|
|
1, 2, 4-三氮唑类衍生物的设计、合成及SHP-2活性评价
|
Abstract:
SHP2作为一种重要的磷酸化酶与多种癌症的发生密切相关，高活化的SHP2使得包括胃癌，乳腺癌在内的各种癌症的发生率增大，因此它成为治疗癌症的重要靶标之一。为了寻找高效的SHP2抑制剂，本文在具有潜在的抗肿瘤活性的1, 2, 4-三氮唑母核基础上，通过化学合成，设计并完成了10个新型1, 2, 4-三氮唑类衍生物，利用核磁共振氢谱技术对结构进行了表征，并进行了生物学活性评价，为后期的基于1, 2, 4-三氮唑母核的SHP2抑制剂发现工作奠定了一定的基础。
SHP2 is closely associated with the development of many cancers as a key phosphatase. Highly activated SHP2 is one of the important targets for cancer treatment as it increases the incidence of several cancers, including gastric and breast cancer. In order to find efficient SHP2 inhibitors, in this work, based on the 1, 2, 4-triazole parent nucleus with potential antitumour activity, ten novel 1, 2, 4-triazole derivatives were designed and completed by chemical synthesis. The structures were characterised by NMR hydrogen spectroscopy and evaluated for biological activity, which laid a certain foundation for the later discovery of SHP2 inhibitors based on the parent nucleus of 1, 2, 4-triazole.
| [1] | Jamieson, C.R., et al. (1994) Mapping a Gene for Noonan Syndrome to the Long Arm of Chromosome 12. Nature Genetics, 8, 357-360. https://doi.org/10.1038/ng1294-357 |
| [2] | Chan, R.J. and Feng, G.S. (2007) PTPN11 Is the First Identified Proto-Oncogene that Encodes a Tyrosine Phosphatase. Blood, 109, 862-867. https://doi.org/10.1182/blood-2006-07-028829 |
| [3] | ？stman, A., Hellberg, C. and B？hmer, F.D. (2006) Protein-Tyrosine Phosphatases and Cancer. Nature Reviews Cancer, 6, 307-320. https://doi.org/10.1038/nrc1837 |
| [4] | Grossmann, K.S., Rosário, M., Birchmeier, C., et al. (2010) The Tyrosine Phosphatase Shp2 in Development and Cancer. Advances in Cancer Research, 106, 53-89. https://doi.org/10.1016/S0065-230X(10)06002-1 |
| [5] | Tartaglia, M., Mehler, E., Goldberg, R., et al. (2001) Mutations in PTPN11, Encoding the Protein Tyrosine Phosphatase SHP-2, Cause Noonan Syndrome. Nature Genetics, 29, 465-468. https://doi.org/10.1038/ng772 |
| [6] | Zhang, J., Zhang, F. and Niu, R. (2015) Functions of Shp2 in Cancer. Journal of Cellular and Molecular Medicine, 19, 2075-2083. https://doi.org/10.1111/jcmm.12618 |
| [7] | Levy, A.D., Xiao, X., Shaw, J.E., et al. (2018) Noonan Syndrome Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell Reports, 24, 1523-1535. https://doi.org/10.1016/j.celrep.2018.07.006 |
| [8] | Mulero-Navarro, S., Sevilla, A., Roman, A., et al. (2015) Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. Cell Reports, 13, 504-515. https://doi.org/10.1016/j.celrep.2015.09.019 |
| [9] | Bentires-Alj, M., Paez, J.G., David, F.S., et al. (2004) Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia. Cancer Research, 64, 8816-8820. https://doi.org/10.1158/0008-5472.CAN-04-1923 |
| [10] | 朱霞. 含唑基多齿柔性配体配位聚合物的合成、结构和性质研究[D]: [博士学位论文]. 苏州: 苏州大学, 2012. |
| [11] | Li, B.L., Li, B., Zhang, R.L., et al. (2016) Synthesis and Antiproliferative Evaluation of Novel 1, 2, 4-Triazole Derivatives Incorporating Benzisoselenazolone Scaffold. Bioorganic & Medicinal Chemistry Letters, 26, 1279-1281. https://doi.org/10.1016/j.bmcl.2016.01.017 |
| [12] | Marwaha, A., White, J., El Mazouni, F., et al. (2012) Bioisosteric Transformations and Permutations in the Triazolopyrimidine Scaffold to Identify the Minimum Pharmacophore Required for Inhibitory Activity against Plasmodium Falciparum Dihydroorotate Dehydrogenase. Journal of Medicinal Chemistry, 55, 7425-7436. https://doi.org/10.1021/jm300351w |
| [13] | Wittine, K., Stipkovi？ Babi？, M., Makuc, D., et al. (2012) Novel 1, 2, 4-Triazole and Imidazole Derivatives of L-Ascorbic and Imino-Ascorbic Acid: Synthesis, Anti-HCV and Antitumor Activity Evaluations. Bioorganic & Medicinal Chemistry, 20, 3675-3685. https://doi.org/10.1016/j.bmc.2012.01.054 |
| [14] | Liu, N., Tu, J., Dong, G.Q., et al. (2018) Emerging New Targets for the Treatment of Resistant Fungal Infections. Journal of Medical Chemistry, 61, 5484-5511. https://doi.org/10.1021/acs.jmedchem.7b01413 |
