新型2,4,6-三取代嘧啶类抗肿瘤化合物的合成及其抗肿瘤细胞增殖活性
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摘要
本研究基于已上市药物奥希替尼的结构特点和最新的构效关系研究,设计合成了10个未见报道的新型2,4,6-三取代嘧啶类抗肿瘤化合物(TM 1～10)。选取人结肠癌细胞(HT29)、肺癌细胞(A549)、乳腺癌细胞(MCF7)、头颈部鳞癌细胞(HN5)4种肿瘤细胞进行肿瘤细胞毒性试验。结果显示,除化合物TM 2外,其余化合物均对4种肿瘤细胞具有良好的抑制作用,其中化合物TM 10活性最佳,对4种肿瘤细胞的IC_(50)值均小于奥希替尼(其中,对肺癌细胞的IC_(50)值为0.86μmol/L),为后续研究其作用机理及设计合成更高效的抗肿瘤药物提供思路。
10 Novel 2,4,6-triaminopyrimidines antitumor compounds(TM 1-10) were designed and synthesized based on the structural characteristics and latest reported structure-activity relationship of osimertinib, a new marketed drug which was used to treat lung cancer. Tumor cytotoxicity assays were executed on human colon cancer cells(HT29),lung cancer cells(A549), breast cancer cells(MCF7) and head-neck squamous carcinoma cells(HN5). The results showed that, all compounds except TM 2 had good inhibitory effects on four tumor cells, of which, TM 10 had the best activity(the IC_(50) values for four tumor cells were better than that of osimertinib, the IC_(50) value for lung cancer cells was0.86 μmol/L). This series of compounds have the potential for further study to synthesis more activity antitumor compounds.
10 Novel 2,4,6-triaminopyrimidines antitumor compounds(TM 1-10) were designed and synthesized based on the structural characteristics and latest reported structure-activity relationship of osimertinib, a new marketed drug which was used to treat lung cancer. Tumor cytotoxicity assays were executed on human colon cancer cells(HT29),lung cancer cells(A549), breast cancer cells(MCF7) and head-neck squamous carcinoma cells(HN5). The results showed that, all compounds except TM 2 had good inhibitory effects on four tumor cells, of which, TM 10 had the best activity(the IC_(50) values for four tumor cells were better than that of osimertinib, the IC_(50) value for lung cancer cells was0.86 μmol/L). This series of compounds have the potential for further study to synthesis more activity antitumor compounds.
引文
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[2]CAVALLI A,BOLOGNESI M L.Neglected tropical diseases:Multi-target-directed ligands in the search for novel lead candidates against trypanosoma and leishmania[J].JMed Chem,2009,52(23):7339-7359.
[3]WILLIAMS K J,TELFER B A,STRATFORD I J,et al.ZD1839(‘Iressa’),a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor,potentiates radiotherapy in a human colorectal cancer xenograft model[J].Br J Cancer,2002,14(86):1157-1161.
[4]PIOTROWSKA Z,NIEDERST M J,KARLOVICH CA,et al.Heterogeneity underlies the emergence of EGFRT790wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor[J].Cancer Discov,2015,5(7):713-722.
[5]FLOC'H N,MARTIN M J,RIESS J W,et al.Anti-tumor activity of osimertinib,an irreversible mutant-selective EGFR tyrosine kinase inhibitor,in NSCLC harboring EGFRExon 20 insertions[J].Mol Cancer Ther,2017,17(5):885-896.
[6]MAKINOSHIMA H,TAKITA M,SARUWATARI K,et al.Signaling through the phosphatidylinositol 3-Kinase(PI3K)/mammalian target of rapamycin(mTOR)axis is responsible for aerobic glycolysis mediated by glucose transporter in epidermal growth factor receptor(EGFR)-mutated lung adenocarcinoma[J].J Biol Chem,2015,290(28):17495-17504.
[7]MOASSER M M,BASSO A,AVERBUCH S D,et al.The tyrosine kinase inhibitor ZD1839(“Iressa”)inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells[J].Cancer Res,2001,61(19):7184-7188.
[8]SMAILL J B,REWCASTLE G W,LOO J A,et al.Tyrosine kinase inhibitors 17 irreversible inhibitors of the epidermal growth factor receptor:4-(phenylamino)quinazoline and4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions[J].J Med Chem,2000,43(7):1380-1397.
[9]MU F,COFFING S L,RIESE D J,et al.Design synthesis and biological evaluation of a series of Lavendustin Aanalogues that inhibit EGFR and SYK Tyrosine kinases,as well as tubulin polymerization[J].J Med Chem,2001,44(3):441-452.
[10]IOANNIDIS S,LAMB M L,WANG T,et al.Discovery of 5-Chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-pyrimidine-2,4-diamine(AZD1480)as a novel inhibitor of the Jak/Stat pathway[J].J Med Chem,2011,54(1):262-276.
[11]NOWAK T,THOMAS A P.4-(Pyrazol-3-ylamino)-pyrimidine derivatives for use in the treatment of cancer:US,7579349 B2[P].2007-02-15.
[12]MOSMAN T.Rapid colorimetric assay for cellular growth and survival:Application to proliferation and cytotoxicity assays[J].J Immunol Methods,1983,65(1-2):55-63.