 9 ± 2.2 | 18 ± 2.4 | 10 ± 1.8 | 20 ± 1.1 |
3e | H | — | 4-Br-Ph- | 27 ± 1.2 | 28 ± 2.9 | NT | 21 ± 2.8 | 34 ± 1.6 |
3f | Me | — | Phenyl | 7 ± 1.7 | NT | NT | NT | NT |
3g | Me | — | 3-MeO-4-OH-Ph- | 3 ± 1.3 | NT | NT | NT | 17 ± 3.1 |
3h | Me | — | 3,4-di MeO-Ph- | 10 ± 0.8 | 16 ± 1.7 | NT | 17 ± 2.2 | 23 ± 0.7 |
3i | Me | — | Thiazolyl | NT | NT | NT | NT | NT |
3j | Me | 2-methylbenzyl | 3,4-di MeO-Ph- | 14 ± 2.1 | NT | NT | NT | NT |
3k | Me | 2-methylbenzyl | 3-MeO-4-(2-Me-BnO)-Ph | 85 ± 2.8 | 26 ± 3.6 | NT | 28 ± 3.3 | 9 ± 4.0 |
3l | Me | 2-methylbenzyl | Phenyl | 36 ± 0.9 | NT | NT | 10 ± 3.8 | NT |
3m | Me | 2-fluorobenzyl | Phenyl | 48 ± 4.3 | 52 ± 2.3 | 32 ± 2.1 | 20 ± 1.9 | NT |
3n | Me | 3-fluorobenzyl | Phenyl | 42 ± 3.1 | 55 ± 1.1 | NT | 16 ± 0.5 | 14 ± 2.8 |
3o | Me | 2-(4-fluorophenyl)-2-oxoethyl | Phenyl | 38 ± 1.7 | 22 ± 3.9 | 8 ± 2.5 | 24 ± 5.4 | 23 ± 1.9 |
3p | Me | 2-(4-methoxyphenyl)-2-oxoethyl | Phenyl | 21 ± 0.9 | 38 ± 2.8 | 38 ± 1.0 | 20 ± 1.4 | NT |
3q | Me | Propargyl | Phenyl | 25 ± 3.7 | 28 ± 1.6 | 7 ± 2.9 | 20 ± 3.3 | 19 ± 0.8 |
3r | Me | Cyclopentyl | Phenyl | 52 ± 2.2 | NT | NT | 21 ± 1.7 | 14 ± 3.6 |
3s | Me | Butyl | Phenyl | 35 ± 1.5 | 20 ± 1.8 | NT | NT | 13 ± 4.5 |
Cis c | — | — | — | 72 ± 2.1 | 68 ± 1.8 | 67 ± 1.9 | 80 ± 2.8 | 80 ± 3.5 |
Compd. | IC50 a(μM) | Compd. | IC50(μM) | Compd. | IC50(μM) | Compd. | IC50(μM) |
---|---|---|---|---|---|---|---|
3j | >80 | 3p | 59.6 ± 2.1 | 3m | 65.1 ± 1.1 | 3s | >80 |
3k | 12.5 ± 0.7 | 3q | 71.9 ± 1.5 | 3n | 79.6 ± 2.7 | Cis b | 9.5 ± 0.5 c |
3l | 76.1 ± 1.9 | 3r | 29 ± 0.9 | 3o | 71.5 ± 1.8 |
Compd. | R2 | R3 | R4 | IC50 a(μM) |
---|---|---|---|---|
4a | | | OMe | 6.9 ± 0.4 |
4b | “ | “ | H | >40 |
4c | | | OMe | >40 |
4d | “ | “ | H | >40 |
4e | H | | OMe | 36.8 ± 1.1 |
Cis b | - | - | - | 9.5 ± 0.5 |
2.3. Cell-Cycle Analyses
3. Experimental
3.1. General
3.2. General Procedure for the Synthesis of 2a–j
3.3. The Structure of Reagents R2-X (Figure 5) and General Procedure for the Synthesis of 1-(2-Bromoethyl)-3,7-dimethyl-1H– purine-2,6(3H,7H)-diones
3.4. Syntheses of Compounds 3a–s
3.5. Synthesis of Compounds 4a–d
3.6. Synthesis of Compound 4e
3.7. Cell Proliferation Assay (MTT Assay)
3.8. Apoptosis Analyses
4. Conclusions
Acknowledgments
Conflict of Interest
- Sample Availability: Samples of the compounds are available from the authors.
References and Notes
- Hirsch, J. An anniversary for cancer chemotherapy. JAMA 2006, 296, 1518–1520. [Google Scholar] [CrossRef]
- Arias, J.L. Drug Targeting Strategies in Cancer Treatment: An Overview. Mini. Rev. Med. Chem. 2011, 11, 1–17. [Google Scholar] [CrossRef]
- John, P.G.; Stephen, L.R.; Hans, E.G.; Greg, A.M.; Michael, C.W. Drug resistance and tumor. CME J. Gynecol. Oncol. 2002, 7, 25–28. [Google Scholar]
- Brown, D. Unfinished business: Target-based drug discovery. Drug. Discov. Today 2007, 12, 1007–1012. [Google Scholar] [CrossRef]
- Swinney, D.C.; Anthony, J. How were new medicines discovered? Nat. Rev. Drug. Discov. 2011, 10, 507–519. [Google Scholar] [CrossRef]
- Taltavull, J.; Serrat, J.; Gracia, J.; Gavalda, A.; Andres, M.; Cordoba, M.; Miralpeix, M.; Vilella, D.; Beleta, J.; Ryder, H.; Pages, L. Synthesis and Biological Activity of Pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines as Phosphodiesterase Type 4 Inhibitors. J. Med. Chem. 2010, 53, 6912–6922. [Google Scholar]
- Radi, M.; Dreassi, E.; Brullo, C.; Crespan, E.; Tintori, C.; Bernardo, V.; Valoti, M.; Zamperini, C.; Daigl, H.; Musumeci, F.; Carraro, F.; Naldini, A.; Filippi, I.; Maga, G.; Schenone, S.; Botta, M. Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-d]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study. J. Med. Chem. 2011, 54, 2610–2626. [Google Scholar]
- William, J.C. Pyrimido[4,5-d]pyrimidine derivatives for use as bronchodilators. U.S. Patent 5,162,316, 10 November 1992. [Google Scholar]
- Claverie, J.M.; Loiseau, G.; Mattioda, G.; Millischer, R.; Percheron, F. 5-methylthio-pyrimidine vasodilators. U.S. Patent 3,968,214, 6 July 1976. [Google Scholar]
- Gupta, P.P.; Srimal, R.C.; Avasthi, K.; Garg, N.; Chandra, T.; Bhakuni, D.S. Antiallergic activity of alkyl substituted pyrazolo[3, 4-d]pyrimidine (compound 88–765). Indian J. Exp. Biol. 1995, 33, 38–40. [Google Scholar]
- Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. Pyrimidine derivatives. 4. Synthesis and antihypertensive activity of 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives. J. Med. Chem. 1983, 26, 411–416. [Google Scholar]
- El-Deeb, I.M.; Lee, S.H. Design and synthesis of new anticancer pyrimidines with multiple-kinase inhibitory effect. Bioorg. Med. Chem. 2010, 18, 3860–3874. [Google Scholar] [CrossRef]
- Tu, S.J.; Zhang, J.P.; Zhu, X.T.; Xu, J.N.; Zhang, Y.; Wang, Q.; Jia, R.H.; Jiang, B.; Zhang, J.Y. New potential inhibitors of cyclin-dependent kinase 4: Design and synthesis of pyrido[2,3-d]pyrimidine derivatives under microwave irradiation. Bioorg. Med. Chem. Lett. 2006, 16, 3578–3581. [Google Scholar]
- Shi, D.Q.; Niu, L.H.; Shi, J.W.; Wang, X.S.; Ji, S.J. One-pot Synthesis of Pyrido[2,3-d]pyrimidines via Efficient Three-component Reaction in Aqueous Media. J. Heterocycl. Chem. 2007, 44, 1083–1090. [Google Scholar] [CrossRef]
- Rogozin, E.A.; Lee, K.W.; Kang, N.J.; Yu, H.; Nomura, M.; Miyamoto, K.I.; Conney, A.H.; Bode, A.M.; Dong, Z. Inhibitory effects of caffeine analogues on neoplastic transformation: structure–activity relationship. Carcinogenesis 2008, 29, 1228–1234. [Google Scholar] [CrossRef]
- He, Z.; Ma, W.Y.; Hashimoto, T.; Bode, A.M.; Yang, C.S.; Dong, Z. Induction of Apoptosis by Caffeine Is Mediated by the p53, Bax, and Caspase 3 Pathways. Cancer. Res. 2003, 63, 4396–4401. [Google Scholar]
- Shetty, R.S.; Lee, Y.; Liu, B.; Husain, A.; Joseph, R.W.; Lu, Y.; Nelson, D.; Mihelcic, J.; Chao, W.; Moffett, K.K.; Schumacher, A.; Flubacher, D.; Stojanovic, A.; Bukhtiyarova, M.; Williams, K.; Lee, K.J.; Ochman, A.R.; Saporito, M.S.; Moore, W.R.; Flynn, G.A.; Dorsey, B.D.; Springman, E.B.; Fujimoto, T.; Kelly, M.J. Synthesis and Pharmacological Evaluation of N-(3-(1H-Indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a Potent Antimitotic Agent. J. Med. Chem. 2011, 54, 179–200. [Google Scholar]
- Louis, C.; Richard, L.; Carole, L. Cell Cycle Arrest and Apoptosis Responses of Human Breast Epithelial Cells to the Synthetic Organosulfur Compound p-Methoxyphenyl p-Toluenesulfonate. Anticancer. Res. 2008, 28, 2753–2763. [Google Scholar]
© 2012 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 license (http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Yang, T.; He, H.; Ang, W.; Yang, Y.-H.; Yang, J.-Z.; Lin, Y.-N.; Yang, H.-C.; Pi, W.-Y.; Li, Z.-C.; Zhao, Y.-L.; et al. Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents. Molecules 2012, 17, 2351-2366. https://doi.org/10.3390/molecules17032351
Yang T, He H, Ang W, Yang Y-H, Yang J-Z, Lin Y-N, Yang H-C, Pi W-Y, Li Z-C, Zhao Y-L, et al. Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents. Molecules. 2012; 17(3):2351-2366. https://doi.org/10.3390/molecules17032351
Chicago/Turabian StyleYang, Tao, Hong He, Wei Ang, Ying-Hong Yang, Jian-Zhong Yang, Yan-Ni Lin, Hua-Cheng Yang, Wei-Yi Pi, Zi-Cheng Li, Ying-Lan Zhao, and et al. 2012. "Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents" Molecules 17, no. 3: 2351-2366. https://doi.org/10.3390/molecules17032351
APA StyleYang, T., He, H., Ang, W., Yang, Y.-H., Yang, J.-Z., Lin, Y.-N., Yang, H.-C., Pi, W.-Y., Li, Z.-C., Zhao, Y.-L., Luo, Y.-F., & Wei, Y. (2012). Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents. Molecules, 17(3), 2351-2366. https://doi.org/10.3390/molecules17032351